Biomedical subjects

Soo-Hyun Kim

Publications and source records attributed to Soo-Hyun Kim.

At least 19 recordsLinked to original sources

PubMed2006

Molecular pathogenesis of Kallmann's syndrome.

Hypogonadotrophic hypogonadism (HH) is characterized by delayed or absent pubertal development secondary to gonadotrophin deficiency. HH can result from mutations of the gonadotrophin-releasing hormone receptor 1, the gonadotrophin beta-subunits, or various transcription factors involved in pituitary gland development. HH occurs in DAX1 mutations when associated with adrenal insufficiency (adrenal hypoplasia congenita), and is also linked with obesity in patients with mutations of leptin and its receptor, as well as mutations in prohormone convertase 1. Rarely, HH has resulted from kisspeptin receptor (GPR54) mutations, a gene implicated in the regulation of pubertal onset. When occurring with anosmia (a lack of sense of smell), HH is referred to as Kallmann's syndrome (KS). Two KS-related loci are currently known: KAL1, encoding anosmin-1, responsible for X-linked KS, and KAL2, encoding the fibroblast growth factor receptor 1 (FGFR1), mutated in autosomal dominant KS. Anosmin-1 is an extracellular glycoprotein with some unique structural characteristics; it interacts with both urokinase-type plasminogen activator and FGFR1. It has previously been shown that anosmin-1 enhances FGFR1 signalling in a heparan sulphate-dependent manner, and proposed that anosmin-1 fine-tunes FGFR1 signalling during olfactory and GnRH neuronal development. Here, we review the known normosmic causes of HH, and discuss novel developmental and molecular mechanisms underlying KS; finally, we introduce three novel genes (NELF, PKR2, and CHD7) that may be associated with some phenotypic features of KS.

Extracellular Matrix Proteins↗

PubMed2006

The apoptotic effect of intercalating agents on HPV-negative cervical cancer C-33A cells.

Cervical cancer is one of the leading causes of female cancer death worldwide with about 500,000 deaths per year. Both mitomycin C and cisplatin are alkylating agents, which bind and intercalate DNA, and thus used as anti-cancer drugs. In these studies, we focused on investigating the apoptotic effects of intercalating agents on HPV-negative cervical cancer C-33A cells. Accordingly, C-33A cells were treated with carboplatin, mitomycin C or cisplatin. Cell cycle analysis revealed that treatment with mitomycin C and cisplatin but not with carboplatin resulted in apoptosis. Both mitomycin C and cisplatin induced apoptosis in C-33A cells via caspase-8 and -3 processing in a Fas/FasL-dependent manner and also suppressed IL-18 expression, while they down-regulated IkappaB expression and up-regulated p65 expression. These results suggest that both mitomycin C and cisplatin induce apoptosis, not only via the caspase-8 and -3 dependent Fas/FasL pathway, but also via the regulation of NF-kappaB activity and IL-18 expression in HPV-negative cervical cancer C-33A cells.

Apoptosis↗

PubMed2006

Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the signals induced by the NACHT-LRR (NLR) pattern recognition receptors.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of a new family of myeloid receptors, encoded by a gene cluster linked to the MHC. Engagement of TREM-1 stimulates intracellular signals, resulting in activation of phagocytosis, neutrophil degranulation, and amplification of cytokine production induced by TLRs. In the present study, a novel property following engagement of TREM-1 is described, namely the amplification of cytokine production induced by the second major class of pattern recognition receptors, the NAIP, CIITA, HET-E, TP-1-leucine-rich repeat (NACHT-LRR; NLR) receptors, which recognize intracellular microorganisms through sensing their muropeptide components of peptidoglycan. The TREM-1/NLR synergism was observed for the production of TNF-alpha, IL-1beta, and IL-6, leading to an increase in cytokine production up to tenfold greater than the additive value of TREM-1 or muropeptide stimulation alone. Several putative mechanisms are proposed to be involved in the synergism between NLRs and TREM-1, including the increase in TREM-1 expression by NLR ligands, and of the expression of nucleotide oligomerization domain-2 receptor by TREM-1 engagement. In contrast, although caspase-1 modulates IL-1beta and IL-6 production after stimulation with anti-TREM-1 antibodies or NLR ligands, it does not appear to be responsible for the synergism between these two pathways. These findings demonstrate that TREM-1 acts on both major recognition pathways of bacterial structures: the extracellular TLR receptors, and the intracellular NLR molecules. This latter finding supports the concept that TREM-1 provides optimal amplification of cytokine-induced inflammation during the initiation of host defense.

