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Biomedical subjects

P K Kim

Publications and source records attributed to P K Kim.

At least 19 recordsLinked to original sources
PubMed2001

Nitric oxide suppresses the expression of Bcl-2 binding protein BNIP3 in hepatocytes.

Nitric oxide (NO) is not only an important signaling molecule, but it also regulates the expression of a number of genes in the liver. We have previously shown that apoptosis in hepatocytes exposed to tumor necrosis factor-alpha and actinomycin D is prevented by NO derived from the inducible nitric-oxide synthase (iNOS), by mechanisms that are both dependent on and independent of modulation of cyclic guanosine monophosphate (cGMP) subsequent to activation of soluble guanylyl cyclase (sGC). We hypothesize that one mechanism by which NO exerts these effects is by regulating the expression of genes involved in apoptosis. We used differential display-polymerase chain reaction to isolate NO-regulated genes in hepatocytes from iNOS knockout mice (to eliminate endogenous inducible NO production). Using this analysis, we identified a NO-suppressed gene fragment homologous with the pro-apoptotic Bcl-2 binding protein BNIP3. Northern analysis confirmed the NO-dependent suppression of BNIP3 in cultured cells. Similarly, the NO donor S-nitroso-N-acetyl-dl-penicillamine (1-1000 microm) down-regulated the expression of BNIP3 in both iNOS knockout and wild-type hepatocytes. This effect of NO was reversed by the sGC inhibitor 1H-(1,2,4)-oxadiazole[4,3-a]quinoxalon-1-one (ODQ),suggesting the involvement of the sGC/cGMP pathway in the modulation of BNIP3 by NO. We propose that suppression of BNIP3 expression is one sGC/cGMP-dependent mechanism by which NO might affect the process of hepatocyte apoptosis.

Adenoviridae↗
PubMed2001

The regulatory role of nitric oxide in apoptosis.

Nitric oxide (NO) is a multi-faceted molecule with dichotomous regulatory roles in many areas of biology. The complexity of its biological effects is a consequence of its numerous potential interactions with other molecules such as reactive oxygen species (ROS), metal ions, and proteins. The effects of NO are modulated by both direct and indirect interactions that can be dose-dependent and cell-type specific. For example, in some cell types NO can promote apoptosis, whereas in other cells NO inhibits apoptosis. In hepatocytes, NO can inhibit the main mediators of cell death-caspase proteases. Moreover, low physiological concentrations of NO can inhibit apoptosis, but higher concentrations of NO may be toxic. High NO concentrations lead to the formation of toxic reaction products like dinitrogen trioxide or peroxynitrite that induce cell death, if not by apoptosis, then by necrosis. Long-term exposure to nitric oxide in certain conditions like chronic inflammatory states may predispose cells to tumorigenesis through DNA damage, inhibition of DNA repair, alteration in programmed cell death, or activation of proliferative signaling pathways. Understanding the regulatory mechanisms of NO in apoptosis and carcinogenesis will provide important clues to the diagnosis and treatment of tissue damage and cancer. In this article we have reviewed recent discoveries in the regulatory role of NO in specific cell types, mechanisms of pro-apoptotic and anti-apoptotic induction by NO, and insights into the effects of NO on tumor biology.

Animals↗
PubMed2001

The role of caspase-8 in resistance to cancer chemotherapy.

Toxicity of chemotherapeutic agents against cancer cells is mediated through the initiation of programmed cell death. Apoptosis is an evolutionarily conserved cascade of intracellular proteolytic events propagated by a family of cysteine proteases called caspases. Many receptor- and non-receptor-mediated death signals induce apoptosis via activation of caspase-8 (FLICE/MACH). Mechanisms of tumor resistance to cytotoxic drugs through decreased apoptosis may occur by altered expression of caspase-8, upregulation of caspase-8 inhibitors like FLIP (FLICE-like Inhibitory Protein), or sequestration of caspase-8 by Bcl-2. Modulation of caspase-8 and apoptosis may be a therapeutic strategy for sensitization of drug-resistant malignancies to radiation or combination chemotherapy.

