Biomedical subjects
Publications and source records attributed to D K Lee.
A series of pyrrolo[3,2,1-ij]quinoline derivatives was synthesized, evaluated for their activity against the 5-HT2c and 5-HT2a, receptors and found to be agonists at 5-HT2c with selectivity over 5-HT2a.
Recently, we reported that momordin I from Ampelopsis radix is an activator protein-1 (AP-1) function inhibitor. Mormordin I showed both inhibition of AP-1 transcriptional activity and cellular cytotoxicity. Moreover, its inhibitory action was also identified in the animal experiments. The present study attempted to determine the mechanism of the action of momordin I more clearly. In mouse fibroblast cells, momordin I suppressed the AP-1 activity induced by phorbol 12-myristate 13-acetate (PMA), as well as blocked the de novo synthesis of AP-1 protein. Momordin I also showed cell cytotoxic activities on various cell lines and blocked the uptake of [(3)H]thymidine in cell proliferation induced by PMA. From these results, the inhibitory action of momordin I on AP-1 was clearly identified. Through the competitive binding assays, it appears that the inhibitory site of momordin I might be in the Jun/Fos dimer, and not in the DNA. Momordin I also showed the inhibitory action on the Jun/Jun homodimer, as well as on the Jun/Fos heterodimer. It also inhibited the autoregulated de novo synthesis of AP-1 by the Jun/Jun homodimer. In addition, since the truncated AP-1 used in this study only has the bZip regions of c-Jun and c-Fos, it appears that the inhibitory action site of momordin I may be the basic region of c-Jun instead of on the same region of c-Fos.
The androgen receptor (AR), like other steroid receptors, modulates the activity of the general transcription machinery on the core promoter to exert its function as a regulator. Co-immunoprecipitation of prostate cancer LNCaP cell extract using protein A-Sepharose coupled with anti-AR antibody indicates that the AR interacts with the general transcription factor TFIIH in a physiological condition. Co-transfection of cdk activating kinase (CAK), the kinase moiety of TFIIH, enhanced AR-mediated transcription in a ligand-dependent manner in human prostate cancer PC-3 and LNCaP cells, and in a ligand-independent manner in human prostate cancer DU145 cells. Detailed interaction studies further revealed that the AR NH(2)-terminal domain interacting with CAK was essential for the CAK-induced AR transactivation. Together, our data suggest that the AR may interact with TFIIH for efficient communication with the general transcription factors/RNA polymerase II on the core promoter.
Several 2-alkyl-5-methoxytryptamine analogues were designed and prepared as potential 5-HT(6) serotonin agonists. It was found that 5-HT(6) receptors accommodate small alkyl substituents at the indole 2-position and that the resulting compounds can bind with affinities comparable to that of serotonin. In particular, 2-ethyl-5-methoxy-N, N-dimethyltryptamine (8) binds with high affinity at human 5-HT(6) receptors (K(i) = 16 nM) relative to 5-HT (K(i) = 75 nM) and was a full agonist, at least as potent (8: K(act) = 3.6 nM) as serotonin (K(act) = 5.0 nM), in activating adenylate cyclase. Compound 8 displays modest affinity for several other populations of 5-HT receptors, notably h5-HT(1A) (K(i) = 170 nM), h5-HT(1D) (K(i) = 290 nM), and h5-HT(7) (K(i) = 300 nM) receptors, but is otherwise quite selective. Compound 8 represents the first and most selective 5-HT(6) agonist reported to date. Replacing the 2-ethyl substituent with a phenyl group results in a compound that retains 5-HT(6) receptor affinity (i.e., 10: K(i) = 20 nM) but lacks agonist character. 2-Substituted tryptamines, then, might allow entry to a novel class of 5-HT(6) agonists and antagonists.
Alpha-synuclein, a presynaptic protein of the central nervous system, has been implicated in the synaptic events such as neuronal plasticity during development and learning, and neuronal degeneration under pathological conditions. As an effort to understand the biological function of alpha-synuclein, we examined the expression patterns of alpha-synuclein in various human hematopoietic cells, and in Drosophila at different developmental stages. The alpha-synuclein was ubiquitously expressed in all the tested hematopoietic cells including T cells, B cells, NK cells, and monocytes, as well as in the lymphoma cell lines, Jurkat and K562. A potential alpha-synuclein homologue was also expressed in Drosophila, and its expression appeared to be temporally and spatially regulated during development. Our data suggest that alpha-synuclein may function in invertebrates as well as in vertebrates and its function may not be restricted to the neuron.