Caspase 1↗

PubMed2006

Patient-reported assessment of quality care at end of life: development and validation of Quality Care Questionnaire-End of Life (QCQ-EOL).

Our goal was to validate an instrument with which terminally ill patients could evaluate the quality of care they receive at the end of life (EOL). Questionnaire development followed a four-phase process: item generation and reduction, construction, pilot testing, and field-testing. Using relevance and priority criteria and pilot testing, we developed a 16-item questionnaire. Factor analyses of data from 235 patients resulted in the Quality Care Questionnaire-End of Life (QCQ-EOL) covering dignity-conserving care, care by health care professionals, individualised care, and family relationships. All subscales and total scores showed high internal consistency (Cronbach alpha range, 0.73-0.89). The ability of total score and selective subscale scores clearly differentiated patients on the basis of clinical situation, sense of dignity, and general rating of care quality. Correlations of scores between patients and caregivers were substantial. The QCQ-EOL can be adopted to assess the quality of care received by terminally ill patients.

Adult↗

PubMed2006

A simple method to screen ligands of peroxisome proliferator-activated receptor delta.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that belong to the nuclear receptor superfamily directly modulating gene expression by binding to specific ligands. Recently, it has been reported that PPARdelta ligands play an essential role in improvement of metabolic disorders and skin disorders. We introduce an enzyme-linked immunosorbent assay (ELISA) to screen new PPARdelta ligands. This method is based on the activation mechanism of PPARdelta where the ligand binding to PPARdelta induces the interaction of the receptor with transcriptional co-activators. We optimized a simple ELISA method for screening PPARdelta ligands. Among co-activators such as SRC-1, TIF-2, and p300, PPARdelta had more strong binding with SRC-1 in an ELISA system. GW501516 and linoleic acid, the well-known ligands of PPARdelta, increased the binding between PPARdelta and co-activators in a ligand dose-dependent manner. The recruitment of co-activator SRC-1 was also more effective than those of TIF-2 and p300. We optimized and developed a novel and useful ELISA system for the mass screening of PPARdelta ligands. This screening system may be useful in the development of drugs for metabolic disorders and skin disorders.

Cloning, Molecular↗

PubMed2006

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.

Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.

Animals↗

PubMed2006

Upregulation of chicken p15INK4b at senescence and in the developing brain.

In mammalian cells, products of the INK4a-ARF locus play major roles in senescence and tumour suppression in different contexts, whereas the adjacent INK4b gene is more generally associated with transforming growth factor beta (TGF-beta)-mediated growth arrest. As the chicken genome does not encode an equivalent of INK4a, we asked whether INK4b and/or ARF contribute to replicative senescence in chicken cells. In chicken embryo fibroblasts (CEFs), INK4b levels increase substantially at senescence and the gene is transcriptionally silenced in two spontaneously immortalised chicken cell lines. By contrast, ARF levels are unaffected by prolonged culture or immortalisation. These expression patterns resemble the behaviour of INK4a and ARF in human fibroblasts. However, short-hairpin RNA (shRNA)-mediated knockdown of chicken INK4b or ARF provides only modest lifespan extension, suggesting that other factors contribute to senescence in CEFs. As well as underscoring the importance of the INK4b-ARF-INK4a locus in senescence, these findings imply that the encoded products have assumed different roles in different evolutionary niches. Although ARF RNA is not detectable in early chicken embryos, the INK4b transcript is expressed in the roof-plate of the developing hind-brain, consistent with a role in limiting cell proliferation.