Animals↗
PubMed2001

Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats.

Sepsis is the leading cause of death in surgical intensive care units. Although both mild sepsis secondary to cecal ligation and single puncture (CLP) and fulminant, double puncture CLP (2CLP) may provoke hepatocyte death, we hypothesize that regeneration compensates for cell death after CLP but not 2CLP. In male Sprague-Dawley rats, hepatic necrosis, as determined by serum alpha-glutathione S-transferase (alpha-GST) levels, was significantly but equally elevated over time after both CLP and 2CLP. Apoptosis, evaluated using both terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and morphological examination, was minimal after both CLP and 2CLP. Regeneration, assayed by staining tissue for incorporation of exogenously administered bromodeoxyuridine, was present after CLP but not after 2CLP. To further substantiate impaired regeneration, steady-state levels of mRNAs encoding JunB, LRF-1, and cyclin D1 were determined. After 2CLP, the absence of JunB, LRF-1, and cyclin D1 mRNAs confirmed failed activation of the mitogen-activated protein kinase-linked proliferative pathway and progression through the cell cycle. Therefore, failed hepatocyte regeneration may be a manifestation of hepatic dysfunction in fulminant sepsis.

Activating Transcription Factor 3↗
PubMed2001

An analysis of 4,514 cases of renal biopsy in Korea.

To evaluate the distribution and changing patterns of renal diseases in Korea, a total of 4,514 cases of renal biopsy collected over a 23-year period between 1973 and 1995 were reviewed. Of 4,200 cases excluding 314 unsatisfactory biopsies, adult cases comprised 59.5% and pediatric cases, 40.5%. The male to female ratio was 1.5:1 in adults and 2.2:1 in children. Glomerulonephritis (GN) comprised 80.0% of the total. The most common primary GN in adults was minimal change disease (MCD) (26.6%), followed by IgA nephropathy (IgAN) (22.1%), membranous GN (MGN) (11.8%), and membranoproliferative GN (MPGN) (5.9%). In children, the primary GN incidence rates were MCD (24.8%), IgAN (10.3%), poststreptococcal (including postinfectious) GN (PSGN) (8.6%), and focal segmental glomerulosclerosis (FSGS) (4.0%). The most common secondary GN in adults was lupus nephritis and in children Henoch-Schonlein purpura nephritis. The most common cause of nephrotic syndrome was MCD in both adults and children, followed by MGN and FSGS. The elderly, aged sixty years and older, comprised 2.7% of cases and recorded equal numbers of MCD and MGN. The proportion of the biopsies found to be seropositive for HBs antigen was 27.9%, and these showed either MGN or MPGN pattern. Repeat biopsy was performed in 168 patients, due to previous biopsy failure in 15.5%. When the primary GN cases were analyzed at 5-year intervals, the prevalence of PSGN, which was greater than 25% during the 1973-1982 period, decreased abruptly in children thereafter, whereas the prevalence of FSGS increased slowly since the 1988-1992 period in both adults and children. The decrease of PSGN and the increase of FSGS suggest a role for socioeconomic and environmental factors in Korea.

Adult↗
PubMed2001

Glomerular growth under cyclosporine treatment in childhood nephrotic syndrome.

BACKGROUND: Glomerular hypertrophy is important in children with idiopathic nephrotic syndrome in regard to diagnosis and pathogenesis. Moreover, glomerular growth may be altered by cyclosporine (CsA) treatment in these patients. METHODS: Bowman's area (BA) and the glomerular tuft area (GA) of pre- and post-treatment biopsies was measured by morphometry in 47 children with idiopathic nephrotic syndrome (39 MCD and 8 FSGS) treated with CsA and low-dose prednisolone for up to 2 years. RESULTS: BA and GA increased with age. The mean BA and GA were 1.2 times larger in FSGS than in MCD and the proportional increase was similar in both diseases after treatment. BA and GA decreased in 48.9% and 40.4% of cases after treatment, respectively, whereas tubulointerstitial lesion (TIL) developed in 27.7%. BA and GA decreased to 10.4% and 8.3%, respectively in children who developed TIL after treatment and the values were largely unchanged in those treated for more than 16 months. CONCLUSIONS: Glomerular growth is hampered by CsA nephrotoxicity, which is a more common complication than TIL. The impairment of glomerular growth is related to the duration of treatment and the development of TIL, but not to age or diagnosis.