A search of the expressed sequence tag (EST) database retrieved a human cDNA sequence which partially encoded a novel G protein-coupled receptor (GPCR) GPR26. A human genomic DNA fragment encoding a partial open reading frame (ORF) and a rat cDNA encoding the full length ORF of GPR26 were obtained by library screening. The rat GPR26 cDNA encoded a protein of 317 amino acids, most similar (albeit distantly related) to the serotonin 5-HT(5A) and gastrin releasing hormone BB2 receptors. GPR26 mRNA expression analysis revealed signals in the striatum, pons, cerebellum and cortex. HEK293 and Rh7777 cells transfected with GPR26 cDNA displayed high basal cAMP levels, slow growth rate of clonal populations and derangements of normal cell shape. We also used a sequence reported only in the patent literature encoding GPR57 (a.k.a. HNHCI32) to PCR amplify a DNA fragment which was used to screen a human genomic library. This resulted in the cloning of a genomic fragment containing a pseudogene, psiGPR57, with a 99.6% nucleotide identity to GPR57. Based on shared sequence identities, the receptor encoded by GPR57 was predicted to belong to a novel subfamily of GPCRs together with GPR58 (a.k.a. phBL5, reported only in the patent literature), putative neurotransmitter receptor (PNR) and a 5-HT(4) pseudogene. Analysis of this subfamily revealed greatest identities (approximately 56%) between the receptors encoded by GPR57 and GPR58, each with shared identities of approximately 40% with PNR. Furthermore, psiGPR57, GPR58, PNR and the 5-HT(4) pseudogene were mapped in a cluster localized to chromosome 6q22-24. PNR and GPR58 were expressed in COS cells, however no specific binding was observed for various serotonin receptor-specific ligands.
Effect of the aqueous extract from a medicinal plant Dryobalanops aromatica(Dipterocarpaceae) on catecholamine secretion was investigated in bovine adrenal chromaffin cells. The aqueous extract inhibited [(3)H]norepinephrine ([(3)H]NE) secretion induced by 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), a nicotinic acetylcholine receptor (nAChR) agonist, with a half-maximal inhibitory concentration (IC(50)) of 8.4 +/- 1.7 microgml(-1). Increases in cytosolic calcium ([Ca(2+)](i)) and sodium ([Na(+)](i)) induced by DMPP were also inhibited by the extract. However, the binding of [(3)H]nicotine to nAChRs was not affected by the addition of the extract in receptor binding competition analysis, suggesting that active components in the extract and nicotine do not share the binding site in the nAChR. On the other hand, [Ca(2+)](i)increases induced by high K(+), ionomycin, bradykinin, angiotensin II, and thapsigargin were not inhibited by the extract. The data suggest that the extract from D. aromatica specifically inhibits catecholamine secretion by blocking nAChR in a noncompetitive manner.
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BACKGROUND AND AIMS: Ulcerative colitis (UC) is regarded as a rare disease in developing countries, but accurate data are generally lacking. We performed the present study to evaluate the incidence and prevalence of UC in Korea. METHODS: A retrospective study was performed from 1986 to 1997 in the Songpa-Kangdong district of Seoul, Korea. To recruit UC patients as completely as possible, multiple information sources including all medical facilities in the study area and three referral centres located nearby, but outside the study area were used. The incidence and prevalence rates were adjusted using the 1997 Korean population statistics. RESULTS: During the study period, a total of 94 incident cases were identified, for an adjusted mean annual incidence rate of 0.68 per 100,000 inhabitants. On 31 December 1997, 91 patients with UC lived in the study area, giving an adjusted prevalence rate of 7.57 per 100,000 inhabitants. By using the Poisson regression analysis, the annual incidence rate increased significantly from 0.20 per 100,000 inhabitants in 1986-1988 to 1.23 per 100,000 inhabitants in 1995-1997 (P < 0.005). Patient age at diagnosis, the interval from onset of symptoms to diagnosis, and the disease extent at diagnosis were fairly constant throughout the study period. CONCLUSIONS: The incidence and prevalence of UC in our study area are still low compared with those of Western countries, but the incidence rate is steadily increasing.
