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Biomedical subjects

S Kim

Publications and source records attributed to S Kim.

At least 883 records · Page 49Linked to original sources
PubMed1996

Angiotensin II and calcium blockers prevent glomerular phenotypic changes in remnant kidney model.

Recent studies on various models of glomerular diseases indicate that glomerular injury is associated with the phenotypic modulation of glomerular cells. However, the effect of renoprotective agents on glomerular phenotype remains to be determined. This study examined the effects of angiotensin II Type 1 (AT1) receptor antagonists and calcium antagonists on glomerular phenotypic changes in rats with subtotal renal ablation. Rats were subjected to 5/6 nephrectomy and were given oral TCV-116, a selective AT1 receptor antagonist (1 mg/kg), manidipine, a dihydropyridine calcium antagonist (3 mg/kg), or vehicle for 8 wk. Glomerular phenotypic modulation was determined by the staining of alpha-smooth muscle actin and desmin in glomerular cells with an immunohistochemical technique. At the start of drug treatment, alpha-smooth muscle actin and desmin were already significantly expressed in the glomerular cells of 5/6-nephrectomized rats, in contrast to a negligible glomerular expression of these proteins in sham-operated rats. Treatment of 5/6-nephrectomized rats with TCV-116 or manidipine significantly decreased glomerular expression of alpha-smooth muscle actin and desmin, thereby indicating that these drugs prevented glomerular phenotypic changes in 5/6-nephrectomized rats. Furthermore, their inhibitory effects on glomerular phenotypic modulation were associated with the prevention of glomerular cell proliferation, hypertrophy, and sclerosis. Therefore, this study provides the first evidence that the renoprotection is linked to the prevention of glomerular phenotypic modulation and supports the idea that this phenotypic modulation may serve as an important cellular marker of glomerular injury.

Actins↗
PubMed1996

Augmented contractile function and abnormal Ca2+ handling in the aorta of Zucker obese rats with insulin resistance.

To investigate the role of hyperinsulinemia/insulin resistance in vasomotor tone regulation, we studied the effects of vasoactive substances on tension and intracellular free calcium concentration ([Ca2+]i) of aortic smooth muscle derived from rats that were made hyperinsulinemic by insulin infusion and from Zucker obese rats with insulin resistance. The tension and [Ca2+]i of fura 2-loaded aortic strip preparations without endothelium were simultaneously measured by using a fluorimeter. Ten male Wistar rats received a continuous subcutaneous infusion of insulin (18 nmol x kg(-1) x day(-1)) for 2 weeks with osmotic minipumps (INS group). A control group of 10 rats received vehicle. The plasma immunoreactive insulin concentration in the INS group increased to 930 +/- 54 pmol/l. The increase in [Ca2+]i and tension by KCl and phenylephrine (PE) were lower in the INS group without alteration of the [Ca2+]i-tension relationship. The responses to serotonin (5-HT) in the INS group were similar to those in the control group. In contrast, responses to KCl, PE and 5-HT were markedly enhanced in Zucker obese rats compared with those in Zucker lean rats. The pretreatment of aortic preparations from lean rats with Bay K8644 significantly enhanced the responses to KCl to the level observed in the preparations from obese rats; however, Bay K 8644 failed to affect the responses to KCl in obese rats. These results suggest that enhanced vascular contractile responses to vasoactive substances, possibly due to altered function of the voltage-dependent Ca2+ channel in vascular smooth muscle, may play an important role in the pathogenesis of hypertension in the insulin resistance syndrome.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Edema from intracerebral hemorrhage: the role of thrombin.

The mechanism by which intracerebral hemorrhage leads to the formation of brain edema is unknown. This study assesses the components of blood to determine if any are toxic to surrounding brain. Various solutions were infused stereotactically into the right basal ganglia of rats. The animals were sacrificed 24 hours later; brain edema and ion contents were measured. Whole blood caused an increase in brain water content and ion changes consistent with brain edema. Concentrated blood cells, serum from clotted blood, and plasma from unclotted blood all failed to provoke edema formation when infused directly into the brain. On the other hand, activation of the coagulation cascade by adding prothrombinase to plasma did produce brain edema. The edema response to whole blood could be prevented by adding a specific thrombin inhibitor, hirudin, to the injected blood. This study indicates that thrombin plays an important role in edema formation from an intracerebral blood clot.

Animals↗
PubMed1996

Antiproliferative effects of low-dose micronized progesterone.

