Biomedical subjects

Taehoon Lee

Publications and source records attributed to Taehoon Lee.

10 recordsLinked to original sources

PubMed2006

A small compound that inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production.

Lipopolysaccharide (LPS) is critically involved in the inflammatory responses via generation of several pro-inflammatory cytokines. Since tumor necrosis factor-alpha (TNF-alpha) is one of the major pro-inflammatory cytokines which is induced by LPS treatment, the development of molecules capable of modulating LPS-induced TNF-alpha production is an issue of concern. We identified a novel synthetic compound that inhibits LPS-induced TNF-alpha production in human peripheral blood mononuclear cells (PBMCs). The active compound SM-7409 inhibited LPS-induced TNF-alpha production in a concentration-dependent manner, showing maximal activity at 5 microM. SM-7409 inhibited LPS-induced TNF-alpha mRNA transcript accumulation and protein expression. We also found that SM-7409 strongly inhibits LPS-induced extracellular signal-regulated protein kinase activity in PBMCs. Moreover, we found that SM-7409 strongly inhibits the LPS-induced other pro-inflammatory cytokines, such as interleukin (IL)-1beta and IL-8 in PBMCs. SM-7409 also dramatically inhibits the LPS-induced TNF-alpha production in neutrophils. Taken together, our results demonstrate that SM-7409 is a synthetic compound that inhibits LPS-induced TNF-alpha production, and thus SM-7409 should be useful for the development of chemotherapies targeting LPS-mediated inflammatory responses.

Butyrates↗

PubMed2006

Pituitary adenylate cyclase-activating polypeptide 27 is a functional ligand for formyl peptide receptor-like 1.

Although the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in the regulation of several immune responses, its target receptors and signaling mechanisms have yet to be fully elucidated in immune cells. In this study, we found that PACAP27, but not PACAP38, specifically stimulated intracellular calcium mobilization and ERK phosphorylation in human neutrophils. Moreover, formyl peptide receptor-like 1 (FPRL1) was identified as a PACAP27 receptor, and PACAP27 was found to selectively stimulate intracellular calcium increase in FPRL1-transfected rat basophil leukocytes-2H3 cell lines. In addition, PACAP27-induced calcium increase and ERK phosphorylation were specifically inhibited by an FPRL1 antagonist, Trp-Arg-Trp-Trp-Trp-Trp (WRW4), thus supporting the notion that PACAP27 acts on FPRL1. In terms of the functional role of PACAP27, we found that the peptide stimulated CD11b surface up-regulation and neutrophil chemotactic migration, and that these responses were completely inhibited by WRW4. The interaction between PACAP27 and FPRL1 was analyzed further using truncated PACAPs and chimeric PACAPs using vasoactive intestinal peptide, and the C-terminal region of PACAP27 was found to perform a vital function in the activation of FPRL1. Taken together, our study suggests that PACAP27 activates phagocytes via FPRL1 activation, and that this results in proinflammatory behavior, involving chemotaxis and the up-regulation of CD11b.

Amino Acid Sequence↗

PubMed2006

Identification of a new functional target of haloperidol metabolite: implications for a receptor-independent role of 3-(4-fluorobenzoyl) propionic acid.

Haloperidol, a dopamine D2 receptor blocker, is a classical neuroleptic drug that elicits extrapyramidal symptoms. Its metabolites include 3-(4-fluorobenzoyl) propionic acid (FBPA) and 4-(4-chlorophenyl)-4-piperidinol (CPHP). Until now, the biological significance of these metabolites has remained largely unknown. Here, we report that the administration of FBPA to mice effected a suppression of locomotor activity and induced catalepsy in a manner similar to that observed with haloperidol, whereas CPHP had no significant effects. Neither of these two metabolites, however, exhibited any ability to bind to the dopamine D2 receptor. FBPA blocked dopamine-induced extracellular signal-regulated kinase 1/2 phosphorylation, and it specifically affected mitogen-activated protein kinase kinase (MEK)1/2 activity in hippocampal HN33 cells. Moreover, FBPA was capable of direct interaction with MEK1/2, and inhibited its activity in vitro. We demonstrated the generation of haloperidol metabolites within haloperidol-treated cells by mass spectrometric analyses. Collectively, our results confirm the biological activity of FBPA, and provide initial clues as to the receptor-independent role of haloperidol.

Animals↗

PubMed2005

A small compound that inhibits tumor necrosis factor-alpha-induced matrix metalloproteinase-9 upregulation.