The apelin peptide was recently discovered and demonstrated to be the endogenous ligand for the G protein-coupled receptor, APJ. A search of the GenBank databases retrieved a rat expressed sequence tag partially encoding the preproapelin sequence. The GenBank search also revealed a human sequence on chromosome Xq25-26.1, containing the gene encoding preproapelin. We have used the rat sequence to screen a rat brain cDNA library to obtain a cDNA encoding the full-length open reading frame of rat preproapelin. This cDNA encoded a protein of 77 amino acids, sharing an identity of 82% with human preproapelin. Northern and in situ hybridization analyses revealed both human and rat apelin and APJ to be expressed in the brain and periphery. Both sequence and mRNA expression distribution analyses revealed similarities between apelin and angiotensin II, suggesting they that share related physiological roles. A synthetic apelin peptide was injected intravenously into male Wistar rats, resulting in immediate lowering of both systolic and diastolic blood pressure, which persisted for several minutes. Intraperitoneal apelin injections induced an increase in drinking behavior within the first 30 min after injection, with a return to baseline within 1 h.
Nodular fasciitis, a benign, pseudosarcomatous proliferative lesion of the soft tissue, is frequently misinterpreted as a sarcoma, both clinically and microscopically. Lesions associated with the parotid gland have been very rarely reported. We report a case of nodular fasciitis mimicking a parotid tumour after a facelift. We performed histological and immunohistochemical study and CT scan for it is difficult to make a differential diagnosis. We confirmed the final diagnosis as intraparotid nodular fasciitis. Superficial parotidectomy was performed because of initial pathological misdiagnosis reported as a dermatofibroma. The subsequent diagnosis was confirmed to be nodular fasciitis on the basis of immunohistochemical study. There was no recurrence after follow-up to 18 months. Proper diagnosis of nodular fasciitis in the parotid region and early recognition of its benign nature are necessary to differentiate it from other various benign and malignant tumours of the parotid gland.
Pneumosinus dilatans is a term used to describe enlargement of one or more paranasal sinuses without radiological evidence of localized bone destruction, hyperostosis, or mucous-membrane thickening. To date, many cases have been reported that involved frontal, ethmoid, sphenoid, and maxillary sinus. However, no case has been reported that involved all paranasal sinuses. Our case involved mastoid air cells as well as all paranasal sinuses. It is named pneumosinus dilatans multiplex by us. This is the first case to be reported in English literature that has this syndromic condition of pneumosinus dilatans multiplex, mental retardation, and facial deformity.
TRH (thyroliberin) is a tripeptide (pGlu-His-ProNH2) that signals via G protein-coupled receptors. Until recently, only a single receptor for TRH was known (TRH-R1), but two groups identified a second receptor, TRH-R2. We independently discovered TRH-R2. Using an extensive set of TRH analogs, we found no differences in TRH-R1 and TRH-R2 binding or in acute stimulation of signaling. TRH-R2 was more rapidly internalized upon binding TRH and exhibited a greater level of TRH-induced down-regulation than TRH-R1. During prolonged exposure to TRH, cells expressing TRH-R2 exhibited a lower level of gene induction than cells expressing TRH-R1. TRH-R2 receptor mRNA was present in very discrete nuclei and regions of rat brain. A major mRNA transcript for TRH-R2 was seen in the cerebral cortex, pons, thalamus, hypothalamus, and midbrain with faint bands found in the striatum and pituitary. The extensive distribution of TRH-R2 in the brain suggests that it mediates many of the known functions of TRH that are not transduced by TRH-R1. The variations in agonist-induced internalization and down-regulation/desensitization, and anatomic distribution of TRH-R2 compared with TRH-R1, suggest important functional differences between the two receptors.
Endoscopic mucosal resection with a ligation device (EMR-L) has become important in the curative treatment of precancerous lesions and early gastric cancers (EGCs), but little is known of the long-term efficacy and survival rates of EMR-L compared with surgical resection. We analyzed the therapeutic efficacy and safety of EMR-L in cases of EGC and precancerous lesions and compared the results of EMR-L with those of gastrectomy in patients with EGC over the same periods. EMR-L was performed on 20 EGCs and 54 precancerous lesions including tubular adenomas with or without severe dysplasias in 74 patients. Macroscopic type, size and location of the lesion were determined by endoscope, and the depth of invasion in EGCs was determined by endoscopic ultrasonography and confirmed by pathologic examination of the resected specimens. All the EGC cases were endoscopically followed up for at least 18 months (range, 18-66 months). Patients were selected that underwent subtotal gastrectomy and the survival rates were compared with those that underwent EMR-L. Complete resection was made in a single EMR-L treatment session in 61 cases (82.4%; 91.5%, were precancerous lesions and 65% were EGCs). After a repeat trial of EMR-L, the total rate of complete resection of precancerous lesions and EGCs was 92.6% and 85.0%, respectively. The survival rate of EGCs showed that complete resection by EMR-L resulted in 2 and 5 year survival rates of 100% and 95%, which are comparable to those of surgery (100% and 100%). This study suggests that EMR-L is a technically simple, minimally invasive and highly safe and effective treatment modality for selective EGCs, and offers an alternative to surgical treatment.
