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Biomedical subjects

Y M Wang

Publications and source records attributed to Y M Wang.

At least 55 records · Page 3Linked to original sources
PubMed2000

Mice lacking the norepinephrine transporter are supersensitive to psychostimulants.

The action of norepinephrine (NE) is terminated, in part, by its uptake into presynaptic noradrenergic neurons by the plasma-membrane NE transporter (NET), which is a target for antidepressants and psychostimulants. Disruption of the NET gene in mice prolonged the clearance of NE and elevated extracellular levels of this catecholamine. In a classical test for antidepressant drugs, the NET-deficient (NET-/-) animals behaved like antidepressant-treated wild-type mice. Mutants were hyper-responsive to locomotor stimulation by cocaine or amphetamine. These responses were accompanied by dopamine D2/D3 receptor supersensitivity. Thus altering NET expression significantly modulates midbrain dopaminergic function, an effect that may be an important component of the actions of antidepressants and psychostimulants.

Amphetamine↗
PubMed2000

Purification, cloning and sequence analyses for pro-metalloprotease-disintegrin variants from Deinagkistrodon acutus venom and subclassification of the small venom metalloproteases.

Acidic and basic hemorrhagic metalloproteases were purified from the venom of Deinagkistrodon acutus (from Fujian Province, China) using gel filtration and anion exchange on FPLC and reversed-phase HPLC. Their hemorrhagic activities and N-terminal sequences were characterized. Extensive screening of the venom gland cDNA after PCR amplification resulted in the identification and sequencing of a total of seven cDNA clones encoding the multidomain precursors of six acidic and one alkaline low molecular mass metalloproteases. Two of the precursors contain a processable disintegrin domain. Disintegrins of 5 kDa were also purified from the venom. The partial amino-acid sequences and molecular masses determined by electrospray ionization mass spectrometry of the purified proteins specifically match those deduced from two of the cDNA sequences. Moreover, phylogenetic analyses based on 30 complete sequences of low molecular mass venom metalloproteases revealed that they may be classified into three functional subtypes: acidic hemorrhagins, basic and moderate hemorrhagins, and nonhemorrhagic enzymes. Subtype-specific amino-acid substitutions in the C-terminal regions of the enzymes were highlighted to explore the structure-activity relationships of the enzymes.

Agkistrodon↗
PubMed2000

Phospholipases A2 from Callosellasma rhodostoma venom gland cloning and sequencing of 10 of the cDNAs, three-dimensional modelling and chemical modification of the major isozyme.

Callosellasma rhodostoma (Malayan pitviper) is a monotypic Asian pitviper of medical importance. Three acidic phospholipases A2 (PLA2s) and one basic PLA2-homolog were purified from its venom while 10 cDNAs encoding distinct PLA2s were cloned from venom glands of a Thailand specimen of this species. Complete amino-acid sequences of the purified PLA2s were successfully deduced from their cDNA sequences. Among the six un-translated PLA2 cDNAs, two apparently result from recombination of its Lys49-PLA2 gene with its Asp49-PLA2 genes. The acidic PLA2s inhibit platelet-aggregation, while the noncatalytic PLA2-homolog induces local edema. This basic PLA2-homolog contains both Asp49 and other, unusual substitutions unique for the venom Lys49-PLA2 subtype (e.g. Leu5, Trp6, Asn28 and Arg34). Three-dimensional modelling of the basic protein revealed a heparin-binding region, and an abnormal calcium-binding pocket, which may explain its low catalytic activity. Oxidation of up to six of its Met residues or coinjection with heparin reduced its edema-inducing activity but methylation of its active site His48 did not. The distinct Arg/Lys-rich and Met-rich region at positions 10-36 of the PLA2 homolog presumably are involved in its heparin-binding and the cell membrane-interference leading to edema and myotoxicity.

Amino Acid Sequence↗
PubMed2000

Hypervariable region 1 sequence stability during hepatitis C virus replication in chimpanzees.

The putative envelope 2 (E2) gene of hepatitis C virus (HCV) contains a highly variable region referred to as hypervariable region 1 (HVR1). We hypothesized that this genetic variability is driven by immune selection pressure, rather than representing the accumulation of random mutations in a region with relatively little functional constraint. To test this hypothesis, we examined the E2 sequence of a human inoculum that was passaged through eight chimpanzees, which appear to have a replicative rate (opportunity for chance mutation) similar to that of humans. Acute-phase plasma samples from a human (the inoculum) and six of eight serially infected chimpanzees were studied. For each, 33 cloned cDNAs were examined by a combined heteroduplex-single-stranded conformational polymorphism assay to assess quasispecies complexity and optimize selection of clones with unique gel shift patterns (clonotypes) for sequencing. The sequence diversity of HCV was significantly lower in the chimpanzees than in the humans, and during eight serial passages there was no change in the sequence of the majority clonotype from each animal examined. Similarly, the rates of protein sequence altering (nonsynonymous) substitution were lower in the chimpanzees than in the humans. These findings demonstrate that nonsynonymous mutations indicate selection pressure rather than being an incidental result of HCV replication.