Matrix metalloproteinase-9 (MMP-9) is critically involved in the tumor invasion and metastasis processes. Since TNF-alpha plays a crucial role in the regulation of MMP-9 expression, the development of molecules capable of modulating TNF-alpha-induced signaling is an issue of concern. We identified a novel synthetic compound that inhibits TNF-alpha-induced MMP-9 upregulation in the HT1080 human fibrosarcoma cell line. The active compound SM-7368 inhibited TNF-alpha-induced MMP-9 upregulation in a concentration-dependent manner and showed maximal activity at 10 microM. SM-7368 inhibited TNF-alpha-induced MMP-9 mRNA transcript accumulation and protein expression. We also found that SM-7368 strongly inhibits TNF-alpha-induced NF-kappaB activity but not AP-1 activity. Moreover, we found that SM-7368 strongly inhibits the TNF-alpha-induced invasion of HT1080 human fibrosarcoma cell line. Taken together, our results demonstrate that SM-7368 is a synthetic compound that inhibits TNF-alpha-induced MMP-9 expression, and thus SM-7368 should be useful for the development of chemotherapies targeting TNF-alpha-mediated tumor invasion and metastasis.

Benzamides↗

PubMed2004

Compounds stimulating cytosolic phospholipase A2 activity with a combinational action mode.

The screening of small synthetic compound libraries is a useful means of identifying molecules that modulate various cellular responses. We screened more than 10,000 different small compounds and identified three synthetic compounds that stimulate arachidonic acid (AA) release in a combinational manner in neutrophil-like differentiated HL60 cells. These three compounds were designated as AARIC-1, -2, and -3, representing AA release inducing compounds-1, -2, and -3. Although AA release was not induced by any single one of these compounds, it was dramatically stimulated by the three compounds in combination. Moreover, the effect of combined treatment by these compounds on AA release was completely abolished by MAFP and AACOCF(3), specific cytosolic phospholipase A(2) inhibitors. Furthermore, we found that AARIC-3 stimulates cytosolic calcium influx, while AARIC-1 induces ERK activation. Taken together, we demonstrate a useful approach to the study of complicated and nonlinear intracellular signaling networks using small synthetic compounds in combination.

Acetamides↗

PubMed2003

Phosphatidic acid regulates systemic inflammatory responses by modulating the Akt-mammalian target of rapamycin-p70 S6 kinase 1 pathway.

Macrophages are pivotal effector cells in the innate immune system. When microbial products bind to pathogen recognition receptors, macrophages are activated and release a broad array of mediators, such as cytokines, that orchestrate the inflammatory responses of the host. Phosphatidic acid (PA) has been implicated as an important metabolite of phospholipid biosynthesis and in membrane remodeling and has been further suggested to be a crucial second messenger in various cellular signaling events. Here we show that PA is an essential regulator of inflammatory response. Deleterious effects of PA are associated with the secretion of proinflammatory cytokines, such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and the production of nitric oxide, prostaglandin E2, which are predominantly released by macrophage Raw264.7 cells. Furthermore, the administration of PA to mice increased the serum cytokine level. Moreover, direct or lipopolysaccharide-induced PA accumulation by macrophages led to the Akt-dependent activation of the mammalian target of rapamycin-p70 S6 kinase 1, a process required for the induction of inflammatory mediators. These findings demonstrate the importance of the role of PA in systemic inflammatory responses, and provide a potential usefulness as specific targets for the development of therapies.

Animals↗

PubMed2003

Nonuniform Ca2+ transients in arrhythmogenic Purkinje cells that survive in the infarcted canine heart.

OBJECTIVE AND METHODS: In this study, we investigated whether Ca(2+) transients are altered in Purkinje cell aggregates dispersed from the subendocardium overlying the infarcted zone of the left ventricle (IZPCs) 48 h after coronary artery occlusion. To do so, we combined epifluorescent imaging with microelectrode recordings of IZPCs and normal canine Purkinje cell aggregates (NZPCs). RESULTS: NZPCs respond to an action potential (AP) by a small Ca(2+) transient at the cell surface immediately after the AP upstroke followed by a large [Ca(2+)] transient, which propagates to the cell core. In addition, focal Ca(2+) waves can originate spontaneously later during the AP or during the diastolic interval (Circ Res 2000;86:448-55) and then propagate throughout the aggregate as 'cell-wide Ca(2+) waves'. Electrically-evoked Ca(2+) transients in IZPCs arose significantly faster than those in NZPCs, and showed substantial spatiotemporal nonuniformity within an IZPC aggregate as well as between IZPC aggregates. IZPCs showed, hitherto undetected, low amplitude, micro Ca(2+) transients (extent <or=5 microm) at a fivefold higher incidence than in NZPCs. Micro Ca(2+) transients appeared to meander over distances <or=100 microm and reduced the local Ca(2+) transient of the next paced beat. Micro Ca(2+) transients nearly always preceded the cell-wide Ca(2+)waves, which occurred more frequently in IZPCs than in NZPCs and caused non-driven electrical activity of the Purkinje aggregate. CONCLUSIONS: Micro Ca(2+) transients preceded cell-wide Ca(2+) waves so often that it is probable that micro Ca(2+) transients induced cell-wide Ca(2+) waves. Cell-wide Ca(2+) waves, in turn, clearly elicited spontaneous APs. We propose that the high incidence of micro Ca(2+) transients in IZPCs is a fundamental element of the abnormal Ca(2+) handling of diseased Purkinje cells, underlying arrhythmias originating in the subendocardial Purkinje network post myocardial infarction.

