• 대한임상독성학회지
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• 제11권1호
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• pp.49-52
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• 2013

Fentanyl, a synthetic, highly selective opioid ${\mu}$-receptor agonist, is 50 to 100 times more potent than morphine. The low molecular weight, high potency, great transdermal permeation rate and lipid solubility of fentanyl make it very suitable for transdermal administration. Durogesic is a novel matrix transdermal system providing continuous systemic delivery of fentanyl. In recently, there are many reports that misused or overused fentanyl transdermal patches result in severe intoxication of fentanyl. We present a case of fentanyl toxicity with misused durogesic transdermal patch and discuss the safe and appropriate application of the patches. In conclusion, fentanyl patches should be used in opioid tolerant patients and prescribed at the lowest possible dose and titrated upward as needed. All patients and their caregivers should be educated safe application of fentanyl patches and advised to avoid exposing the patches application site to direct external heat sources, such as heating pads, or electric blankets, heat lamps, sauna, hot tubs, and others. In addition, concomittant medications that affect fentanyl's metabolism should be avoided.

• Molecules and Cells
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• 제24권2호
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• pp.185-193
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• 2007

Symbiotic nitrogen fixation with nitrogen-fixing bacteria in the root nodules is a distinctly beneficial metabolic process in legume plants. Legumes control the nodule number and nodulation zone through a systemic negative regulatory system between shoot and root. Mutation in the soybean NTS gene encoding GmNARK, a CLAVATA1-like serine/threonine receptor-like kinase, causes excessive nodule development called hypernodulation. To examine the effect of nts mutation on the gene expression profile in the leaves, suppression subtractive hybridization was performed with the trifoliate leaves of nts mutant 'SS2-2' and the wild-type (WT) parent 'Sinpaldalkong2', and 75 EST clones that were highly expressed in the leaves of the SS2-2 mutant were identified. Interestingly, the expression of jasmonate (JA)-responsive genes such as vspA, vspB, and Lox2 were upregulated, whereas that of a salicylate-responsive gene PR1a was suppressed in the SS2-2 mutant. In addition, the level of JA was about two-fold higher in the leaves of the SS2-2 mutant than in those of the WT under natural growth conditions. Moreover, the JA-responsive gene expression persists in the leaves of SS2-2 mutant without rhizobia infection in the roots. Taken together, our results suggest that the nts mutation increases JA synthesis in mature leaves and consequently leads to constitutive expression of JA-responsive genes which is irrelevant to hypernodulation in the root.

• 고려인삼학회:학술대회논문집
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• 고려인삼학회 1998년도 Advances in Ginseng Research - Proceedings of the 7th International Symposium on Ginseng -
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• pp.224-230
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• 1998

This study showed the anti-invasive activity of ginseng components, panaxadiol (PD) and panamatrlol (PT) on the highly metastatic HT1080 human flbrosarcoma cell line. PD and PT reduced tumor cell invasion through a reconstitute basement membrane in the transwell chamber. A significant down regulation of MMP-9 by PD and PT was detected by northern blot analysis. However, MMP-2 was constantly expressed. Quantitative gelatin based zymography confirmed a marked reduced expression of MMP-9 but not MMP-2 in the treatment of PD and PT. Since the chemical structures of PD and PT are very similar to that of dexamethasone, a synthetic glucocorticoid, it was investigated whether PD and PT act through GR. Western blot analysis and immunocytochemistry showed that PD and PT increased the GR fraction in the nucleus. These results suggest that ursolic acid may induce repression of MMP-9 by stimulating the nuclear translocation of GR and hence inhibiting the activity of AP-1 to TPA-responsible element of MMP-9 promoter region. In conclusion, we suggest that CR-induced down-regulation of MMP-9 by PD and PT contributes to reduce the invasive capacity of HT 1080 cells.

• Bulletin of the Korean Chemical Society
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• 제34권8호
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• pp.2387-2393
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• 2013

Benzotriazole is an important synthetic auxiliary for potential clinical applications. A series of benzotriazoles as potential antiproliferative agents by inhibiting histone deacetylase (HDAC) were recently reported. Three-dimensional quantitative structure-activity relationship (3D-QSAR), including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were performed to elucidate the 3D structural features required for the antiproliferative activity. The results of both ligand-based CoMFA model ($q^2=0.647$, $r^2=0.968$, ${r^2}_{pred}=0.687$) and CoMSIA model ($q^2=0.685$, $r^2=0.928$, ${r^2}_{pred}=0.555$) demonstrated the highly statistical significance and good predictive ability. The results generated from CoMFA and CoMSIA provided important information about the structural characteristics influence inhibitory potency. In addition, docking analysis was applied to clarify the binding modes between the ligands and the receptor HDAC. The information obtained from this study could provide some instructions for the further development of potent antiproliferative agents and HDAC inhibitors.