Amino Acid Sequence↗
PubMed2000

Fibrinogen levels and obstructive sleep apnea in ischemic stroke.

The plasma level of fibrinogen is felt to be an independent risk factor for vascular events. Obstructive sleep apnea (OSA) has a high prevalence in patients with stroke and may also be an independent risk factor. The aim of our study was to determine the association between OSA and plasma levels of fibrinogen in patients with stroke. Polysomnography was performed during neurological rehabilitation in 113 patients (82 men, 31 women, age 58 +/- 11.1 yr, mean +/- SD) with ischemic stroke. OSA was absent (RDI < 5) in 44 patients, 42 had mild OSA (5 < or = RDI < 20), and 27 had moderate to severe OSA (RDI > or = 20). Parameters of OSA (respiratory disturbance index [RDI], oxygen indices) were correlated to plasma levels of fibrinogen, measured in the morning after admission to rehabilitation. Fibrinogen was positively correlated with RDI (r = 0.24, p = 0.007), duration of the longest apnea (r = 0.18, p = 0.049), and negatively correlated with several oxygen indices including average minimal oxygen saturation (r = -0.41, p < 0.001). Correlation coefficients were slightly higher when excluding patients with stroke of presumed cardiac origin. Multiple linear regression identified minimal mean oxygen saturation and sex as independent predictors of fibrinogen level. The correlation between severity of coexisting OSA and fibrinogen level in patients with stroke suggests a possible pathophysiological mechanism for an increased risk of stroke in patients with OSA.

Aged↗
PubMed2000

[Analysis of phenylethanoid glycosides in the extract of herba Cistanchis by LC/ESI-MS/MS].

AIM: To analyze the phenylethanoid glycosides in Cistanche deserticola Y. D. Ma and its alternatives. METHODS: An HPLC/MS/MS method has been developed for the analysis of seven kinds of phenylethanoid glycosides in Cistanche deserticola Y. D. Ma, C. salsa (C. A. Mey) G. Beck and C. tubulosa (Schenk) R. Wight. The [M - H]- ions were observed for five standards and Cistanche extracts. The glycosidic linkages, the core, and the attached sugar (s) of the phenylethanoid glycosides can be determined from the collision-induced dissociation spectra of the molecular. RESULTS: Seven kinds of phenylethanoid glycosides (echinacoside, acteoside, cisacteoside, isoacteoside, 2'-acetylacteoside, cistanoside A, osmanthuside B) in Cistanche deserticola Y. D. Ma, six kinds (echinacoside, acteoside, cisacteoside, isoacteoside, 2'-acetylacteoside and cistanoside A) in C. salsa (C. A. Mey) G. Beck and five kinds (echinacoside, acteoside, cisacteoside, isoacteoside and 2'-acetylacteoside) in C. tubulosa (Schenk) R. Wight were detected. CONCLUSION: The difference of the relative distribution of these phenylethanoid glycosides in each extract was found out. Phenylethanoid glycosides are the specific constituents in Cistanchis, which can be used to distinguish different species in Genus Cistanchis.

Drugs, Chinese Herbal↗
PubMed1999

Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors.

Mapping the effects of alcohol consumption on neural activity could provide valuable information on mechanisms of alcohol's effects on behavior. The present study sought to identify effects of alcohol consumption on expression of inducible transcription factors (ITFs) in mouse brain. C57BL/6J mice were trained to consume 10% ethanol/10% sucrose solution during a 30-min limited access period. Control animals were given access to 10% sucrose solution or water. Following the final day of the procedure, animals were sacrificed and immunohistochemical analyses were performed for three ITFs (c-Fos, FosB, and Zif268). Alcohol-consuming animals had increased ITF expression in several brain areas. Specifically, c-Fos was significantly induced in the nucleus accumbens core (AcbC), the medial posteroventral portion of the central nucleus of the amygdala (CeMPV), and the Edinger-Westphal nucleus (EW). Expression of c-Fos was significantly lower in the dentate gyrus of alcohol-consuming animals vs. sucrose-consuming animals. However, it was not significantly different from the water controls. Induction of c-Fos in AcbC, CeMPV and EW was significantly related to blood alcohol concentrations (BAC). Furthermore, FosB expression in the CeMPV and the EW was also significantly higher in the alcohol-consuming animals vs. water controls. FosB expression in the EW was significantly related to BAC. The significance of these results is two-fold. First, our experiments demonstrate that ITF mapping is an effective strategy in identifying alcohol-induced changes following voluntary consumption. Second, they suggest a relationship between ITF expression in AcbC, CeMPV and EW and the level of alcohol intoxication.

