Biomedical subjects
Publications and source records attributed to H Cho.
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1. We have investigated the effect of U73122, a specific inhibitor of phospholipase C (PLC), on acetylcholine-activated K(+) currents (I(KACh)) in mouse atrial myocytes. 2. In perforated patch clamp mode, I(KACh) was activated by 10 microM acetylcholine. When atrial myocytes were pretreated with U73122 or U73343, I(KACh) was inhibited dose-dependently (half-maximal inhibition at 0.12+/-0.0085 and 0.16+/-0.0176 microM, respectively). The current-voltage relationships for I(KACh) in the absence and in the presence of U73122 showed that the inhibition occurred uniformly from -120 to +40 mV, indicating a voltage-independent inhibition. 3. When U73122 was applied after I(KACh) reached steady-state, a gradual decrease in I(KACh) was observed. The time course of the current decrease was well fitted to a single exponential, and the rate constant was proportional to the concentration of U73122. 4. When K(ACh) channels were directly activated by adding 1 mM GTP gamma S to the bath solution in inside-out patches, U73122 (1 microM) decreased the open probability significantly without change in mean open time. When K(ACh) channels were activated independently of G-protein activation by 20 mM Na(+), open probability was also inhibited by U73122. 5. Voltage-activated K(+) currents and inward rectifying K(+) currents were not affected by U73122. 6. These findings show that inhibition by U73122 and U73343 of K(ACh) channels occurs at a level downstream of the action of G beta gamma or Na(+) on channel activation. The interference with phosphatidylinositol 4,5-bisphosphate (PIP(2))-channel interaction can be suggested as a most plausible mechanism.
Hepatitis B virus X (HBx) protein is a multifunctional protein that exerts dual activity on cell proliferation and death. Although HBx is thought to be a major determinant that leads to hepatocellular carcinoma, its pathophysiological role in humans remains to be established. Attempts have been made to evaluate the role of HBx in liver specimens derived from patients with chronic B viral hepatitis and hepatocellular carcinoma. Among 25 paired liver specimens of hepatocellular carcinoma and corresponding nontumour liver tissues, HBx mRNA was hardly detected and was significantly lower than other HBV transcripts. An immunohistochemical study demonstrated that expression of HBx protein was also lower than other HBV gene products. Interestingly, however, expression of HBx protein changed with the progression of chronic hepatitis. HBx was expressed in 5.0% of patients with chronic hepatitis without cirrhosis but increased to 44.8% in chronic hepatitis with cirrhosis. In contrast, only one (3.7%) of 27 hepatocellular carcinomas showed HBx positivity whereas 29.6% of surrounding nontumour tissues was still HBx-positive. These results suggest that HBx may play a major role at the promotion stage of carcinogenesis. Noticeably, HBx-positive cells were preferentially localized in the periportal region of chronic hepatitis or periphery of cirrhotic nodules where high necroinflammatory activity was accompanied. We found a positive correlation between HBx expression and periportal inflammatory activity (P < 0.001). Thus, HBx may potentiate cell destruction and regeneration of liver that provide an opportunity for the accumulation of genetic mutations, which contribute to multistep hepatocarcinogenesis.
Bioassay-guided fractionation of the H(2)O extract of the seeds of Psoralea corylifolia furnished one hepatoprotective compound, bakuchiol (1), together with two moderately active compounds, bakuchicin (2) and psoralen (3), on tacrine-induced cytotoxicity in human liver-derived Hep G2 cells. The EC(50) values of compounds 1 - 3 are 1.0, 47.0, 50.0 microg/ml, respectively. Silymarin as a positive control showed the EC(50) value with 5.0 microg/ml.