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Assessments of the biological control potential of muddy loaches, Misgurnus mizolepis, were conducted against Aedes togoi, Culex pipiens pallens, and Culex inatomii larvae both in the laboratory and in small rice plots in Pusan, Korea, from June to September 1997. Medium-sized fish consumed almost all of 500 3rd-stage larvae of Cx. pipiens pallens offered daily in the laboratory. Predation by the fish at release rates of 1, 2, 4, 8, and 16 fish per plot resulted in 1,004, 1,197, 1,198, 1,200, and 1,200 larvae of Ae. togoi consumed in 12 h, respectively, when each 1,200 3rd-stage larvae were given in the 1-m2 small rice plots. The average numbers of larvae eaten after introduction of the fish were 1,121.8 larvae in 24 h and 1,195.8 larvae in 36 h. Muddy loaches showed slightly higher predation rates on Cx. pipiens pallens and Culex inatomii larvae than on larvae of Ae. togoi. Therefore, M. mizolepis might be an efficient biological control agent against mosquito species in rice fields.
Several new androgen receptor (AR) coregulators, including ARA70, ARA55, ARA54, ARA160 and ARA24, associated with the N-terminal or the ligand-binding domain (LBD) of AR, have been identified by our group. We first identified the AR-LBD coregulators ARA70, ARA55, and ARA54. Our previous reports suggest that ARA70 can enhance the androgenic activity of 17 beta-estradiol (E2) and antiandrogens toward AR. It is of interest to compare and determine if the specificity of sex hormones and antiandrogens can be modulated by different coregulators. Our results indicate that, ARA70 is the best coregulator for increasing the androgenic activity of E2. Only ARA70 and ARA55 were able to significantly increase the androgenic activity of hydroxyflutamide, the active metabolite of a widely-used antiandrogen for the treatment of prostate cancer. Furthermore, our results suggest that among the LBD coregulators, ARA70 has a relatively high specificity for AR in the human prostate cancer cell line DU145. Together, our data suggest that the androgenic activity of some sex hormones and antiandrogens can be modulated by selective AR coactivators. In addition to the AR-LBD associated proteins, ARA24 and ARA160 have been identified as AR coregulators, interacting with the AR N-terminal instead of the LBD. Functional analysis revealed that the AR N-terminal coregulator ARA160 could cooperate with the AR LBD-associated coregulator ARA70. Our data indicate that ARA24 could also interact with AR, and that this binding is decreased by an expanding poly-glutamine (Q) length within AR. The length of the poly-Q stretch in the AR N-terminal domain is inversely correlated with the transcriptional activity of AR. Our data suggest that optimal AR transactivation may require interaction of AR with AR coregulators. The identification of factors or peptides that can interrupt androgen-mediated AR-ARA interactions may be useful in the development of better antiandrogens for treating androgen-related diseases, such as prostate cancer.
OBJECTIVE: To detect anaerobic bacteria Clostridium sp. and Bacteroides fragilis in intrahepatic stones by molecular genetic method. METHODS: DNA was extracted from 59 stone samples and subjected to polymerase chain reaction (PCR) amplification targeting the 16S rRNA gene of Clostridium sp. and the glutamine synthetase gene of Bacteroides fragilis. Single-strand conformational polymorphism (SSCP) analysis was performed to identify the Clostridium sp. RESULTS: 16S rRNA gene sequences for Clostridium sp. were identified in 49 stones (83%, 49/59). The two most common groups were detected in 19 (41%) and 17 (37%) of the 46 samples using SSPC analysis, and 25/59 (42%) stones were tested positive for Bacteroides fragilis. CONCLUSIONS: Anaerobes such as Clostridium sp. and Bacteroides fragilis present in intrahepatic stones and may play a role in stone formation. PCR is a useful technique to detect fastidious pathogens, which are difficult to culture. SSCP of PCR products is a rapid method in differentiating bacterial species.