Child↗
PubMed2000

Paclitaxel-induced apoptosis in non-small cell lung cancer cell lines is associated with increased caspase-3 activity.

OBJECTIVE: Our objective was to determine whether paclitaxel-induced apoptosis in human lung cancer cells is Fas dependent. METHODS: Human lung cancer cell lines were evaluated for morphologic evidence of apoptosis, DNA fragmentation (TUNEL positivity), and caspase-3 activation after paclitaxel treatment. Human lung adenocarcinoma, squamous cell carcinoma, undifferentiated lung carcinoma, and bronchoalveolar carcinoma cell lines were each cultured in 10 micromol/L paclitaxel. RESULTS: After 24 hours of culture in paclitaxel, a 22% to 69% increase in the number of apoptotic cells was evident by means of methylene blue-azure A-eosin staining with characteristic blebbing and nuclear condensation. TUNEL assay also confirmed an increase of 19.9% to 73.0% of cells with nuclear fragmentation. Caspase-3 activity, assayed by Z-DEVD cleavage, increased from 20% to 215% (P <.05). ZB4, an antagonistic anti-Fas antibody, did not block paclitaxel induction of caspase-3 activity (155.8 vs 165.8 U, not significant). Apoptotic morphologic changes were inhibited in cells cultured in the presence of paclitaxel and Ac-DEVD-CHO, a caspase-3 inhibitor. CONCLUSIONS: Paclitaxel induces apoptosis in lung cancer cell lines, as assessed by a consistent increase in caspase-3 activity, DNA laddering, and characteristic morphologic changes. Paclitaxel-induced apoptosis in human lung cancer cells is associated with caspase-3 activation but is not Fas dependent.

Antineoplastic Agents, Phytogenic↗
PubMed2000

Inflammatory responses and mediators.

The host response to injury is usually appropriate in degree and is self-limited. In more severe injury, the host response may persist inappropriately, leading to SIRS and MODS and possibly multiple organ failure. The initial response to injury is mediated primarily by norepinephrine, and is directed toward preservation of circulation to the heart and brain at the expense of other vascular beds. If fluid resuscitation is adequate and necrotic tissue is débrided, a hypermetabolic state ensues, mediated by epinephrine and directed toward supporting repair of injured tissue by leukocytes. Inflammatory cells are recruited to the site of injury and elaborate cytokines, which promote repair locally, but in severe injury may be systemically released and trigger remote inflammation. Cytokine biology presently is poorly understood, and simple anticytokine strategies have failed to improve survival of critically ill patients. Current therapy of SIRS and MODS is directed toward symptoms. Presently, it is unclear how an abnormal stress response arises. Cytokine spillover into the systemic circulation may occur. Selective transcriptional failure may be the cellular basis of organ dysfunction. Inappropriate production of peroxynitrite or its precursor, NO, is implicated in mediating cellular injury in SIRS and MODS.

Adrenergic alpha-Agonists↗
PubMed2000

Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats.