OBJECTIVE: To study the pharmacodynamic effects of oral micronized P on endometrial maturation. DESIGN: This was a controlled, open, parallel group, pilot study. SETTING: The experiment was performed in an outpatient academic clinical research unit. PATIENTS: Twelve healthy, P-challenged, estrogen-primed, postmenopausal women participated in the study. INTERVENTIONS: Patients were given 300 mg micronized P daily (8:00 A.M.) or twice (8:00 A.M. and 4:00 P.M.) daily from study days 1 through 14 after estrogen priming for 30 days. Blood samples were taken at 0, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 hours after the 8:00 A.M. dose on study day 1 and 14 and again at 8:00 and 9:30 A.M. on days 3 and 5 fasting, days 7 and 9 after a fatty meal, and day 11 after a high fiber meal. Endometrial biopsies were taken on day 1 and 14. MAIN OUTCOME MEASURES: Progesterone concentrations were measured. Endometrial biopsies were studied for effects on histology, glycogen content of glands, ribosomal RNA, and nuclear estrogen receptors in glands, surface epithelium, and stroma. RESULTS: Day 1 and 14 P kinetics were similar for 8 hours. Dose-dependent increases in glandular glycogen, decrease in ribosomal RNA, and decrease in nuclear estrogen receptors were demonstrated. CONCLUSIONS: Oral micronized P can induce antiproliferative changes in the human endometrium at doses lower than those required for transformation of the endometrium to a full secretory state.

Cell Division↗
PubMed1996

The importance of choice of anaesthetics in studying radiation effects in the 9L rat glioma.

In the present study we demonstrate that the glycolysis of the tumour 9L glioma, in vivo, may be manipulated with ketamine/xylazine combinations of anaesthetics. Xylazine alone or in combination with ketamine causes hyperglycaemia which is enhanced by glucose injections. Intracellular tumour pH is acidified when glucose is administered with ketamine/xylazine. However, the combination of inorganic phosphate and insulin with ketamine/xylazine and glucose caused an alkaline shift in the tumour pH as measured by 31P NMR. The anaesthetic combination of ketamine/acepromazine did not produce alterations in blood glucose or in tumour pH status as detected by 31P NMR spectroscopy. These results demonstrate dramatic effects of ketamine/xylazine on the acidification or alkalinisation of the cells of 9L glioma. These altered metabolic states are of potential therapeutic importance. The choice of xylazine alone would be useful for chemotherapy and hyperthermia modalities, both known to be dependent upon glucose metabolism and resultant acidification.

Anesthetics↗
PubMed1996

Analysis of the relative level of gene expression from different retroviral vectors used for gene therapy.

We have analyzed the relative level of gene expression and viral titer from different types of retroviral vectors used for gene therapy, the LTR-based MFG vector and the internal promoter-containing vectors, LNCX, LNSX and LXSN. The CAT gene was used for comparison of retroviral vector gene expression in both transfected and transduced cells, while the neo gene was used to evaluate viral liter. In transfected cells, MFG-CAT expressed higher levels of CAT then the other vectors, LNC-CAT was next, while L-CAT-SN and LNS-CAT produced much lower levels. CAT expression from MFG-CAT was particularly high in the human T lymphoid cell lines CEM-SS and H9. In nonselected transduced cells. CAT expression from MFG was 10- to 50-fold higher than with the other vectors. Similar observations were made with retroviral constructs expressing human EPO and murine GM-CSF. In transient transfection assays, the titer of MFG was at least five-fold higher than the other vectors as determined by Southern analysis and G418 resistance. Analysis of the steady-state RNAs produced after transfection of the packaging cell lines showed that MFG expressed a significantly higher level of genomic RNA, which contains the packaging signal, than the other vectors while still expressing a high level of the subgenomic RNA encoding CAT. The high level of genomic RNA most likely contributes directly to the higher titer of MFG. We also compared viral titers from subcloned PA317 producer lines containing LNC-CAT and MFG-CAT-Neo, and confirmed that the titer of the MFG virus was higher than that of the LNCX. In selected subcloned transduced NIH3T3 cells, average levels of CAT activity were nine-fold higher from MFG-based vector. Our results suggest that there are significant differences in both the titer and the level of gene expression between retroviral vectors which are currently being used in gene therapy clinical trials.

Animals↗
PubMed1996

Molecular effects of M17055, furosemide and thiazide on cardiac hypertrophy of spontaneously hypertensive rats.

