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Biomedical subjects

S K Chung

Publications and source records attributed to S K Chung.

At least 19 recordsLinked to original sources
PubMed2005

Aldose reductase in diabetic microvascular complications.

Most long-term diabetic patients develop microvascular diseases such as retinopathy, nephropathy and neuropathy. Although tight control of blood glucose greatly reduces the incidence of these complications, a significant fraction of diabetic patients with good glycemic control still develop these diseases. Therefore, it is imperative to understand the underlying mechanisms of these diseases such that effective treatment or preventive methods can be developed to augment euglycemic control. In animal studies, there is strong evidence that aldose reductase, the first and rate-limiting enzyme of the polyol pathway that converts glucose to fructose, plays a key role in the pathogenesis of microvascular complications. However, clinical trials of the aldose reductase inhibitors were disappointing and several pharmaceutical companies had abandoned the development of this line of drugs. In this review, the potential pathogenic mechanisms of the polyol pathway are presented, the evidence for the involvement of the polyol pathway in diabetic complications summarized, and the reasons for the unimpressive results of the clinical trials of the aldose inhibitors discussed. It appears that renewed efforts to develop aldose reductase inhibitors for the treatment and prevention of diabetic complications are warranted.

Aldehyde Reductase↗
PubMed2003

Neuroprotective effects of tanshinones in transient focal cerebral ischemia in mice.

Tanshinones are the major lipid soluble pharmacological constituents of Danshen, the dried roots of Salvia miltiorrhiza Bunge (Labiatae), a well known traditional Chinese medicine used for the treatment of cerebrovascular diseases including stroke. Potential neuroprotective effects of tanshinones IIA (TsIIA) and IIB (TsIIB) were examined in adult mice subjected to transient focal cerebral ischemia caused by middle cerebral artery occlusion (MCAo). Our results revealed that TsIIA (16 mg/kg) readily penetrated the blood brain barrier reaching a peak concentration of 0.41 nmol/g brain wet weight 60 minutes after intraperitoneal injection and decreased slowly over several hours. Twenty-four hours after middle cerebral artery occlusion, brain infarct volume was reduced by 30% and 37% following treatment with TsIIA and TsIIB, respectively. The reduction in brain infarct volume was accompanied by a significant decrease in the observed neurological deficit. Tanshinones or other structurally related compounds may have potential for further development as neuroprotective drugs.

Abietanes↗
PubMed2003

Genetic analysis of aldose reductase in diabetic complications.

Diabetes Mellitus is an increasing concern, worldwide in terms of health. Long-term diabetes often leads to secondary diseases such as cataract, retinopathy, neuropathy, nephropathy, and cardiovascular diseases. The enzyme aldose reductase (AR) has been implicated in the pathogenesis of some of these diseases and inhibitors of AR (ARIs) were effective in preventing some of the diabetic complications in animal models. However, clinical trials of these drugs were disappointing, casting doubt on the role of AR in these diseases. This review focuses on the recent studies using transgenic and gene knockout mice to analyze the role of AR in diabetic cataract and neuropathy. These studies clearly demonstrated that AR is crucial to the pathogenesis of these diseases, and that the mechanism leading to diabetic cataract may be different from that which causes diabetic neuropathy. A number of studies showed that there is a correlation between AR gene markers and susceptibility to develop complications among diabetic patients, suggesting that AR is also involved in the pathogenesis of diabetic complications in human. Together, these genetic studies strongly indicate that AR is an important target for the prevention of diabetic complications in human. This may provide impetus to develop more effective ARIs and to conduct better-designed clinical trials for ARIs in the prevention and treatment of these diseases.

Aldehyde Reductase↗
PubMed2002

Evidence of thalamic disinhibition in patients with hemichorea: semiquantitative analysis using SPECT.

