• Bulletin of the Korean Chemical Society
• /
• 제34권5호
• /
• pp.1543-1546
• /
• 2013

• Asian Pacific Journal of Cancer Prevention
• /
• 제16권9호
• /
• pp.3817-3825
• /
• 2015

Background: The human protein methyl-transferase DOT1L catalyzes the methylation of histone H3 on lysine 79 (H3K79) at homeobox genes and is also involved in a number of significant processes ranging from gene expression to DNA-damage response and cell cycle progression. Inhibition of DOT1L activity by shRNA or small-molecule inhibitors has been established to prevent proliferation of various MLL-rearranged leukemia cells in vitro, establishing DOT1L an attractive therapeutic target for mixed lineage leukemia (MLL). Most of the drugs currently in use for the MLL treatment are reported to have low efficacy, hence this study focused on various natural compounds which exhibit minimal toxic effects and high efficacy for the target receptor. Materials and Methods: Structures of human protein methyl-transferase DOT1L and natural compound databases were downloaded from various sources. Virtual screening, molecular docking, dynamics simulation and drug likeness studies were performed for those natural compounds to evaluate and analyze their anti-cancer activity. Results: The top five screened compounds possessing good binding affinity were identified as potential high affinity inhibitors against DOT1L's active site. The top ranking molecule amongst the screened ligands had a Glide g-score of -10.940 kcal/mol and Glide e-model score of -86.011 with 5 hydrogen bonds and 12 hydrophobic contacts. This ligand's behaviour also showed consistency during the simulation of protein-ligand complex for 20000 ps, which is indicative of its stability in the receptor pocket. Conclusions: The ligand obtained out of this screening study can be considered as a potential inhibitor for DOT1L and further can be treated as a lead for the drug designing pipeline.

• The Korean Journal of Pain
• /
• 제9권2호
• /
• pp.318-325
• /
• 1996

Background: Sympathectomy relieves pain in sympathectically maintained pain, and subcutaneous injection of norepinephrine(NE) can rekindle mechanical allodynia. However, the mechanism of rekindling is not clear. The purpose of this study is to investigate which subtype of $\alpha$-adrenoceptor is involved in NE-induced rekindling of mechanical allodynia in sympathectomized neuropathic rats. Methods: Neuropathic injury was produced by tightly ligating the left L5 and L6 spinal nerves of 36 male Sprague-Dawley rats and bilateral lumbar sympathectomy was done at two weeks postoperatively. Starting at 7 days after sympathectomy, rekindling of mechanical allodynia was induced by NE and clonidine injected into the left paw, which was reversed by pretreatment of phentolamine and idazoxan. Mechanical allocynia was quantified by measuring the frequency of foot lifts to two von Frey filaments applied to the paw. Results: All tested rats displayed well-developed signs of mechanical allodynia at the left paw that were abolished by a bilateral lumbar sympathectomy. Subcutaneous (s.c.) injection of NE (0.05 ${\mu}g$) into the affected paw of sympathectomized neuropathic rats rekindled previous mechanical allodynia. These effects could be mimicked by an ${\alpha}_2$-receptor agonist clonidine, but not by an ${\alpha}_1$-receptor agonist phenylephrine. The NE-induced rekindling of mechanical allodynia was significantly reduced by prior s.c. injection of a mixed $\alpha$-receptor antagonist phentolamine (20${\mu}g$) and ${\alpha}_2$-receptor antagonist idazoxan(20${\mu}g$), but not by a ${\alpha}_1$-receptor antagonist terazosin (20${\mu}g$). The pretreatment of idazoxan produced dose-related inhibition of NE-induced rekindling of mechanical allodynia. The rekindling induced by ${\alpha}_2$-receptor agonist clonidine (5${\mu}g$) was also reversed by prior s.c. injection of ${\alpha}_2$-receptor antagonist idazoxan (20${\mu}g$). Conclusion: Subcutaneous injection of NE into the paw of sympathectomized neuropathic rats rekindles mechanical allodynia, which is reversed by an ${\alpha}_2$-, but not by an ${\alpha}_1$-receptor antagonist. Therefore, rekindling of mechanical allodynia in sympathectomized neuropathic rats is mediated by ${\alpha}_2$-adrenoceptor.

• 한국미생물·생명공학회지
• /
• 제22권3호
• /
• pp.233-239
• /
• 1994

The characteristics of the bacteriophage resistant Lactococcus lactis subsp. cremoris ATCC 11602-A1, the phage-resistant mutant of Lactococcus lactis subsp. cremoris ATCC 11602, was examined. Electron microscopic study of phage adsorption to A1 revealed that after 10 min. incubation of the host-phage mixture, A1 did not show phage adsorption, and after 60 min. did not show a real burst and the release of new phage particles which could be detected in the mixture of its parent strain and phage. However, the phage adsorption rate of A1 after SDS treatment increased to 98%. Moreover, when the cell walls from A1 and parent strain, and the polysaccharide(PS) and peptidoglycan(PG) of their cell wall were mixed with phage and incubated for 15 min., PS and PG from A1 did not bind phage, but only SD-treated cell wall bound phage, and the cell wall and PS of parent strain bound phage. Both A1 and parent strain treated with 0.2 N HCl-and 5% TCA(100$$C) did not bind phage. The results suggest that the phage receptor is still present in the cell wall of the A1, but a cell wall constituent hydrolyzed by SDS blocks phage adsorption by masking the phage receptor. It also suggests that the phage receptor of parent strain is associated with PS of the cell wall.