Alcohol Drinking↗
PubMed1999

Genetic approaches to studying norepinephrine function: knockout of the mouse norepinephrine transporter gene.

Norepinephrine is an important chemical messenger in the nervous system. It regulates affective states, learning and memory, endocrine and autonomic functions. It has been implicated in depression, aggression, and addiction, as well as cardiac and thermal dysregulation. The norepinephrine transporter functions by uptaking norepinephrine back into the cell for cyclic use, and is a direct target of a number of antidepressants and psychostimulants. Functional deletion (knockout) of monamine transporters results in increases in extracellular levels of neurotransmitters, thereby prolonging their actions. For the norepinephrine transporter knockout mice, this altered state of the norepinephrine system should simulate the therapeutic effects of norepinephrine selective antidepressants and some of the effects of psychostimulants. Careful use of such an animal model can hopefully provide valuable insight into the multiple roles norepinephrine plays in normal and pathological physiology.

Animals↗
PubMed1999

The dopamine D2, but not D3 or D4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice.

Brain dopamine (DA) systems are involved in the modulation of the sensorimotor gating phenomenon known as prepulse inhibition (PPI). The class of D2-like receptors, including the D2, D3, and D4 receptor subtypes, have all been implicated in the control of PPI via studies of DA agonists and antagonists in rats. Nevertheless, the functional relevance of each receptor subtype remains unclear because these ligands are not specific. To determine the relevance of each receptor subtype, we used genetically altered strains of "knock-out" mice lacking the DA D2, D3, or D4 receptors. We tested the effects of each knock-out on both the phenotypic expression of PPI and the disruption of PPI produced by the indirect DA agonist d-amphetamine (AMPH). No phenotypic differences in PPI were observed at baseline. AMPH significantly disrupted PPI in the D2 (+/+) mice but had no effect in the D2 (-/-) mice. After AMPH treatment, both DA D3 and D4 receptor (+/+) and (-/-) mice had significant disruptions in PPI. These findings indicate that the AMPH-induced disruption of PPI is mediated via the DA D2 receptor and not the D3 or D4 receptor subtypes. Uncovering the neural mechanisms involved in PPI will further our understanding of the substrates of sensorimotor gating and could lead to better therapeutics to treat gating disorders, such as schizophrenia.

Acoustic Stimulation↗
PubMed1999

Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knock-out mice.

Methamphetamine (METH) is a powerful psychostimulant that is increasingly abused worldwide. Although it is commonly accepted that the dopaminergic system and oxidation of dopamine (DA) play pivotal roles in the neurotoxicity produced by this phenylethylamine, the primary source of DA responsible for this effect has remained elusive. In this study, we used mice heterozygous for vesicular monoamine transporter 2 (VMAT2 +/- mice) to determine whether impaired vesicular function alters the effects of METH. METH-induced dopaminergic neurotoxicity was increased in striatum of VMAT2 +/- mice compared with wild-type mice as revealed by a more consistent DA and metabolite depletion and a greater decrease in dopamine transporter expression. Interestingly, increased METH neurotoxicity in VMAT2 +/- mice was accompanied by less pronounced increase in extracellular DA and indices of free radical formation compared with wild-type mice. These results indicate that disruption of vesicular monoamine transport potentiates METH-induced neurotoxicity in vivo and point, albeit indirectly, to a greater contribution of intraneuronal DA redistribution rather than extraneuronal overflow on mediating this effect.

Animals↗
PubMed1999

Atypical PKC zeta is activated by ceramide, resulting in coactivation of NF-kappaB/JNK kinase and cell survival.