Animals↗

PubMed2006

IL-32, a proinflammatory cytokine in rheumatoid arthritis.

IL-32 is a recently discovered cytokine that induces TNFalpha, IL-1beta, IL-6, and chemokines. We investigated whether IL-32 is expressed in the synovia of patients with rheumatoid arthritis (RA) and studied associations with disease severity and the presence of other cytokines. Immunohistochemistry revealed that IL-32 is highly expressed in RA synovial tissue biopsies, whereas IL-32 was not observed in synovial tissues from patients with osteoarthritis. Moreover, in synovial biopsies from 29 RA patients with active disease, the level of IL-32 staining correlated with erythrocyte sedimentation rate, a marker of systemic inflammation (R = 0.63 and P < 0.0003). Synovial staining of IL-32 also correlated with indices of synovial inflammation (R = 0.80 and P < 0.0001) as well as synovial presence of TNFalpha (R = 0.68 and P < 0.004), IL-1beta (R = 0.79 and P < 0.0001), and IL-18 (R = 0.82 and P < 0.001). IL-32 was a potent inducer of prostaglandin E(2) release in mouse macrophages and human blood monocytes, an important property for inflammation. After the injection of human IL-32gamma into the knee joints of naïve mice, joint swelling, with pronounced influx of inflammatory cells and cartilage damage, was observed. In TNFalpha-deficient mice, IL-32-driven joint swelling was absent and cell influx was markedly reduced, but loss of proteoglycan was unaffected, suggesting that IL-32 activity is, in part, TNFalpha-dependent. IL-32, strongly associated with TNFalpha, IL-1beta, and IL-18, appears to play a role in human RA and may be a novel target in autoimmune diseases.

Animals↗

PubMed2006

Proteinase 3 is an IL-32 binding protein.

IL-32, a recently discovered proinflammatory cytokine with four isoforms, induces IL-1beta, TNF-alpha, IL-6, and chemokines. Here, we used ligand (IL-32alpha) affinity chromatography in an attempt to isolate an IL-32alpha soluble receptor or binding protein. Recombinant IL-32alpha was covalently immobilized on agarose, and preparations of concentrated crude human urinary proteins were applied for chromatographic separation. A specific 30-kDa protein eluted from the column during acid washing and was identified by mass spectrometry as proteinase 3 (PR3) and confirmed by N-terminal microsequencing. PR3, a neutrophil granule serine protease, exists in a soluble or membrane form and is the major autoantigen for autoantibodies in the systemic vasculitic disease, Wegener's granulomatosis. The affinity of IL-32alpha to PR3 was determined by surface plasmon resonance. The dissociation constants were 2.65 +/- 0.4 nM for urinary PR3 and 1.2 +/- 0.05 nM for neutrophil-derived PR3. However, irreversible inactivation of PR3 enzymatic activity did not significantly change binding to the cytokine. Nevertheless, limited cleavage of IL-32 yielded products consistent with PR3 enzyme activity. Moreover, after limited cleavage by PR3, IL-32alpha was more active than intact IL-32alpha in inducing macrophage inflammatory protein-2 in mouse macrophages and IL-8 in human peripheral blood mononuclear cells. We suggest that PR3 is a specific IL-32alpha binding protein, independent of its enzymatic activity. However, limited cleavage of IL-32alpha by PR3 enhances activities of the cytokine. Therefore, specific inhibition of PR3 activity to process IL-32 or neutralization of IL-32 by inactive PR3 or its fragments may reduce the consequences of IL-32 in immune regulated diseases.

Animals↗

PubMed2006

Symptom experience in Korean patients with liver cirrhosis.