• The Korean Journal of Physiology and Pharmacology
• /
• 제9권5호
• /
• pp.263-268
• /
• 2005

Striatum has important roles in motor control, habitual learning and memory. It receives glutamatergic inputs from neocortex and thalamus, and dopaminergic inputs from substantia nigra. We examined effects of dopamine (DA) on the corticostriatal synaptic transmission using in vitro extracellular recording technique in rat brain corticostriatal slices. Synaptic responses were elicited by stimulation of cortical glutamatergic inputs on the corpus callosum and recorded in the dorsal striatum. Corticostriatal population spike (PS) amplitudes were decreased ($39.4{\pm}7.9$%) by the application of $100{\mu}M$ DA. We applied receptor subtype specific agonists and antagonists and characterized the modulation of corticostriatal synaptic transmission by different DA receptor subtypes. $D_2$ receptor agonist (quinpirole), antagonist (sulpiride), and $D_1$ receptor antagonist (SKF 83566), but not $D_1$ receptor agonist (SKF 38393), induced significantly the reduction of striatal PS. Pretreatment neither with SKF 83566 nor sulpiride significantly affected corticostriatal synaptic inhibition by DA. However, the inhibition of DA was completely blocked by pretreatment with mixed solution of both SKF 83566 and sulpiride. These results suggest that DA inhibits corticostriatal synaptic transmission through both $D_1$ and $D_2$ receptors in concert with each other.

• Journal of Ginseng Research
• /
• 제17권1호
• /
• pp.1-12
• /
• 1993

The Preventive effect of the saponin fraction of Panax ginseng C.A. Meyer against hyperchole- sterolemia was demonstrated by assaying the cholesterol and triacylglyceride level of the blood serum and liver of rats fed high-cholesterol diet with and/or without ginsenoside. To understand the mechanism of the preventive action of ginsenoside, ginsenoside effect on LDL receptor binding ability, cholesterol level, and cAMP level of Chinese hamster ovary (CHO) cells cultured under various conditions were examined. When LDL (20 $\mu$g/ml) was added to the culture medium for CHO cell culture, LDL receptor binding activity of the cell was suppressed down to 58% of that of normal group. Ginsenosides at 10--2% and 10-3% level (w/v) were shown to exert an appreciable stimulatory effect on CHO cell LDL receptor activity, which partially overcame the suppression due to the presence of LDL (20 $\mu\textrm{g}$/ml) in the medium. Ginsenosides also reduced the increased cholesterol level of test group almost to that of normal group, and it increased cAMP level, which was usually reduced to 55% of that of the normal group due to the presence of LDL in the medium. Comparison of Kd and Bmax value of CHO cells cultured under different conditions revealed that this stimulation was due not to the receptor's binding affinity but to its number. Addition of ginsenoside (10-2%) decreased the uptake of taurocholic acid as much as 20% at the actively transporting everted ileal sacs, but it failed to form a large mixed micelles with taurocholic acid, which was one of the proposed mechanisms by which ginsenoside inhibits bile acid reabsorption. From the above results, it seemed likely that ginsenoside prevented hypercholestrolemia by decreasing cholesterol level in cells thereby relieving the inhibition of LDL receptor synthesis by cholesterol and also by inhibiting bile acid reabsorption from the small intestine.

• Parasites, Hosts and Diseases
• /
• 제59권6호
• /
• pp.547-556
• /
• 2021

Our objective was to investigate whether inflammatory microenvironment induced by Trichomonas vaginalis infection can stimulate proliferation of prostate cancer (PCa) cells in vitro and in vivo mouse experiments. The production of CXCL1 and CCL2 increased when cells of the mouse PCa cells (TRAMP-C2 cell line) were infected with live T. vaginalis. T. vaginalis-conditioned medium (TCM) prepared from co-culture of PCa cells and T. vaginalis increased PCa cells migration, proliferation and invasion. The cytokine receptors (CXCR2, CCR2, gp130) were expressed higher on the PCa cells treated with TCM. Pretreatment of PCa cells with antibodies to these cytokine receptors significantly reduced the proliferation, mobility and invasiveness of PCa cells, indicating that TCM has its effect through cytokine-cytokine receptor signaling. In C57BL/6 mice, the prostates injected with T. vaginalis mixed PCa cells were larger than those injected with PCa cells alone after 4 weeks. Expression of epithelial-mesenchymal transition markers and cyclin D1 in the prostate tissue injected with T. vaginalis mixed PCa cells increased than those of PCa cells alone. Collectively, it was suggested that inflammatory reactions by T. vaginalis-stimulated PCa cells increase the proliferation and invasion of PCa cells through cytokine-cytokine receptor signaling pathways.