Although diuretics have been clinically shown to reduce cardiovascular morbidity and mortality, the effects of diuretics on cardiac hypertrophy are poorly understood. In this study, we examined the molecular effects of diuretics on hypertensive cardiac hypertrophy. Spontaneously hypertensive rats (SHR) were given p.o. M17055 (a novel "high ceiling" diuretic) 1.25, 2.5 or 5 mg/kg/day, furosemide 50 mg/kg/day or trichlormethiazide 30 mg/kg/day for 5 weeks. After the treatment, cardiac myosin isoforms were analyzed by gel electrophoresis, and cardiac hypertrophy-related gene expressions were examined by Northern blot analysis. These three diuretics significantly reduced cardiac hypertrophy of SHR. M17055 and furosemide, but not trichlormethiazide, significantly increased the proportion of cardiac V3 myosin of SHR by enhancing the gene expression of beta-myosin heavy chain. On the other hand, trichlormethiazide, but not M17055 or furosemide, suppressed the increased cardiac gene expression of skeletal alpha-actin in SHR. Cardiac collagen type III expression of SHR was decreased only by treatment with M17055. Plasma thyroid hormone levels of SHR were slightly decreased by M17055 and by furosemide and were negatively correlated with cardiac V3 myosin contents. Thus the effects on the gene expression of cardiac contractile proteins and collagen are significantly different among these three types of diuretics, which suggests that these diuretics may have different cardiac actions independent of their diuretic and antihypertensive actions. The increased cardiac V3 myosin induced by M17055 and by furosemide may be partially due to the decreased plasma thyroid hormone.

Animals↗
PubMed1996

A simple and rapid method for the determination of recombinant retrovirus titer by G418 selection.

We have developed a simple and rapid method for the determination of retroviral titer by G418 selection which is both accurate and reproducible. NIH3T3 cells were transduced with recombinant retroviral vectors harboring the neo gene and selected in the presence of the antibiotic G418 for 3 days. Cells were then trypsinized, harvested, and counted on a hemacytometer. The control NIH3T3 cells were completely dead 3 days after treatment with G418, while cells transduced with retroviral vectors containing the neo gene produced an average of 15 progeny cells per colony. To estimate viral titer, therefore, the total number of trypsinized G418-resistant cells was divided by 15. Retroviral titers measured by this method did not differ significantly from those determined by the conventional method based on counts of G418-resistant colonies 10-14 days after G418 selection. The method worked well with various retroviral constructs and its efficacy was not influenced by cDNA insert. This method not only reduces the amount of work but also shortens the time needed for determining viral titer.

3T3 Cells↗
PubMed1996

Development of immunotherapy for the treatment of malignancies refractory to conventional therapies.

The key to understanding cancer has eluded scientists for years. As we discover new and more effective approaches to the treatment of cancer, the more we have yet to explore. Despite landmark advances in molecular biology and surgical adjuvant therapy in the past decade, cancer remains a significant life threat. Most metastatic cancers are refractory to conventional therapies, including surgery, radiation therapy and chemotherapy. Therefore constant efforts are being made to develop more effective treatment modalities. Immunotherapy, which is based on the enhancement of an immune response against the host tumor, has been particularly promising. In this review, we shall address the origins, development and future directions of immunotherapy.

Adoptive Transfer↗
PubMed1996

Inhibition of the growth of glioblastomas by CGP 41251, an inhibitor of protein kinase C, and by a phorbol ester tumor promoter.

Protein kinase C (PKC) plays a central role in signal transduction pathways that mediate the action of certain growth factors, tumor promoters, and cellular oncogenes. To explore whether PKC might be an appropriate target for the chemotherapy of human brain tumors, cell lines were established from five glioblastomas, one mixed gliosarcoma and glioblastoma, two astrocytomas, and one choroid plexus carcinoma. The staurosporine derivative CGP 41251, an inhibitor of PKC, inhibited cell proliferation in all nine cell lines with an IC50 in the range of 0.4 micrometer. Drug withdrawal and clonogenicity assays showed that CGP 41251 induced an irreversible growth arrest. Three cell lines were examined in detail: two human glioblastoma cell lines, GB-1 and GB-2, and one gliosarcoma cell line, GS-1. All of these three cell lines were highly aneuploid and displayed morphologies and immunohistochemical markers characteristic of the glial lineage. The compound 12-O-tetradecanoylphorbol-13-acetate (TPA), a tumor promoter and activator of PKC, also inhibited the growth of these cell lines. CGP 41251 in combination with TPA caused further growth inhibition. Cultures treated with CGP 41251 displayed an increase in the fraction of cells in G2-M, a decrease of cells in S phase, and no consistent effect on G0-G1. Immunohistochemical analyses demonstrated that growth inhibition by CGP 41251 was associated with the formation of giant nuclei with extensive fragmentation and apoptotic bodies. These effects of CGP 41251 were abrogated by withdrawal of serum from the medium or by exposure of these cells to aphidicolin, actinomycin D, cycloheximide, or TPA. In contrast to the effects seen with the glioblastoma cell lines, nontransformed astrocyte lines remained viable in the presence of 0.4 and 0.8 micrometer CGP 41251 and displayed only a slight increase in the fraction of giant nuclei with fragmentation. The antitumor activity of CGP 41251 was demonstrated in vivo against xenografts of the glioblastoma cell lines U87 MG and U373 MG. These findings suggest that CGP 41251 might be a useful agent for the treatment of glioblastomas.