Assay-guided fractionation of the EtOAc soluble fraction of the rhizomes of Curcuma longa furnished three DPPH free radical scavenging diarylheptanoids, curcumin (1), demethoxycurcumin (2), and bisdemethoxycurcumin (3). Compounds 1-3 showed the DPPH radical scavenging effects with IC(50) values of 2.8, 39.2, 308.7 microM, respectively. L-Ascorbic acid and resveratrol as positive controls exhibited IC(50) values of 22.5 and 25.0 microM, respectively. Compounds 1-3 showed significant hepatoprotective effects on tacrine-induced cytotoxicity in human liver-derived Hep G2 cells. The EC(50) values of 1-3 are 86.9, 70.7, and 50.2 microM, respectively. Silybin (EC(50) = 69.0 microM) and silychristin (EC(50) = 82.7 microM) were used as positive controls.
Estrogen is synthesized in the male reproductive system and is found in high concentrations in rete testis and seminal fluids. This luminal estrogen targets estrogen receptors (ER) along the male reproductive tract, and in particular the efferent ductules, where ERalpha is abundant. However, both ERalpha and ERbeta are found in various regions of the male reproductive tract. The transgenic ER knockout mice (alphaERKO and betaERKO) have been used to help define the role of ER in the male. In the alphaERKO animal model, the efferent ductules are dramatically altered, forming an epithelium in which fluid reabsorption is inhibited and epithelial cells have greatly reduced numbers of lysosomes and organelles associated with endocytosis. The betaERKO male reproductive tract appears normal. Because these animals are transgenic and lack ER throughout development, we developed animal models using pure antiestrogen ICI 182,780 treatments in adult males. The data show that ERalpha participates in the regulation of the apical cytoplasm of non-ciliated cells of the efferent ductules, narrow cells of initial segment epididymis and clear cells in the remaining segments of the epididymis. There appears to be no effect on vas deferens. The inhibition of ERalpha function in the male leads to decreases in sperm concentrations and eventually to infertility. The current literature leaves the mechanisms of estrogen action in the male reproductive tract unsettled and raises the question of androgen's contribution to the regulation of fluid transport, especially in the efferent ductules.
OBJECTIVES: To examine the prevalence, persistence, and correlates of depressive symptoms in mothers of toddlers in a nationally representative sample. METHOD: The self-report components of two linked databases were used for this study, the 1988 National Maternal and Infant Health Survey and the 1991 Longitudinal Followup. Depressive symptoms of 7,537 mothers were measured by the Center for Epidemiologic Studies-Depression Scale (CES-D) at both time points. Weighted bivariate and multivariate analyses were used to assess the stability of maternal depressive symptoms across two time points and maternal and child predictors of elevated depressive symptoms. RESULTS: Twenty-four percent of mothers at time 1 (mean child age 17 months) and 17% at time 2 (mean child age 35 months) had elevated depressive symptoms (CES-D score > or =16). Thirty-six percent of those with elevated scores at time 1 also had elevated scores at time 2. Not having breast-fed, a mistimed or unwanted pregnancy, and poor child health status were related to elevated depressive symptoms but not persistence. CONCLUSIONS: Elevated depressive symptoms are common in mothers of toddlers. Given the potential magnitude of need, a systematic clinical and public health approach may be required.
BACKGROUND: Although antisecretory medications such as histamine type II receptor antagonists or proton pump inhibitors have been used to treat reflux oesophagitis, a considerable number of patients do not achieve complete mucosal healing or suffer from either sustained symptoms or ensuing complications, suggesting other damaging factors or impaired mucosal resistance are also involved in the pathogenesis of reflux oesophagitis. AIMS: The present study was designed to evaluate oxidative stress as the major pathogenic factor of reflux oesophagitis and to determine the usefulness of antioxidants in the treatment of reflux oesophagitis. MATERIALS AND METHODS: Reflux oesophagitis was induced by insertion of a 3 mm calibre ring into the duodenum, 1 cm distal to the ligament of Treitz, in Sprague-Dawley rats. RESULTS: DA-9601, a novel antioxidant substance, significantly attenuated the gross and histopathological scores of reflux oesophagitis compared with those treated with ranitidine alone or reflux oesophagitis controls in a dose dependent manner. Only scattered erosions were observed in the antioxidant pretreated group but acid suppression by ranitidine was not effective in decreasing the severity of reflux oesophagitis. Significantly increased amounts of malondialdehyde (MDA), increased nuclear factor kappaB (NFkappaB) activation, and depletion of reduced glutathione (GSH) were observed in experimentally induced reflux oesophagitis. DA-9601 pretreatment attenuated the decrement in mucosal GSH levels and decreased MDA formation significantly. DA-9601 treatment caused significant reductions in activation of NFkappaB transcription factor, especially the p50 subunit, in accordance with the significantly higher levels of inhibitory protein of NFkappaB expression. CONCLUSION: Reflux oesophagitis caused considerable levels of oxidative stress in the oesophageal mucosa and antioxidant treatment should be considered as supplementary therapy in the prevention or treatment of reflux oesophagitis with acid suppression.