OBJECTIVES: Hemichorea sometimes occurs after lesions that selectively involve the caudate nucleus, putamen, and globus pallidus. Some reports have hypothesised that the loss of subthalamic nucleus control on the internal segment of the globus pallidus, followed by the disinhibition of the thalamus may contribute to chorea. However, the pathophysiology is poorly understood. Therefore, clinicoradiological localisation was evaluated and a comparison of the haemodynamic status of the basal ganglia and thalamus was made. METHODS: Six patients presenting with acute onset of hemichorea were assessed. Neuroimaging studies, including MRI and SPECT examinations in addition to detailed biochemical tests, were performed. A semiquantitative analysis was performed by comparing the ratio of blood flow between patients and normal controls. In addition, the ratio of perfusion asymmetry was calculated as the ratio between each area contralateral to the chorea and that homolateral to the chorea. The comparison was made with a two sample t test. RESULTS: The causes of hemichorea found consisted of four cases of acute stroke, one non-ketotic hyperglycaemia, and one systemic lupus erythematosus. Brain MRI indicated lesion sites in the contralateral putamen, globus pallidus, caudate nucleus, and subthalamic nucleus. A significant decrease in the ratio of blood flow in the basal ganglia contralateral to the chorea and a significant increase in the thalamus was found when comparing the perfusion asymmetries, which were calculated as the ratio of cerebral blood flow (CBF) for each region to that in the homolateral occipital area (p<0.05). CONCLUSION: An alteration in CBF in both the contralateral thalamus and basal ganglia reflect the loss of pallidal inhibitory input from the pallidum to the thalamus. This change in CBF may be one of epiphenomena, which implicates an occurrence of hemichorea in humans.

Adult↗
PubMed2001

Perinatal hypoxia-/ischemia-induced endothelin-1 mRNA in astrocyte-like and endothelial cells.

Under pathological conditions in the adult CNS, such as ischemia, subarachnoid hemorrhage and Alzheimer's disease, endothelin (ET)-1- and -3-like immunoreactivities are elevated in astrocytes of the injured adult brain. However, it is not clear whether this is due to increased synthesis or increased binding of ET-1. Further, it is not known whether ET-1 expression is altered in the perinatal brain after cerebral hypoxia/ischemia (H/I). Here, we determined the sites of ET-1 expression in perinatal mouse brain after H/I injury by in situ hybridization using a probe specific for the ET-1 gene. Astrocyte-like cells, which do not normally express ET-1 mRNA, showed high levels of ET-1 mRNA expression. Endothelial cells of the capillaries and small vessels also showed an increased level of ET-1 mRNA. Our data suggest that ET-1 mRNA levels in the astrocyte-like cells and vascular endothelial cells are dynamically regulated by ischemia and may participate in perinatal ischemia-related neural damage.

Animals↗
PubMed2001

Is the re-closure of surgically induced open neural tube defect the repetition of primary neurulation? An experimental study with chick embryos.

It is well known that surgically induced open neural tube defects (ONTDs) tend to re-close in early embryonic stages. To investigate whether the process of re-closure is a repetition of primary neurulation, the morphological changes of surgically induced ONTDs were chronologically examined in early chick embryos. Longitudinal incisions of 3-somite length were made in the neural tubes of chick embryos at Hamburger and Hamilton stage 18 or 19. About half of the embryos showed complete closure of the skin on surgical microscopic examination. The re-closed neural tubes showed no remarkable differences from the controls on histological examination. The process of re-closure involved a zipper-like (ventral to dorsal) closure in the transverse sections of neural tubes. The results indicate that the re-closure of surgically induced ONTDs does not repeat the process of natural primary neurulation.

Age Factors↗
PubMed2001

Hydrogen peroxide is a novel inducer of connective tissue growth factor.

Connective tissue growth factor (CTGF) has recently been described as a fibrogenic factor and is greatly induced by various extracellular stimuli, such as transforming growth factor-beta (TGF-beta), dexamethasone, and serotonin. CTGF induces collagen type I and fibronectin, and the deposition of such molecules leads to fibrotic disease in many tissues. Intracellular reactive oxygen species (ROS) are generated by extracellular stress conditions and are produced as by-products of cellular metabolism. Imbalanced cellular redox status is a potent pathogenic factor that leads to various degenerative diseases, including tissue fibrosis. Since CTGF is believed to play a crucial role in fibrotic disease formation in many tissues, we examined the role of ROS in CTGF gene expression in human lens epithelial cell line B3. The results showed that CTGF was induced by reactive oxygen species such as hydrogen peroxide and hydroxyl radicals. Next, we examined whether CTGF induction by ROS is via newly synthesized TGF-beta. The results showed that ROS directly induced CTGF mRNA not via the increased TGF-beta synthesis or activation. Next, we treated AG490, which is the well-known inhibitor of Janus kinase (JAK), with hydrogen peroxide. AG490 abrogated the CTGF induction by ROS in a dose-dependent manner. The results suggest that JAK-2/-3 seems to be involved in the enhanced CTGF mRNA expression by hydrogen peroxide. In this report, we present that hydrogen peroxide is a novel inducer of CTGF gene expression and that JAK-2/-3 activation seems to play a role in CTGF induction.