Hepatic dysfunction in sepsis is characterized by hyperbilirubinemia and intrahepatic cholestasis. We hypothesize that sepsis causes decreased hepatic transcription of the bile acid transporter sodium taurocholate cotransporter (Ntcp) and the organic anion transporter multidrug resistance-associated protein (Mrp2) and that interleukin (IL)-6 is important in the down-regulation of Ntcp and Mrp2 expression. Male Sprague-Dawley rats underwent induction of mild, nonlethal sepsis by cecal ligation and single puncture (CLP) or fulminant sepsis by cecal ligation and double puncture (2CLP). Hepatic transcription of Ntcp and Mrp2 rapidly decreased after CLP or 2CLP. Seventy-two hours later, transcription was 60% of baseline in CLP and 14% of baseline in 2CLP. Serum bilirubin was elevated from 24 h onward and cholestasis was observed on fixed liver specimens at 24, 48, and 72 h after 2CLP but not after CLP. Steady-state Ntcp and Mrp2 mRNA was decreased in IL-6-treated cultured hepatocytes and in normal rats given 1 mg/kg intravenous IL-6. We conclude that 1) Ntcp and Mrp2 transcription is down-regulated transiently after CLP and persistently after 2CLP; 2) 2CLP results in hyperbilirubinemia and cholestasis, in part due to persistently decreased transcription of Ntcp and Mrp2; and 3) altered Ntcp and Mrp2 transcription is mediated in part by IL-6.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

Identification of the endoplasmic reticulum targeting signal in vesicle-associated membrane proteins.

The vesicle-associated membrane proteins (Vamp(s)) function as soluble N-ethylmaleimide-sensitive factor attachment receptor proteins in the intracellular trafficking of vesicles. The membrane attachment of Vamps requires a carboxyl-terminal hydrophobic sequence termed an insertion sequence. Unlike other insertion sequence-containing proteins, targeting of the highly homologous Vamp1 and Vamp2 to the endoplasmic reticulum requires ATP and a membrane-bound receptor. To determine if this mechanism of targeting to the endoplasmic reticulum extends to other Vamps, we compared the membrane binding of Vamp1 and Vamp2 with the distantly related Vamp8. Similar to the other Vamps, Vamp8 requires both ATP and a membrane component to target to the endoplasmic reticulum. Furthermore, binding curves for the three Vamps overlap, suggesting a common receptor-mediated process. We identified a minimal endoplasmic reticulum targeting domain that is both necessary and sufficient to confer receptor-mediated, ATP-dependent, binding of a heterologous protein to microsomes. Surprisingly, this conserved sequence includes four positively charged amino acids spaced along an amphipathic sequence, which unlike the carboxyl-terminal targeting sequence in mitochondrial Vamp isoforms, is amino-terminal to the insertion sequence. Because Vamps do not bind to phospholipid vesicles, it is likely that these residues mediate an interaction with a protein, rather than bind to acidic phospholipids. Therefore, we suggest that a bipartite motif is required for the specific targeting and integration of Vamps into the endoplasmic reticulum with receptor-mediated recognition of specifically configured positive residues leading to the insertion of the hydrophobic tail into the membrane.

Adenosine Triphosphate↗
PubMed1999

Pediatric peritoneal dialysis in Korea: practical solutions to the problems of peritoneal dialysis for children.

PURPOSE: To find and solve the common problems of peritoneal dialysis (PD) by analyzing the clinical data of pediatric PD performed in Korea. METHODS: We looked at 264 cases of continuous ambulatory peritoneal dialysis (CAPD) and acute PD that were performed in 18 institutions of pediatric nephrology in Korea from November 1987 to October 1997. RESULTS: CAPD was performed in 114 cases. The mean age of the patients was 10.5+/-6.6 years, and the male-to-female ratio was 1.4:1. The original causes of end-stage renal disease (ESRD) were proven in 92 cases (81%). The most common renal diseases were focal segmental glomerulosclerosis (17%), reflux nephropathy (11%), and chronic glomerulonephritis (11%). Mean duration of CAPD was 20 months+/-16.9 months. Peritonitis was the most common complication, and the peritonitis incidence was 0.96 episode per patient-year. Other complications were exit-site infection in 10 cases, obstruction in 7 cases, and leakage of dialysate in 6 cases. The most common etiologic organism of peritonitis was Staphylococcus aureus and the next most common was coagulase-negative staphylococcus. Acute PD was performed in 150 cases. The most common underlying causes were congenital heart disease, hemolytic uremic syndrome, sepsis, and dehydration. The mean duration was 10.3+/-11.3 days. The most common complication was peritonitis (78.3%). The most common etiologic organisms of peritonitis were Staphylococcus aureus, coag-neg staphylococcus, Acinetobacter, and Pseudomonas. CONCLUSION: Reflux nephropathy should be emphasized in early diagnosis and treatment to prevent ESRD. Incidence of congenital anomaly (7%) as a original cause of ESRD was relatively low in Korea. Growth status was not significantly improved after CAPD. In acute PD, the incidence of peritonitis rapidly increased at 2 weeks after the start of dialysis.