The PACS system built and used in hospitals nowadays has quite significant overload on its central server because of both treatment of very large data and full management of medical images. We suggest a distributed communication and management methodology using PC to PC multicasting strategy for efficient management of medical images produced by DICOM modalities. It is absolutely necessary for reducing strict degradation of PACS system due to large size of medical images and its very high transport rates. DICOM PC to PC component is composed a service manager to execute requested queries, a communication manager to take charge of file transmission, and a DICOM manager to manage stored data and system behavior. Each manager itself is a component to search for requested file by interaction or transmit the file to other PCs. Distributed management and transformation of medical information based on PC to PC multicasting methodology will enhance performance of central server and network capacity reducing overload on them.
To evaluate the relationship between radical surgery of recurrent tumor and prognosis in cases of recurrent gastric cancer, we analyzed data on 202 patients with relapsed gastric cancer, focusing on surgical recurrent tumor removal. In our series, 18 of the 202 patients underwent radical recurrent tumor resection. Resected tumors were located in the ovarium (n = 4), colorectum (n = 3), liver (n = 3), lymph node (n = 2), locoregional stoma (n = 2), and peritoneum, adrenal gland, brain, and lung (n = 1 each). No surgery-related mortality occurred. One patient remains alive over 5 years after hepatectomy without recurrence, and 17 died within 3 years: 7 patients from primary recurrence and 10 from multiple modes of recurrence. Median survival after recurrence (MSTAR) in the 18 radical surgery patients was 14 months, against 5 months in those treated palliatively (p = 0.0001). MSTAR for the ovary and the liver were 30 months and 15 months in the radical surgery cases, and 2.5 months for the ovary and 5 months for the liver in the palliative cases. Significant differences were thus seen between radical and palliative cases in the ovary (p = 0.010) and in the liver (p = 0.036). Median survival after gastrectomy was 45 months in the radical surgery cases, and 28 months in the palliative cases (p = 0.024). In postoperative gastric cancer follow-up, early detection of recurrence and radical surgery may well benefit patients with relapse, especially in the liver and ovary, in terms of survival.
Hepatitis B virus X (HBx) protein implicated in the development of liver cancer may inhibit the function of p53 tumor suppressor protein through cytoplasmic retention of p53 protein. Here, we attempt to investigate whether the functional inhibition of p53 protein by HBx protein is reversible. First, we provide the evidence for the association of endogenous p53 protein with HBx by co-immunoprecipitation in stable Chang cells that express HBx protein in an inducible manner (ChangX-34). By immunofluorescence microscopy, the major location of p53 protein of ChangX-34 cells was confirmed at the nuclear periphery as well as in the cytoplasm where HBx protein is mainly expressed. Surprisingly, anticancer drug, adriamycin induces the nuclear translocation of p53 protein sequestered in the cytoplasm. This change is accompanied by the restoration of p53 activity, which results in increased transcriptional activity at the p53-responsive DNA elements as well as increase of p21WAF1 mRNA expression. Further, we observed the induction of cell death and G1 arrest in these cells upon adriamycin treatment regardless of HBx expression. Together, we demonstrate that functional inhibition of p53 protein through its cytoplasmic retention by HBx protein is reversible. These results may be extended into other tumors of which p53 activity is modulated by viral oncoproteins.