Aged↗
PubMed1996

The mechanism of local tumor irradiation combined with interleukin 2 therapy in murine renal carcinoma: histological evaluation of pulmonary metastases.

We have demonstrated that tumor irradiation enhanced the therapeutic effect of interleukin 2 (IL-2) on pulmonary metastases from a murine renal adenocarcinoma, Renca. To investigate the mechanism of interaction between tumor irradiation and IL-2 therapy, we have histologically evaluated the effects of each therapy alone or in combination on Renca pulmonary metastases. Following treatment of established lung metastases with irradiation and IL-2 therapy, lung sections were processed for H&E or immunohistochemical staining. We found that tumor irradiation or IL-2 therapy locally induced vascular damage, resulting in multifocal hemorrhages and mononuclear cell mobilization in the lung tissue. This effect was amplified in lungs treated with the combined therapy. Immunohistochemistry showed that irradiation produced a macrophage influx into irradiated tumor nodules, and systemic IL-2 therapy induced T-cell infiltration in tumor nodules. Lungs treated with the combined therapy exhibited massive macrophage, T-cell, and natural killer cell mobilization in disintegrating tumor nodules and in the lung tissue. This combined therapy caused a decrease in the number of proliferating tumor cells and an increase in the number of apoptotic cells, which were more marked than with either therapy alone. We suggest that the macrophages mobilized by radiation-induced tissue injury could play a role in phagocytosis of apoptotic tumor cells, processing and presenting of tumor antigens for a systemic immune response activated by IL-2. Tumor destruction may result from the concomitant action of activated T cells, natural killer cells, and macrophages infiltrating the tumor nodules.

Animals↗
PubMed1995

Molecular mechanisms of Spemann's organizer formation: conserved growth factor synergy between Xenopus and mouse.

Mesoderm induction assays in Xenopus have implicated growth factors such as activin, Vg1, Xwnt-8, and noggin as important in directing the formation of dorsal mesoderm (Spemann's organizer). Because these growth factors are structurally very different, they presumably act through distinct cell surface receptors that initiate different intracellular signaling cascades. A consequence of all of these signaling pathways, however, seems to be the induction of goosecoid (gsc) gene expression. To understand how integration of these different signaling pathways results in formation of Spemann's organizer, we sought to identify growth factor-responsive elements within the gsc promoter. Through microinjection of reporter genes we have identified two cis-acting elements, a distal element (DE) and a proximal element (PE), that are required for activin/BVg1 and Wnt induction, respectively. We have shown that the DE mediates activin induction in the absence of protein synthesis and therefore constitutes the first activin response element identified to interpret transforming growth factor-beta (TGF-beta) superfamily member signaling directly. Using a reporter gene construct containing a multimerized DE, we find that an activin/BVg1-type signaling cascade is active throughout the vegetal hemisphere and marginal zone but not in the animal hemisphere. We demonstrate further that both the distal and proximal elements are essential for high-level transcription of the gsc gene, specifically in dorsal mesoderm, strongly suggesting that establishment of Spemann's organizer requires synergistic input from activin/BVg1-like and Wnt signaling pathways. Finally, mechanisms of establishing the organizer are likely to be conserved throughout vertebrate evolution.

Amino Acid Sequence↗
PubMed1995

ROK1, a high-copy-number plasmid suppressor of kem1, encodes a putative ATP-dependent RNA helicase in Saccharomyces cerevisiae.

The KEM1 gene is involved in nuclear fusion during conjugation, and chromosome transmission and spindle pole body duplication/or separation during mitotic cell division in the yeast Saccharomyces cerevisiae. KEM1 was also independently identified as DST2, SEP1, XRN1 and RAR5 on the basis of DNA strand transferase or exoribonuclease activity in vitro or mutations affecting plasmid stability. To understand the various functions suggested for KEM1 and to identify other genes with functions similar or related to those of KEM1, we have characterized the ROK1 gene which was isolated as a high-copy-number plasmid suppressor of the kem1 null mutation. Sequence analysis of the smallest subclone with the suppression activity revealed an open reading frame of 564 amino acids. The ROK1 aa sequence contains highly conserved domains found in the DEAD protein family of ATP-dependent RNA helicases. ROK1 is essential for viability and is closely linked to KEM1 on chromosome VII.

Amino Acid Sequence↗