Adolescent↗
PubMed1998

Analysis of the envelope region of hepatitis G virus isolated from Korean patients.

The genetic diversity of hepatitis G virus (HGV) was investigated. By using a RT-PCR procedure, 14% of either HBV (hepatitis B virus)- or HCV (hepatitis C virus)-positive Korean hepatitis patients were proved to be HGV positives. Nucleotide sequences in the E1 region of the eight isolates from Korean patients and the six previously reported isolates were compared. Nucleotide substitutions spread uniformly throughout the E1 region. Sequence homology among the Korean isolates was 84-99% and 88-99% at the nucleotide and amino acid sequences, respectively, whereas those from different geographic areas was slightly lower at both levels. At least two genotypes might exist among the Korean HGV isolates. Compared to the corresponding region of HCV, the E1 sequence from HGV is moderately conserved. In addition, as frameshift mutations were observed in most of the Korean isolates compared to the prototype HGV sequence, the Korean isolates might not use the translational initiation site of the prototype HGV for polyprotein translation. Because a putative signal sequence of E1 for entry into endoplasmic reticulum starts from the N-terminus of the polyprotein, and capsid-like peptides composed of basic amino acids could not be detected from the upstream region of E1, the core protein of HGV is absent, or at least not present, at the region next to 5'-UTR. Therefore, HGV could be clearly distinguished from other genera of Flaviviridae.

Amino Acid Sequence↗
PubMed1997

Evidence for multiple mechanisms for membrane binding and integration via carboxyl-terminal insertion sequences.

Subcellular localization of proteins with carboxyl-terminal insertion sequences requires the molecule be both targeted to and integrated into the correct membrane. The mechanism of membrane integration of cytochrome b5 has been shown to be promiscuous, spontaneous, nonsaturable, and independent of membrane proteins. Thus endoplasmic reticulum localization for cytochrome b5 depends primarily on accurate targeting to the appropriate membrane. Here direct comparison of this mechanism with that of three other proteins integrated into membranes via carboxyl-terminal insertion sequences [vesicle-associated membrane protein 1(Vamp1), polyomavirus middle-T antigen, and Bcl-2] revealed that, unlike cytochrome b5, membrane selectivity for these molecules is conferred at least in part by the mechanisms of membrane integration. Bcl-2 membrane integration was similar to that of cytochrome b5 except that insertion into lipid vesicles was inefficient. Unlike cytochrome b5 and Bcl-2, Vamp1 binding to canine pancreatic microsomes was saturable, ATP-dependent, and abolished by mild trypsin treatment of microsomes. Surprisingly, although the insertion sequence of polyomavirus middle-T antigen was sufficient to mediate electrostatic binding to membranes, binding did not lead to integration into the bilayer. Together these results demonstrate that there are at least two different mechanisms for correct membrane integration of proteins with insertion sequences, one mediated primarily by targeting and one relying on factors in the target membrane to mediate selective integration. Our results also demonstrate that, contrary to expectation, hydrophobicity is not sufficient for insertion sequence-mediated membrane integration. We suggest that the structure of the insertion sequence determines whether or not specific membrane-bound receptor proteins are required for membrane integration.

Adenosine Triphosphate↗
PubMed1997

Long-term results of cyclosporine-induced remission of relapsing nephrotic syndrome in children.