Activating mutations in the Met receptor tyrosine kinase, both germline and somatic, have been identified in human papillary renal cancer. Here we report a novel germline missense Met mutation, P1009S, in a patient with primary gastric cancer. The dosage of the mutant Met DNA was elevated in the tumor when compared to its matched normal DNA. Therefore, as with hereditary renal papillary cancer, the mutant Met allele may also be selectively duplicated in the tumor. Different from previously reported Met mutations, which occur in the tyrosine kinase domain, this missense mutation is located at the juxtamembrane domain, and is not constitutively activated. However, following treatment with HGF/SF, the P1009S mutant Met protein, expressed in NIH3T3 cells, displays increased and persistent tyrosine phosphorylation compared to the wild-type Met. Importantly, these cells also form colonies in soft agar, and are highly tumorigenic in athymic nude mice. A second nucleotide change in this region of Met, T1010I, was found in a breast cancer biopsy and a large cell lung cancer cell line. Although this previously reported 'polymorphism' did not stimulate NIH3T3 cell growth in soft agar, it was more active than the wild-type Met in the athymic nude mice tumorigenesis assay, suggesting that it may have effects on tumorigenesis. Met has been shown to be highly expressed in human gastric carcinoma cell lines, and our results raise the possibility that activating missense Met mutations could contribute to tumorigenesis of gastric cancer.
The posttranslational regulation of protein tyrosine phosphatases (PTPs) has been suggested to have a crucial role in maintaining the phosphotyrosine level in cells. Here we examined the regulatory effects of metal ions on human dual-specificity vaccinia H1-related protein tyrosine phosphatase (VHR) in vitro. Among various metal ions examined, Fe3+, Cu2+, Zn2+, and Cd2+ exerted their inactivational effects on VHR, and Cu2+ is the most potent inactivator. The VHR activity inactivated by the metal ions except Cu2+ was significantly restored by EDTA. The efficacy of Cu2+ for the VHR inactivation was about 200-fold more potent than that of H2O2. Cu2+ also inactivated other PTPs including PTP1B and SHP-1. The Cu2+-mediated inactivation at the submicromolar range was eradicated by dithiothreitol treatment. The loss of VHR activity correlated with the decreased [14C]iodoacetate labeling of active-site cysteine, suggesting that Cu2+ brought about the oxidation of the active-site cysteine. On the contrary, Zn2+ that exerted an inactivational effect at millimolar concentrations appeared not directly linked to the active-site cysteine, as indicated by the fact that [14C]iodoacetate labeling was unaffected and that the effect of Zn2+ on the Y78F mutant was increased. The reduction potential of VHR was estimated to be -331 mV by utilizing the reversibility of the redox state of VHR. Thus, we conclude that the highly potent Cu2+ inactivation of VHR is a consequence of the oxidation of the active-site cysteine and the mode of Zn2+ inactivation is distinct from that of Cu2+.
Experiments on a nearly spin degenerate two-dimensional electron system reveals unusual hysteretic and relaxational transport in the fractional quantum Hall effect regime. The transition between the spin-polarized (with fill fraction nu = 1/3) and spin-unpolarized (nu = 2/5) states is accompanied by a complicated series of hysteresis loops reminiscent of a classical ferromagnet. In correlation with the hysteresis, magnetoresistance can either grow or decay logarithmically in time with remarkable persistence and does not saturate. In contrast to the established models of relaxation, the relaxation rate exhibits an anomalous divergence as temperature is reduced. These results indicate the presence of novel two-dimensional ferromagnetism with a complicated magnetic domain dynamic.