• Journal of Ginseng Research
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• 제41권1호
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• pp.52-59
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• 2017

Background: Korean Red Ginseng extract (KRG, Panax ginseng Meyer) and its constituents have been used for treating diabetes. However, in diet-induced obese mice, it is unclear whether KRG can enhance the glucose-lowering action of rosiglitazone (ROSI), a peroxisome proliferator-activated receptor gamma synthetic activator. Methods: Oral glucose tolerance tests (oGTTs) were performed after 4 days of treatment with a vehicle (CON), KRG [500 mg/kg body weight (b.w.)], ROSI (3.75 mg/kg b.w, 7.5 mg/kg b.w, and 15 mg/kg b.w.), or ROSI and KRG (RK) in obese mice on a high-fat diet. Adipose tissue morphology, crown-like structures (CLSs), and inflammation were compared by hematoxylin-eosin staining or quantitative reverse transcription polymerase chain reaction. Results: The area under the glucose curve (AUC) was significantly lower in the RK group (15 mg/kg b.w. and 500 mg/kg b.w. for ROSI and KRG, respectively) than in the CON group. There was no significant difference in the AUC between the CON and the other groups. Furthermore, the AUC was significantly lower in the RK group than in the ROSI group. The expression of the Ccl2 gene and the number of CLSs were significantly reduced in the RK group than in the CON group. Conclusion: Our results show a potential enhancement of ROSI-induced improvement of glucose regulation by the combined treatment with KRG.

• Molecules and Cells
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• 제27권2호
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• pp.251-255
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• 2009

Sepsis is the leading cause of death in critically ill patients. Today, around 60% of all cases of sepsis are caused by Gram-negative bacteria. The cell wall component lipopolysaccharide (LPS) is the main initiator of the cascade of cellular reactions in Gram-negative infections. The core receptors for LPS are toll-like receptor 4 (TLR4), MD-2 and CD14. Attempts have been made to antagonize the toxic effect of endotoxin using monoclonal antibodies against CD14 and synthetic lipopolysaccharides but there is as yet no effective treatment for septic syndrome. Here, we describe an inhibitory effect of a phosphatidylethanolamine derivative, PE-DTPA (phosphatidylethanolamine diethylenetriaminepentaacetate) on LPS recognition. PE-DTPA bound strongly to CD14 ($K_d$, $9.52{\times}10^{-8}M$). It dose dependently inhibited LPS-mediated activation of human myeloid cells, mouse macrophage cells and human whole blood as measured by the production of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and nitric oxide, whereas other phospho-lipids including phosphatidylserine and phosphatidylethanolamine had little effect. PE-DTPA also inhibited transcription dependent on $NF-{\kappa}B$ activation when it was added together with LPS, and it rescued LPS-primed mice from septic death. These results suggest that PE-DTPA is a potent antagonist of LPS, and that it acts by competing for binding to CD14.

• Biomolecules & Therapeutics
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• 제20권3호
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• pp.313-319
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• 2012

In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. But their precise mechanism of action has not been elucidated. In this study, a novel synthetic inhibitor of HDAC, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide [IN-2001] was examined for its antitumor activity and the underlying molecular mechanisms of any such activity on human breast cancer cell lines. IN-2001 effectively inhibited cellular HDAC activity ($IC_{50}$ = 0.585 nM) inMDA-MB-231 human breast cancer cells. IN-2001 caused a significant dose-dependent inhibition of cell proliferation in estrogen receptor (ER) negative MDA-MB-231human breast cancer cells. Cell cycle analysis revealed that the growth inhibitory effects of IN-2001 might be attributed to cell cycle arrest at $G_0/G_1$ and/or $G_2$/Mphase and subsequent apoptosis in human breast cancer cells. These events are accompanied by modulating several cell cycle and apoptosis regulatory genes such as CDK inhibitors $p21^{WAF1}$ and $p27^{KIP1}$ cyclin D1, and other tumor suppressor genes such as cyclin D2. Collectively, IN-2001 inhibited cell proliferation and induced apoptosis in human breast cancer cells and these findings may provide new therapeutic approaches, combination of antiestrogen together with a HDAC inhibitor, in the hormonal therapy-resistant ER-negative breast cancers. In summary, our data suggest that this histone deacetylase inhibitor, IN-2001, is a novel promising therapeutic agent with potent antitumor effects against human breast cancers.