Action Potentials↗

PubMed2003

Thiram and ziram stimulate non-selective cation channel and induce apoptosis in PC12 cells.

The neurotoxicity of dithiocarbamates has been previously reported, however, the detailed mechanism underlying the neurotoxicity is still not fully understood. Among the dithiocarbamates, we investigated thiram and ziram in a neuronal-like pheochromocytoma (PC12) cells. Thiram and ziram strongly induced cell death in both dose- and time-dependent manners with the LC(50) of 0.3 and 2 microM, respectively. The cell death showed typical apoptotic features, such as DNA fragmentation and an increase of subdiploidy nuclei. Interestingly, both thiram and ziram induced rapid and sustained increases of intracellular Ca(2+) in PC12 cells, which were almost completely blocked by flufenamic acid (FFA), an inhibitor of non-selective cation channel. BAPTA-AM, an intracellular Ca(2+) chelator, inhibited the thiram- and ziram-induced apoptotic cell death. These results suggest that thiram and ziram induce apoptotic neuronal cell death by Ca(2+) influx through non-selective cation channels. The present study may provide a clue for understanding the mechanism of neurotoxicity of thiram and ziram.

Animals↗

PubMed2002

Molecular basis of R-type calcium channels in central amygdala neurons of the mouse.

R-type Ca2+ channels play a critical role in coupling excitability to dendritic Ca2+ influx and neuronal secretion. Unlike other types of voltage-sensitive Ca2+ channels (L, N, P/Q, and T type), the molecular basis for the R-type Ca2+ channel is still unclear, thereby limiting further detailed analyses of R-type Ca2+ channel physiology. The prevailing hypothesis is that alpha(1E) (Ca(V)2.3) gene encodes for R-type Ca2+ channels, but the dearth of critical evidence has rendered this hypothesis controversial. Here we generated alpha1E-deficient mice (alpha1E-/-) and examined the status of voltage-sensitive Ca2+ currents in central amygdala (CeA) neurons that exhibit abundant alpha1E expression and R-type Ca2+ currents. The majority of R-type currents in CeA neurons were eliminated in alpha1E-/- mice whereas other Ca2+ channel types were unaffected. These data clearly indicate that the expression of alpha1E gene underlies R-type Ca2+ channels in CeA neurons. Furthermore, the alpha1E-/- sign mice exhibited signs of enhanced fear as evidenced by their vigorous escaping behavior and aversion to open-field conditions. These latter findings imply a possible role of alpha1E-based R-type Ca2+ currents in amygdala physiology associated with fear.

Amygdala↗

PubMed2002

Isochronal difference mapping: an approach for mapping dynamic changes during reentrant ventricular tachycardia.

During clinical electrophysiological study for treatment of reentrant ventricular tachycardia, activation maps constructed from the acquired electrophysiological data can be difficult to interpret when the reentrant circuit is changing from one cardiac cycle to the next. Reduction of complexity would be beneficial but has been difficult. A new technical method termed isochronal difference mapping (IDM) was devised to reduce complexity and enhance distinctive conduction patterns present in the data. Electrograms were acquired from 196 sites using a canine model of a reentrant ventricular tachycardia circuit with a figure eight conduction pattern occurring in the epicardial border zone. Activation maps were constructed for all cardiac cycles during episodes of tachycardia in five experiments. IDM maps were then created, which are subtractive comparisons of the activation maps from two different cardiac cycles during a given tachycardia episode. In each map the electrical activation occurring for only one or for both of the cardiac cycles was separately highlighted in distinct spatial areas of the border zone during an isochronal interval. Based on the mappings, areas of conduction velocity change, regions of breakthrough of the wavefront across functional lines of block, regions with coherent activation, and regions with irregular activation became readily apparent. IDM maps showed that when cycle length prolonged due to deceleration of conduction within the reentrant circuit isthmus, conduction velocity increased elsewhere in the circuit. IDM accentuates cycle-to-cycle differences in multi-channel electrophysiological data and can be used to reduce complexity and enhance distinctive conduction patterns.

Animals↗