Both protein kinase C (PKC) and ceramide play a critical role in cell signaling, but the relationship between PKC and ceramide is unclear. Low concentrations of ceramide were observed to transiently stimulate PKC zeta activity in vitro and in vivo, whereas high doses of ceramide lead to inhibition of PKC zeta. Inhibition of activity was accompanied by enhanced binding of the negative regulator, Par4 to PKC zeta. Treatment of PC12 cells with low doses of ceramide promoted survival in serum-free media and activation of nuclear factor-KB, whereas higher doses (>2.5 microM) resulted in cell death. Overexpression of either aPKC isoform, PKC zeta or iota, resulted in enhanced survival of PC12 cells at high doses of ceramide and in ceramide-stimulated Jun N-terminal kinase (JNK), without any apparent effect on mitogen-activated kinase. These findings support a role for ceramide-induced PKC zeta activity in the control of cell survival signaling via a pathway that also activates JNK kinase.

Animals↗
PubMed1999

[Obstructive sleep apnea syndrome. A probably cause of therapy refractory hypertension in intracerebral hemorrhage].

There is clear evidence for obstructive sleep apnea as an independent cause of arterial hypertension. We report a case of intracranial hemorrhage with systemic hypertension resistant to antihypertensive medication, which could only be adjusted after effective treatment of coexisting sleep-disordered breathing. The 36 year old male (body mass index 31 kg/m2) was admitted to hospital three weeks before for intracranial bleeding at the left external capsule. Diagnosis of primary hypertension was made after extensive work-up in the acute hospital. Blood pressure was adjusted with five-fold antihypertensive medication at the time of admission to neurological rehabilitation, but was still elevated with "non-dipping" as determined by long-term measurement despite medications above the recommended dosages. Polysomnography confirmed the diagnosis of obstructive sleep apnea. 10 days after initiation of treatment with nasal CPAP blood pressure control was easier with normal dipping at night. Medication could be reduced during rehabilitation with further reduction after discharge. Moderate obstructive sleep apnea appears to be the cause of severe hypertension resistant to pharmacological therapy in this patient. The case underlines the impact of diagnosis and treatment of sleep-disordered breathing for the secondary prevention of stroke.

Antihypertensive Agents↗
PubMed1999

Suppression of hepatitis C virus by hepatitis B virus in coinfected patients at the National University Hospital of Singapore.

This study was carried out to compare hepatitis B virus (HBV) and hepatitis C virus (HCV) replicative states and to determine possible interference between HBV and HCV. One thousand and sixty-one consecutive patients seen at The Gastroenterology Division of the National University Hospital of Singapore between 1988 and 1995 were screened for HBV and HCV serological markers. Anti-HCV was tested using a second-generation enzyme-linked immunosorbent assay (ELISA) method. HCV-RNA was detected by a reverse-transcription polymerase chain reaction method (RT-PCR). Data were analyzed by either paired t-test or chi2 test. Two hundred and twenty-four patients were infected with HBV alone, while 117 patients were infected with HCV only. Thirty-one patients were coinfected with HBV and HCV. HCV-RNA was detected in 104 of the 117 HCV patients (88.9%), and in 12 of 29 coinfected patients (41.4%). Serum anti-HCV levels in the coinfected patients were lower than those in the HCV-infected patients. A significant difference for anti-HCV reactivity and HCV-RNA positivity was observed between HCV-infected patients and coinfected patients (P < 0.01). In contrast, HBV-DNA and hepatitis B envelope antigen (HBeAg) positive rates were similar in HBV carriers and patients coinfected with HBV and HCV. These results show a possible interaction between HBV and HCV life cycles, and suggest that HCV replication may be negatively affected by HBV.

Adult↗
PubMed1999

Detection of pre-S/S gene mutants in chronic hepatitis B carriers with concurrent hepatitis B surface antibody and hepatitis B surface antigen.

Hepatitis B virus (HBV) with various mutations has been reported. The frequency of the natural occurrence of such variants and whether the heterogeneity of these genomic regions correlates with a specific serologic pattern of concurrent hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) were investigated. We analyzed the perS/S regions of HBV in six asymptomatic HBV carriers who were seropositive for both HBsAg and anti-HBs (group A), four hepatocellular carcinoma (HCC) patients with concurrent HBsAg and anti-HBs (group B), and five asymptomatic HBV carriers without anti-HBs as controls (group C). PreS/S regions of HBV-DNA were amplified by polymerase chain reaction (PCR), cloned, and sequenced. The results showed that, in some of the samples, a few deletions and numerous point mutations were presented in preS/S regions. One of the HBV carriers with anti-HBs (group A) and an HCC patient with anti-HBs (group B) had point mutations in the "a" determinant, resulting in conversion from Ile-126 of wild-type to Asn-126. The patients with anti-HBs (groups A and B) had a significantly greater divergence rate of amino acid for the preS/S gene compared with controls. Our results suggested that the HBV mutants observed in the preS/S gene may have led to changes in the immunogenicity of the viral particles, and thus influence the viral behavior and clinical course. Therefore, some HBV patients with concurrent HBsAg and anti-HBs may be HBV S mutants.