This study was done to examine the level of symptom experience, and symptom variation in relation to demographic and clinical variables, in Korean patients with liver cirrhosis (LC). Symptom experience was measured using a scale developed by the researchers through a literature review on LC. Participants were 129 patients whose mean age was 53.6 (standard deviation [SD] = 9.28) years. The results indicated that (1) overall symptom experience was relatively low (mean 41.67, SD 24.71); (2) the main symptoms needing a management were fatigue, abdominal distension and/or peripheral edema, and muscle cramps; and (3) among the study variables, the severity of LC (P < 0.001) and the number of hospitalizations (P = 0.014) showed a significant relationship with overall symptom experience. These results suggest that symptom assessment requires a multidimensional approach and that it is imperative to consider disease severity in developing tailored symptom management programs for Korean patients with LC.

Adult↗

PubMed2006

Comprehensive analysis of BCR-ABL transcript types in Korean CML patients using a newly developed multiplex RT-PCR.

Diagnosis of chronic myeloid leukemia (CML) is based on the detection of BCR-ABL gene or Philadelphia chromosome (Ph chromosome), and fusion proteins with different sizes are encoded depending on the breakpoint in the BCR gene. In general, 3 breakpoint cluster regions in the BCR gene have been described: major (M-bcr), minor (m-bcr), and micro (mu-bcr). This study was designed to determine the frequency of BCR-ABL transcripts using one-step multiplex reverse transcription polymerase chain reaction (RT-PCR). Bone marrow (BM) or peripheral blood (PB) samples at diagnosis from 548 patients were obtained with a referring diagnosis of Ph-positive (Ph+) CML, and multistep RT-PCR and newly developed one-step multiplex RT-PCR were applied on each sample. Compared with the previous multistep RT-PCR, one-step multiplex RT-PCR with the primers is the more rapid and accurate method to identify the BCR-ABL breakpoints. Most patients (538/548, 98.18%) were found to have b3a2 or b2a2, and total frequency of occurrence of c3a2, e1a2, b2a3, b1a1, and e1a3 or coexpression of b2a2 and b3a2 was less than 2.00%. No differences were observed between women and men. As the multiplex RT-PCR technique distinguishes BCR-ABL transcripts in all samples with high sensitivity and specificity, it easily could be applied at early stages of diagnosis. The incidence of one or the other rearrangement in CML patients varies in different reported series, and the frequency in each type of BCR-ABL transcript in Korean CML patients seems to be different from those of Western countries.

Base Sequence↗

PubMed2006

Mycobacterium tuberculosis induces interleukin-32 production through a caspase- 1/IL-18/interferon-gamma-dependent mechanism.

BACKGROUND: Interleukin (IL)-32 is a newly described proinflammatory cytokine that seems likely to play a role in inflammation and host defense. Little is known about the regulation of IL-32 production by primary cells of the immune system. METHODS AND FINDINGS: In the present study, freshly obtained human peripheral blood mononuclear cells were stimulated with different Toll-like receptor (TLR) agonists, and gene expression and synthesis of IL-32 was determined. We demonstrate that the TLR4 agonist lipopolysaccharide induces moderate (4-fold) production of IL-32, whereas agonists of TLR2, TLR3, TLR5, or TLR9, each of which strongly induced tumor necrosis factor alpha and IL-6, did not stimulate IL-32 production. However, the greatest amount of IL-32 was induced by the mycobacteria Mycobacterium tuberculosis and M. bovis BCG (20-fold over unstimulated cells). IL-32-induced synthesis by either lipopolysaccharide or mycobacteria remains entirely cell-associated in monocytes; moreover, steady-state mRNA levels are present in unstimulated monocytes without translation into IL-32 protein, similar to other cytokines lacking a signal peptide. IL-32 production induced by M. tuberculosis is dependent on endogenous interferon-gamma (IFNgamma); endogenous IFNgamma is, in turn, dependent on M. tuberculosis-induced IL-18 via caspase-1. CONCLUSIONS: In conclusion, IL-32 is a cell-associated proinflammatory cytokine, which is specifically stimulated by mycobacteria through a caspase-1- and IL-18-dependent production of IFNgamma.

Caspase 1↗

PubMed2006

Mental health of healthcare workers who experience needlestick and sharps injuries.