Amino Acid Sequence↗
PubMed2001

Corneal opacity after repeated photorefractive keratectomy.

Corneal opacity developed in an eye that had photorefractive keratectomy (PRK) with a 193 nm excimer laser 5 times over 3 years. Six months after the last PRK, a partial penetrating keratoplasty was performed. The cornea was stained and immunohistochemically evaluated for collagen types. Light microscopy showed thickening of epithelial layers, proliferation of subepithelial fibroblasts, and the absence of Bowman's membrane. Transmission electron microscopy showed irregular collagen lamellae and electron-dense deposits adjacent to keratocytes. The staining was positive for Alcian blue, and immunohistochemistry was positive for type IV and VI collagen. This case suggests that corneal opacity after repeated PRK is the result of deposits of type IV and VI collagen and acidic mucoprotein in the extracellular matrix.

Collagen↗
PubMed2001

Differential effects of intravitreal optic nerve and sciatic nerve grafts on the survival of retinal ganglion cells and the regeneration of their axons.

We have investigated the effects of intravitreal sciatic nerve (SN) and/or optic nerve (ON) grafts on the survival and the axonal regeneration of retinal ganglion cells (RGCs). Following transection of the ON, approximately 40% RGCs survived at 7 days post-axotomy (dpa). Results showed that the intravitreal ON graft significantly promoted the survival of RGCs at 7 dpa (39,063 vs 28,246). Intravitreal SN graft, however, did not rescue axotomized RGCs at 5, 7 or 14 dpa. Axotomized RGCs could be induced to regenerate axons along a segment of SN graft attached to the proximal stump of ON. On average, 608 axotomized RGCs were induced to regenerate axons along the attached SN graft. The presence of intravitreal SN graft promoted about 100% increase in the number of regenerating RGCs (1,227) relative to the control groups. The intravitreal ON graft, surprisingly, also induced about 100% more regenerating RGCs (1220) than in the control group. When SN and ON grafts were co-transplanted into the vitreous, about 200% more regenerating RGCs (1916) were observed than in the control group. These findings illustrated that the intravitreal ON graft rescued axotomized RGCs and enhanced the regeneration of retinal axons. This is the first report to show that ON promotes RGC axonal regeneration. The intravitreal SN graft did not rescue RGCs but promoted axonal regeneration. The differential effects of intravitreal ON and SN grafts on the survival and the RGC regeneration suggest that these might be two independently operating events.

Animals↗
PubMed2001

An improved method for determination of ethyl carbamate in Korean traditional rice wine.

An improved extraction method for ethyl carbamate, a genotoxic and carcinogenic compound found in various fermented foods and beverages, was investigated for its determination in the two most typical Korean traditional rice wines, takju and yakju. When the rice wines were extracted twice with chloroform at 30 degrees C for 60 min, the recovery of ethyl carbamate was less than 16%. When they were saturated with NaCl before extraction, the recovery of ethyl carbamate increased to 24.4% in takju and 67.2% in yakju. Adjustment of pH to 9.0 after NaCl saturation in takju resulted in a dramatic increase of recovery to 81.2%, but not in yakju. When the contents of ethyl carbamate and its precursor, urea, in various Korean traditional rice wines were determined, there was no correlation between the two contents. This is due to the fact that storage time is more important than urea content in the formation of ethyl carbamate in rice wine. In addition, its storage at high temperature resulted in a dramatic increase in ethyl carbamate content according to the prolonged storage time, suggesting that storage time and temperature play a key role in the formation of ethyl carbamate in Korean traditional rice wine.

Carcinogens↗
PubMed2001

Effect of endoscopic sinus surgery on asthmatic patients with chronic rhinosinusitis.

There have been several reports on the effectiveness of endoscopic sinus surgery (ESS) in asthmatic patients with chronic rhinosinusitis. Whether ESS has a positive effect on the clinical course of asthma still remains controversial. There have been several subjective evaluations but few objective results. We performed a study to evaluate the effectiveness of ESS in 19 patients with asthma who underwent ESS for rhinosinusitis. The use of antiasthma medication and postoperative asthma symptoms was analyzed. Objective changes of pulmonary function tests were evaluated. There was a significant improvement in diurnal and nocturnal asthma symptoms. Improvements in asthma medication scores were also confirmed, and individual asthma symptoms (dyspnea, cough, wheezing, and sputum production) improved significantly. Despite a reduction in use of antiasthma medication after ESS, the parameters of the pulmonary function tests did not change. Both subjectively and objectively, it seems that ESS, when used to treat asthmatic patients with chronic rhinosinusitis, can play a significant role in the clinical improvement of asthma.