G(12)alpha/G(13)alpha transduces signals from G-protein-coupled receptors to stimulate growth-promoting pathways and the early response gene c-fos. Within the c-fos promoter lies a key regulatory site, the serum response element (SRE). Here we show a critical role for the tyrosine kinase PYK2 in muscarinic receptor type 1 and G(12)alpha/G(13)alpha signaling to an SRE reporter gene. A kinase-inactivate form of PYK2 (PYK2 KD) inhibits muscarinic receptor type 1 signaling to the SRE and PYK2 itself triggers SRE reporter gene activation through a RhoA-dependent pathway. Placing PYK2 downstream of G-protein activation but upstream of RhoA, the expression of PYK2 KD blocks the activation of an SRE reporter gene by GTPase-deficient forms of G(12)alpha or G(13)alpha but not by RhoA. The GTPase-deficient form of G(13)alpha triggers PYK2 kinase activity and PYK2 tyrosine phosphorylation, and co-expression of the RGS domain of p115 RhoGEF inhibits both responses. Finally, we show that in vivo G(13)alpha, although not G(12)alpha, readily associates with PYK2. Thus, G-protein-coupled receptors via G(13)alpha activation can use PYK2 to link to SRE-dependent gene expression.
Growth hormone and insulin are the primary determinants for cytochrome P450 2E1 (CYP2E1) expression. The role of glucose on the induction of CYP2E1 by hypophysectomy and on the restorative effect by growth hormone was investigated in the rat liver. Western and Northern blot analyses revealed that hypophysectomy induced CYP2E1 by 5-fold at 1-4 weeks, relative to control, with a concomitant increase in CYP2E1 mRNA. Hypophysectomized rats (HXR) showed a 20% reduction in the plasma glucose level. Hypophysectomy-induced increase in the CYP2E1 mRNA was completely abolished by glucose feeding in drinking water (10%) for 7 days. Treatment of HXR with hGH (2 I.U./kg, twice a day, for 7 days) inhibited the increases in CYP2E1 protein and mRNA levels with restoration of the plasma glucose level. In contrast to the effect of human growth hormone (hGH) on CYP2E1 in HXR with free access to foods, CYP2E1 expression failed to be restored by hGH in starving HXR. However, glucose feeding of starving HXR abolished the induction of CYP2E1. Effects of hypophysectomy and hGH treatment were studied in streptozotocin-induced diabetic rats. Insulin, but not hGH, prevented an increase in CYP2E1 mRNA in diabetic rats. The hepatic CYP2E1 induction in hypophysectomized diabetic rats was inhibited by hGH treatment, indicating that the hGH effect on CYP2E1 expression did not involve insulin production. These results provide evidence that the induction of hepatic CYP2E1 by hypophysectomy may result from reduced glucose utilization, and that the effect of hGH on CYP2E1 expression may be mediated with enhanced glucose utilization, but not with insulin production.
Capsaicin, a pungent ingredient of hot peppers, causes excitation of small sensory neurons, and thereby produces severe pain. A nonselective cation channel activated by capsaicin has been identified in sensory neurons and a cDNA encoding the channel has been cloned recently. However, an endogenous activator of the receptor has not yet been found. In this study, we show that several products of lipoxygenases directly activate the capsaicin-activated channel in isolated membrane patches of sensory neurons. Among them, 12- and 15-(S)-hydroperoxyeicosatetraenoic acids, 5- and 15-(S)-hydroxyeicosatetraenoic acids, and leukotriene B(4) possessed the highest potency. The eicosanoids also activated the cloned capsaicin receptor (VR1) expressed in HEK cells. Prostaglandins and unsaturated fatty acids failed to activate the channel. These results suggest a novel signaling mechanism underlying the pain sensory transduction.
A concise synthesis of a versatile chiral C4 building block for 2-aminoalkanols, (1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethylammo nium benzoate (1a), was described. 1 (1a and its enantiomer 1b) acted as four stereoisomers of optically active 2-amino-1,3,4-butanetriol. The versatility of 1 was demonstrated by its application to the practical synthesis of nelfinavir (2), a potent HIV-protease inhibitor, as well as by the stereospecific synthesis of three diastereomers of 2.