Healthcare workers (HCWs) are exposed daily to the risk of injury by needlesticks and other medical instruments. However, the psychiatric impacts of such injuries have not been evaluated. The aim of this study was to evaluate the mental health status of HCWs with experiences of needlestick and sharps injuries. A cross-sectional written survey was performed. The psychological symptoms before injury and current status were measured using the Beck Depression Inventory (BDI), Hamilton Anxiety Scale (HAM-A) and Perceived Stress Scale (PSS). The proportions of HCWs with and without needlestick and sharps injuries were 71.1% (n=263) and 28.9% (n=107), respectively. HAM-A and BDI scores were significantly higher among HCWs with injury experiences (p<0.01). HCWs with injury experiences exhibited higher PSS and BDI scores after the injury and higher levels of anxiety and depression. Particular attention should be directed towards the psychological consequences of needlestick and sharps injuries in HCWs.

Adult↗

PubMed2006

[Association of anger expression patterns and health status in health care workers].

PURPOSE: The purpose of this study was to examine anger-expression patterns and their association with state and trait anger and physical and psychological health status in health care workers. METHOD: Four hundred and forty eight nurses, physicians and technicians from a large medical center completed standardized questionnaires of anger, anger-expression patterns and mood. They also had blood pressure, cholesterol, blood glucose and body mass index measured during their annual physical examinations. Data was analyzed using descriptive statistics, independent t-test, chi-square and ANOVA. RESULTS: Subjects showed two major clusters of anger-expression patterns: anger-control and anger-in/out. Subjects with the anger-in/out pattern reported higher state and trait anger and more anxiety, depression and fatigue than subjects with the anger-control pattern. Physical health indicators, however, were not significantly different between the two clusters of anger-expression patterns. CONCLUSION: Anger-expression patterns are associated with psychological health status but not with physical health status. Anger-expression patterns, however, need to be examined over time to assess their long-term effects on the physical and psychological health status in future studies.

Adult↗

PubMed2005

IL-32 synergizes with nucleotide oligomerization domain (NOD) 1 and NOD2 ligands for IL-1beta and IL-6 production through a caspase 1-dependent mechanism.

The activation of innate immunity requires the amplification of signals induced by pattern-recognition receptors for bacterial products. We have investigated the role of the newly described cytokine IL-32 in the amplification of cytokine production induced by the two most clinically relevant families of microbial receptors, the cell-surface Toll-like receptors (TLRs) and the intracellular nuclear oligomerization domain (NOD) receptor family. IL-32 synergized with the NOD1- and NOD2-specific muropeptides of peptidoglycans for the release of IL-1beta and IL-6 (a 3- to 10-fold increase). In contrast, IL-32 did not influence the cytokine production induced via TLRs. The synergistic effect of IL-32 and synthetic muramyl dipeptide (MDP) on cytokine production was absent in the cells of patients with Crohn's disease bearing the NOD2 frameshift mutation 3020insC, demonstrating that the IL-32/MDP synergism depends on NOD2. This in vitro synergism between IL-32 and NOD2 ligands was consistent with a marked constitutive expression of IL-32 in human colon epithelial tissue. In addition, the potentiating effect of IL-32 on the cytokine production induced by the synthetic muropeptide FK-156 was absent in NOD1-deficient macrophages, supporting the interaction between IL-32 and NOD1 pathways. When specific caspase inhibitors were used, the synergism between IL-32 and MDP/NOD2 depended on the activation of caspase 1. Only additive effects of IL-32 and muropeptides were observed for TNF-alpha production. The modulation of intracellular NOD2 pathways by IL-32, but not cell-surface TLRs, and the marked expression of IL-32 in colon mucosa suggest a role of IL-32 in the pathogenesis of Crohn's disease.

Acetylmuramyl-Alanyl-Isoglutamine↗

PubMed2005

Human AP endonuclease suppresses DNA mismatch repair activity leading to microsatellite instability.