Adult↗
PubMed2001

Endothelin-1 protects astrocytes from hypoxic/ischemic injury.

Under pathological conditions such as ischemia (I), subarachnoid hemorrhage, and Alzheimer's disease, astrocytes show a large increase in endothelin (ET) -like immunoreactivity. However, it is not clear whether ET is protective or destructive to these cells during brain injury. Using astrocytes from ET-1-deficient mice, we determined the effect of ET-1 on these cells under normal, hypoxic (H), and hypoxic/ischemic (H/I) conditions. Under normal culture conditions, astrocytes from wild-type and ET-1-deficient mice showed no difference in their morphology and cell proliferation rates. ET-3 and ETA receptor mRNAs were up-regulated whereas ETB receptor mRNA was down-regulated in ET-1-deficient astrocytes, suggesting that ET-1 and ET-3 may complement each other's functions and that the expressions of these endothelins and their receptors are regulated by a complex feedback mechanism. Under H and H/I conditions, ET-1 peptide and mRNA were up-regulated in wild-type astrocytes, and the astrocytes without ET-1 died faster than the wild-type astrocytes, as indicated by greater efflux of lactate dehydrogenase. The present study suggests that astrocytes without ET-1 are more vulnerable to H and H/I injuries and that the up-regulation of astrocytic ET-1 is essential for the survival of astrocytes.

Animals↗
PubMed2001

New E. coli cloning vector using a cellulase gene (celA) as a screening marker.

The extracellular endoglucanase A gene of Clostridium thermocellum (celA) was used as a screening marker for E. coli cloning vector A 1.4-kb EcoRI fragment containing celA from pTvec/celA was isolated and cloned into a pUC18 deleting beta-galactosidase gene fragment. The constructed vectors, pCEL1, pCEL10, pCEL11, and pCEL20, have different multiple cloning sites within celA. If the cellulase, CelA, is inactivated by insertion of a foreign DNA fragment into multiple cloning sites, the recombinant transformants show no clear halos on an agar plate containing cellulose. This process overcomes the ambiguity of color screening in the X-gal/beta-galactosidase system, and over 90% of the recombinant transformants with no halos have foreign DNA inserts. Several E. coli strains were transformed successfully with pCEL series vectors regardless of mutation for alpha-complementation. Because E. coli strains do not have a cellulase gene, a vector using a cellulase gene screening marker can be used in any E. coli strain without limit. The new cloning system is very efficient, convenient, and cost effective.

Base Sequence↗
PubMed2001

Transgenic mice with overexpression of human scavenger receptor A on endothelial cells.

OBJECTIVES: To establish a new transgenic mouse model for determining the function and role of human scavenger receptor A (SR-A) in atherosclerosis in vivo. METHODS: Human scavenger receptor minigene-driven mouse tie-1 promoter was constructed and confirmed by endonuclease digestion and sequence analysis. Transgenic mice were generated via the microinjection method. PCR and Southern blot were used to screen the positive transgenic mice. RT-PCR and immunohistochemical analysis were used to detect the level and location of human SR-AI expression in transgenic mice. The activity of human SR-AI was determined by morphologic observation of aortic endothelial cells of transgenic mice under transmission electron microscopy. RESULTS: The electrophoresis assay showed the expected 4 fragments of 0.9 kb, 1.1 kb, 1.2 kb and 4.2 kb in the Sma I digest and 2 fragments of 0.8 kb and 6.7 kb in Bgl II digest of plasmids pTie-1/hSR-A. The fragment sequence of tie-1 promoter and human SR-A cDNA in plasmids pTie-1/hSR-A was correct and no ATG before the translation initiation sites of human SR-A was found by sequence analysis. 561 injected and surviving embryos with the purified human SR-A minigene were implanted into the oviducts of 19 ICR pseudopregnant mice. Among the 54 surviving pups from 13 foster mothers, 7 were identified by PCR and Southern blot analysis. The results of RT-PCR and immunohistochemical analysis showed human SR-A was specifically expressed on vascular endothelial cells of the aorta and renal artery, as well as hepatic sinusoidal endothelial cells in transgenic mice. Transmission electron microscope (TEM) of aorta of transgenic mice showed that a large number of vesicles, multivesicle bodies and swollen mitochondria filled the plasma of endothelial cells. CONCLUSIONS: A transgenic mouse model with overexpression of human SR-A in endothelial cells was successfully established. The transgene was integrated and transmitted into the chromosome of transgenic mice. Tie-1 promoter controlled the transgene to express in endothelial cells in mice. Pinocytic activity of aortic endothelial cells in transgenic mice was higher than that of C57BL/6J mice. Our studies will provide a new transgenic model for investigation of atherosclerosis and functions of human SR-A.