• BMB Reports
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• 제52권2호
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• pp.133-138
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• 2019

Upon viral infection, the 2', 5'-oligoadenylate synthetase (OAS)-ribonuclease L (RNaseL) system works to cleave viral RNA, thereby blocking viral replication. However, it is unclear whether OAS proteins have a role in regulating gene expression. Here, we show that OAS1 and OAS3 act as negative regulators of the expression of chemokines and interferon-responsive genes in human macrophages. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease (Cas9) technology was used to engineer human myeloid cell lines in which the OAS1 or OAS3 gene was deleted. Neither OAS1 nor OAS3 was exclusively responsible for the degradation of rRNA in macrophages stimulated with poly(I:C), a synthetic surrogate for viral double-stranded (ds)RNA. An mRNA sequencing analysis revealed that genes related to type I interferon signaling and chemokine activity were increased in $OAS1^{-/-}$ and $OAS3^{-/-}$ macrophages treated with intracellular poly(I:C). Indeed, retinoic-acid-inducible gene (RIG)-I- and interferon-induced helicase C domain-containing protein (IFIH1 or MDA5)-mediated induction of chemokines and interferon-stimulated genes was regulated by OAS3, but Toll-like receptor 3 (TLR3)- and TLR4-mediated induction of those genes was modulated by OAS1 in macrophages. However, stimulation of these cells with type I interferons had no effect on OAS1- or OAS3-mediated chemokine secretion. These data suggest that OAS1 and OAS3 negatively regulate the expression of chemokines and interferon-responsive genes in human macrophages.

• BMB Reports
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• 제52권6호
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• pp.397-402
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• 2019

Middle East respiratory syndrome coronavirus (MERS-CoV) uses the spike (S) glycoprotein to recognize and enter target cells. In this study, we selected two epitope peptide sequences within the receptor binding domain (RBD) of the MERS-CoV S protein. We used a complex consisting of the epitope peptide of the MERS-CoV S protein and CpG-DNA encapsulated in liposome complex to immunize mice, and produced the monoclonal antibodies 506-2G10G5 and 492-1G10E4E2. The western blotting data showed that both monoclonal antibodies detected the S protein and immunoprecipitated the native form of the S protein. Indirect immunofluorescence and confocal analysis suggested strong reactivity of the antibodies towards the S protein of MERS-CoV virus infected Vero cells. Furthermore, the 506-2G10G5 monoclonal antibody significantly reduced plaque formation in MERS-CoV infected Vero cells compared to normal mouse IgG and 492-1G10E4E2. Thus, we successfully produced a monoclonal antibody directed against the RBD domain of the S protein which could be used in the development of diagnostics and therapeutic applications in the future.

• Journal of Animal Science and Technology
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• 제64권1호
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• pp.123-134
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• 2022

Toll-like receptors (TLRs), as a part of innate immunity, plays an important role in detecting pathogenic molecular patterns (PAMPs) which are structural components or product of pathogens and initiate host defense systems or innate immunity. Precise negative feedback regulations of TLR signaling are important in maintaining homeostasis to prevent tissue damage by uncontrolled inflammation during innate immune responses. In this study, we identified and characterized the function of the pancreatic progenitor cell differentiation and proliferation factor (PPDPF) as a negative regulator for TLR signal-mediated inflammation in chicken. Bioinformatics analysis showed that the structure of chicken PPDPF evolutionarily conserved amino acid sequences with domains, i.e., SH3 binding sites and CDC-like kinase 2 (CLK2) binding sites, suggesting that relevant signaling pathways might contribute to suppression of inflammation. Our results showed that stimulation with polyinosinic:polycytidylic acids (Poly [I:C]), a synthetic agonist for TLR3 signaling, increased the mRNA expression of PPDPF in chicken fibroblasts DF-1 but not in chicken macrophage-like cells HD11. In addition, the expression of pro-inflammatory genes stimulated by Poly(I:C) were reduced in DF-1 cells which overexpress PPDPF. Future studies warrant to reveal the molecular mechanisms responsible for the anti-inflammatory capacity of PPDPF in chicken as well as a potential target for controlling viral resistance.