The multifunctional mammalian apurinic/apyrimidinic (AP) endonuclease (APE) participates in the repair of AP sites in the cellular DNA as well as participating in the redox regulation of the transcription factor function. The function of APE is considered as the rate-limiting step in DNA base excision repair. Paradoxically, an unbalanced increase in APE protein leads to genetic instability. Therefore, we investigated the mechanisms of genetic instability that are induced by APE. Here, we report that the overexpression of APE protein disrupts the repair of DNA mismatches, which results in microsatellite instability (MSI). We found that expression of APE protein led to the suppression of the repair of DNA mismatches in the normal human fibroblast cells. Western blot analysis revealed that hMSH6 protein was markedly reduced in the APE-expressing cells. Moreover, the addition of purified Mutalpha (MSH2 and MSH6 complex) to the extracts from the APE-expressing cells led to the restoration of mismatch repair (MMR) activity. By performing MMR activity assay and MSI analysis, we found that the co-expression of hMSH6 and APE exhibited the microsatellite stability, whereas the expression of APE alone generated the MSI-high phenotype. The APE-mediated decrease in MMR activity described here demonstrates the presence of a new and highly effective APE-mediated mechanism for MSI.

Base Pair Mismatch↗

PubMed2005

IL-18 E42A mutant is resistant to the inhibitory effects of HPV-16 E6 and E7 oncogenes on the IL-18-mediated immune response.

Our previous studies showed that the down-modulation of IL-18-induced immune response caused by oncoproteins E6 and E7 as one of the mechanisms underlying immune escape in HPV-induced cervical cancer cells. E42 residue of IL-18 also appears to be critical in the activity of IL-18. Single point mutation E42 in IL-18 show promise in the study of IL-18 binding motifs for HPV oncoproteins. We attempted to ascertain whether site-specific IL-18 mutant E42A would modulate the inhibitory effects of IL-18-induced immune responses via the HPV 16 E6 and E7 oncoproteins. Compared to wild type IL-18, E42A-induced IFN-gamma production was not inhibited by HPV 16 E6 and E7. In vitro and in vivo binding assays have also revealed that E6 and E7 do not result in the inhibition of the binding of E42A to its IL-18 receptor alpha chain. There were no effects on the E42A-induced phosphorylations of p38 and JNK observed in the presence of E6 or E7. The degradation of IkappaB by E42A was not affected by E6 or E7 in NK0 cells. Moreover, E42A-induced NF-kappaB activation was also not inhibited by these oncoproteins. These results suggest that E42A is a stronger activator than wild type IL-18, and is not susceptible to inhibition by the HPV oncoproteins E6 and E7. Thus, it is suggested that E42A could be used in immunotherapy for patients with cervical cancer.

Cell Line, Tumor↗

PubMed2005

Cadmium down-regulates human OGG1 through suppression of Sp1 activity.

Cadmium is a well known human and animal carcinogen and is a ubiquitous contaminant in the environment. Although the carcinogenic mechanism of cadmium is a multifactorial process, oxidative DNA damage is believed to be of prime importance. In particular, cadmium suppresses the capacity of cells to repair oxidative DNA damage. In this study, cadmium treatment led to a significant increase in gamma-ray-induced 8-oxoguanine (8-oxoG) formation. Western blotting and semiquantitative reverse transcription-PCR revealed that cadmium treatment caused a decrease in the expression level of human OGG1 (8-oxoguanine-DNA glycosylase-1; hOGG1) in human fibroblast GM00637 and HeLa S3 cells. In addition, the cadmium-mediated decrease in hOGG1 transcription was the result of decreased binding of the transcription factor Sp1 to the hOGG1 promoter. Finally, we show that an increase in the functional hOGG1 expression level could inhibit the cadmium-mediated increase in gamma-ray-induced 8-oxoG accumulation as well as in gamma-radiation-induced mutation frequency at the HPRT (hypoxanthine-guanine phosphoribosyltransferase) gene locus. These results suggest that cadmium attenuates removal of gamma-ray-induced 8-oxoG adducts, which in turn increases the mutation frequency, and that this effect might, at least in part, result from suppression of hOGG1 transcription via inactivation of Sp1 as a result of cadmium treatment.

Animals↗