• 대한약리학회지
• /
• 제25권1호
• /
• pp.23-30
• /
• 1989

함께 투여되는 마약성진통제에 따라 효능제 또는 길항제(mixed agonist-antagonist)로 작용하는 buprenorphine을 사용하여 개구리 좌골신경에 존재하는 아편수용체의 성질을 검토하였다. 실험은 sucrose-gap apparatus를 사용하여 활동전압에 대한 영향을 관찰하였으며 약물의 상호작용을 검토하고자 meperidine 또는 naloxone을 사용하여 다음과 같은 결과를 얻었다. 1) Buprenorphine은 현저하게 개구리 좌골신경의 활동전압을 저하시켰다. 2) 두 개의 최고작용농도를 보였는데 저농도에서는 $10^{-8}\;M$, 또 고농도에서는 $10^{-4}\;M$에서 현저하게 작용을 나타내었다. 3) Buprenorphine은 meperidine의 활동전압 저하작용을 의의있게 억제하였다. 4) Naloxone에 의하여 Buprenorphine의 저하 작용이 억제되었다. 위의 실험결과로 Buprenorphine은 순수 마약성진통제의 작용을 억제하여 차단제로 작용하는 한편 또한 효능제로 활동전압을 의의있게 억제하였다. 이로써 개구리 좌골신경에 있는 아편수용체는 세포막에 또는 세포막 주위에서 $Na^+-Channel$이 활성화되는 데 중요한 역할을 하는 것으로 간주되며 이 수용체는 또한 Naloxone에 매우 민감한 반응을 나타낸다.

• Animal cells and systems
• /
• 제12권2호
• /
• pp.77-83
• /
• 2008

The canine fearfulness is a behavioral trait known to have a genetic basis. This research analyzed genetic effects of the dopamine D4 receptor polymorphism on this behavior by postulating a mixed model of inheritance. Genotyping for the three different repeat polymorphism found in the third exon of the receptor gene was carried out for the population of the Korean native dogs. Four hundred fifty eight dogs with known pedigree were genotyped, and 264 individuals were tested for their fear responses to an experimenter, in which four different behavioral paradigms were adopted. Since the results assessed by principal factor analysis revealed a major factor explaining 69% of the total phenotypic variance, the subsequent analyses were conducted for this quantity. Analyses of the factor scores by estimating their posterior means indicated that there is a fixed effect exerted by the three different repeat polymorphism found in the D4 receptor as well as sex, in addition to unidentified polygenic effects. The phenotypic contribution of the D4 genotype was roughly estimated to be about 2%, which is a fraction of the total genetic effects responsible for more than 20% of the total phenotypic variance.

• The Korean Journal of Physiology and Pharmacology
• /
• 제8권3호
• /
• pp.153-159
• /
• 2004

The interstitial cells of Cajal (ICCs) are the pacemaker cells in gastrointestinal tract and generate electrical rhythmicity in gastrointestinal muscles. Therefore, ICC may be modulated by endogenous agents such as neurotransmitter, hormones, and prostaglandins (PGs). In the present study, we investigated the effects of prostaglandins, especially $PGE_2$, on pacemaker currents in cultured ICCs from murine small intestine by using whole-cell patch clamp techniques. ICCs generated spontaneous slow waves under voltage-clamp conditions and showed a mean amplitude of $-452{\pm}39\;pA$ and frequency of $18{\pm}2$ cycles/min (n=6). Treatments of the cells with $PGE_2$ $(1\;{\mu}M)$ decreased both the frequency and amplitude of the pacemaker currents and increased the resting currents in the outward direction. $PGE_2$ had only inhibitory effects on pacemaker currents and this inhibitory effect was dose-dependent. For characterization of specific membrane EP receptor subtypes, involved in the effects of $PGE_2$ on pacemaker currents in ICCs, EP receptor agonists were used: Butaprost $(1\;{\mu}M)$, $EP_2$ receptor agonist, reduced the spontaneous inward current frequency and amplitude in cultured ICCs (n=5). However sulprostone $(1\;{\mu}M)$, a mixed $EP_1$ and $EP_3$ agonist, had no effects on the frequency, amplitude and resting currents of pacemaker currents (n=5). SQ-22536 (an inhibitor of adenylate cyclase; $100\;{\mu}M$) and ODQ (an inhibitor of guanylate cyclase; $100\;{\mu}M$) had no effects on $PGE_2$ actions of pacemaker currents. These observations indicate that $PGE_2$ alter directly the pacemaker currents in ICCs, and that the $PGE_2$ receptor subtypes involved are the $EP_2$ receptor, independent of cyclic AMP- and GMP-dependent pathway.