Twenty-nine children with nephrotic syndrome were treated with cyclosporine (CsA), 100 mg/m2/day for 6 months and prednisone, 2 mg/kg every other day for 1 month and then subsequently 1 mg/kg every other day for 5 months. A renal biopsy had shown minimal change disease (MCD) in 18 children, focal segmental glomerulosclerosis (FSGS) in 3 children, membranous glomerulonephritis (MGN) in 4 children, membranoproliferative glomerulonephritis (MPGN) in 2 children, and IgA nephropathy in 2 children. All MCD patients went into complete remission during therapy. Five out of 11 steroid-sensitive patients (45.5%) remained in complete remission, while the remaining 6 (54.5%) had 2 to 3 relapses, 19 to 47 months after CsA discontinuation. Two out of 7 steroid-resistant patients (28.6%) were still in complete remission and 5 (71.4%) had 1 to 6 relapses 25 to 49 months after CsA withdrawal. The mean number of relapses in the steroid-sensitive group before and after CsA treatment decreased more (8.5 vs 1.4) than in the steroid-resistant group (8.1 vs 2.4) (p < 0.05). At the most recent examination, 1 of 3 FSGS patients achieved complete remission and 2 had a partial response. Three of 4 MGN patients were in complete remission and 1 was in partial remission. One of 2 MPGN patients achieved complete remission and 1 showed partial remission. Two patients with IgA nephropathy were in partial remission. We compared MCD patients in sustained remission and relapse; the mean CD4/CD8 ratio decreased from 1.5 to 0.9 in the remission group, in comparison with no change in the relapsed group (p < 0.05). The posttreatment renal biopsy showed lesions of nephrotoxicity in 3 of 18 children with MCD whose renal function did not alter after CsA treatment. We concluded: 1) A 6-month treatment of CsA, in combination with a low-dose alternate-day steroid, proved to be effective in maintaining the remission of steroid-sensitive and steroid-resistant MCD patients. 2) The CD4/CD8 ratio can be used as a index to predict remission or relapse after CsA therapy.

Adolescent↗
PubMed1997

Results of kidney transplantation from 1979 to 1997 at Yonsei University.

1. Long-term graft survival markedly improved after the introduction of CsA as the main immunosuppressant in living-donor kidney transplantation at our institution. 2. HLA-identical LRD kidney transplantation provided the best long-term graft survival rate, probably due to a decreased incidence of graft loss from rejection. 3. We could achieve good long-term graft survival in LURD kidney transplantation compared with that of HLA-haploidentical LRD kidney transplantation. 4. Because of the striking discrepancy between organ donation and the increasing demand for transplantation, distant relative donors and LURDs, including swap donors, should be considered as an alternative way to increase the number of available donors when accompanied by a careful evaluation process.

Adolescent↗
PubMed1996

Genomic structure and mapping of human FADD, an intracellular mediator of lymphocyte apoptosis.

Fas-associated death domain protein (FADD)/MORT1 is a 23-kDa cytoplasmic protein containing a C-terminal death domain that interacts with the intracellular death domain of the Fas transmembrane receptor. Cross-linking of Fas mediates apoptosis in a variety of cells, primarily peripheral T lymphocytes, for which this pathway plays a major role in mature lymphocyte homeostasis. We report the characterization of the human FADD gene, which spans approximately 3.6 kb and contains two exons (286 and 341 bp) separated by a 2.0-kb intron. FADD was mapped to chromosome 11q13.3 by the independent techniques of PCR screening of somatic cell hybrid mapping panels and fluorescence in situ hybridization. In addition FADD was shown by fluorescence in situ hybridization to be amplified along with other 11q13.3 genes previously studied in the breast cancer cell line MDA-MB-134-VI, raising the possibility that overexpression of mutant FADD could contribute to poor prognosis and increased invasiveness of tumors. Its known role in apoptosis has made FADD a candidate susceptibility gene for autoimmune lymphoproliferative syndrome. Now that it has been colocalized in 11q13.3 with IDDM4, a diabetes susceptibility locus, alterations in FADD should also be considered as potential contributors to insulin-dependent familial diabetes. Elucidation of the map position and gene structure of FADD will make possible linkage and mutation analysis to study the role of this gene in human diseases.

Adaptor Proteins, Signal Transducing↗