Animals↗
PubMed2000

Expression and protein-binding studies of the EEN gene family, new interacting partners for dynamin, synaptojanin and huntingtin proteins.

EEN, identified initially as a fusion partner to the mixed-lineage leukaemia gene in human leukaemia, and its related members, EEN-B1 and EEN-B2, have recently been shown to interact with two endocytic molecules, dynamin and synaptojanin, as well as with the huntingtin protein. In the present study, we show that the expression of the EEN gene-family members is differentially regulated. Multiple-spliced variants were identified for EEN-B2. In the brain, EEN-B1 and EEN-B2 mRNA are preferentially expressed in the cerebellar Purkinje and granule cells, dentate gyrus cells, hippocampal pyramidal neurons and cerebral granule cells. The expression patterns of EEN-B1 and EEN-B2 mRNA in the brain overlap with those of dynamin-I/III, synaptojanin-I and huntingtin, whereas the ubiquitous expression of EEN is consistent with that of dynamin-II. In testes, members of the EEN family are co-expressed with testis-type dynamin and huntingtin in Sertoli cells and germ cells respectively. Our results on the overlapping expression patterns are consistent with the proposed interaction of EEN family members with dynamin, synaptojanin and huntingtin protein in vivo. Although all three EEN family members bind to dynamin and synaptojanin, EEN-B1 has the highest affinity for binding, followed by EEN and EEN-B2. We also demonstrate that amphiphysin, a major synaptojanin-binding protein in brain, can compete with the EEN family for binding to synaptojanin and dynamin. We propose that recruitment of the EEN family by dynamin/synaptojanin to clathrin-coated pits can be regulated by amphiphysin.

Alternative Splicing↗
PubMed2000

Differential stereoselectivity of D- and L-myo-inositol 1,2,4, 5-tetrakisphosphate binding to the inositol 1,4,5-trisphosphate receptor and 3-kinase.

D- and L-myo-inositol 1,2,4,5-tetrakisphosphate (Ins(1,2,4,5)P(4)) were investigated for their ability to bind to the D-myo-inositol 1, 4,5-trisphosphate (Ins(1,4,5)P(3)) receptor in a bovine adrenal cortical membrane fraction, to mobilize intracellular Ca(2+) stores in Xenopus oocytes, and to bind to the rat brain Ins(1,4,5)P(3) 3-kinase overexpressed and purified in E. coli. In competitive binding experiments with the Ins(1,4,5)P(3) receptor, D-Ins(1,2,4, 5)P(4) effectively displaced [(3)H]Ins(1,4,5)P(3) in a concentration-dependent manner with a potency comparable to that of D-Ins(1,4,5)P(3), while L-Ins(1,2,4,5)P(4) was approximately 50-fold less effective than D-Ins(1,4,5)P(3) and D-Ins(1,2,4,5)P(4). The DL-Ins(1,2,4,5)P(4) racemate bound to the Ins(1,4,5)P(3) receptor with an apparent intermediate efficiency. Injection of D-Ins(1,2,4, 5)P(4) into oocytes evoked a chloride current dependent on intracellular Ca(2+) mobilization in which the agonists ranked in a similar order of potency as in the Ins(1,4,5)P(3) receptor binding. On the other hand, D-Ins(1,2,4,5)P(4) only inhibited the binding of [(3)H]Ins(1,4,5)P(3) to 3-kinase very weakly with a markedly reduced potency compared to D-Ins(1,4,5)P(3), indicating that D-Ins(1,2,4, 5)P(4) is not an effective competitor in the phosphorylation of [(3)H]-Ins(1,4,5)P(3) by 3-kinase. The results, therefore, clearly indicate that D-Ins(1,2,4,5)P(4) is as effective as D-Ins(1,4,5)P(3) in the binding to the receptor but not 3-kinase, and access of Ins(1, 2,4,5)P(4) over the Ins(1,4,5)P(3) receptor calls for stringent stereospecificity with D-Ins(1,2,4,5)P(4) being the active form in DL-Ins(1,2,4,5)P(4)-mediated Ca(2+) mobilization.

Animals↗