Adult↗
PubMed1999

Different levels of Fos immunoreactivity after repeated handling and injection stress in two inbred strains of mice.

Expression of Fos and Fos-related antigens was immunohistochemically analyzed in DBA/2J and C57BL/6J inbred mice in response to acute or repeated handling and injection stress. Both strains showed a strong induction of Fos and Fos-related antigens in discrete areas of hypothalamus, amygdala, neocortex, septum, and thalamus 2 h after an acute intraperitoneal injection of normal saline. To habituate animals to this procedure, mice were subjected to repeated handling and injections during 2 weeks preceding the experiment. This procedure led to complete habituation of the immediate early gene response to injection stress in stress-responsive brain areas of C57BL/6J mice, such that no significant difference was found between expression of these proteins in brains of saline-injected animals after repeated stress vs. control animals. In contrast, many brain areas of saline-injected DBA/2J mice still showed elevated Fos and Fos-related antigen expression after repeated injections. These results indicate that identical habituation procedures do not necessarily lead to identical levels of gene expression in brains of inbred strains of mice. In turn, they suggest that genetic components for some behavioral and pharmacological traits identified using inbred strains could be related to different rates of habituation to experimental procedures.

Animals↗
PubMed1999

Neonatal platelet counts in fetal brain injury.

UNLABELLED: The objective of this study was to determine whether neonatal platelet counts can be used in fetal brain injury. The initial platelet counts, expressed as 1000 per mm3, of singleton term infants with and without permanent asphyxial brain injury were compared. Neonates with encephalopathy were divided into 3 groups: I--nonreactive fetal heart rate (FHR) pattern from admission until delivery; II--reactive FHR pattern on admission followed by nonreactivity, tachycardia, a loss of variability and repetitive FHR decelerations; and III--acute: reactive FHR pattern followed by a sudden prolonged FHR deceleration that lasted until delivery. The neonates and platelet counts for each group were as follows: CONTROL: 104 neonates, mean 281 +/- 56, range 154 to 411; I: 60, mean 185 +/- 80, range 28 to 365; II: 34, mean 251 +/- 66, range 100 to 375; and III: 35, mean 267 +/- 93, range 86 to 569. Platelet counts were significantly lower in neonates with encephalopathy (p <0.001). Group I differed statistically from both Groups II and III (p <0.001). These data suggest an association between the FHR pattern, fetal asphyxial brain injury, and the initial platelet count in singleton term neonates. Further investigation should be pursued to clarify the physiological processes leading to this result.

Brain Diseases↗
PubMed1999

Selective effects of alcohol drinking on restraint-induced expression of immediate early genes in mouse brain.

BACKGROUND: Analysis of immediate early gene expression in brain is a common contemporary method for mapping changes in neuronal activation with cellular resolution. This method has been applied previously in models of involuntary alcohol exposure. In this study, immunohistochemical expression analysis of immediate early genes c-fos, fosB, and zif268 was performed in brain of C57BL/6J mice after voluntary alcohol consumption. METHODS: Mice were trained to consume 10% ethanol/10% sucrose, using a 30-min limited-access paradigm. Animals consumed approximately 1.5 g/kg of ethanol per session. Control animals consumed 10% sucrose solution. Gene expression was determined in half of the animals 1.5 hr after the drinking session. Gene expression in the remaining animals was determined after 0.5 hr of restraint stress, which is known to elevate expression of immediate early genes in many brain regions. Analysis of the stressed animals was also performed 1.5 hr after the drinking session. RESULTS: Blood alcohol concentrations were significantly reduced in animals exposed to restraint stress. However, stressed mice showed the greatest alcohol-induced changes in gene expression. Specifically, animals consuming ethanol/sucrose with subsequent exposure to restraint stress had lower c-Fos expression in the CA3 region of hippocampus, and higher c-Fos expression in nucleus accumbens than mice exposed to restraint stress after drinking the sucrose solution. Consumption of the ethanol/sucrose solution also significantly reduced FosB expression in the basolateral amygdala and lateral hypothalamus, and Zif268 expression in the CA1 region of the hippocampus of stressed animals. CONCLUSIONS: These data confirm previous observations showing selective effects of alcohol administration on immediate early gene expression. Furthermore, the effects of voluntary alcohol self-administration on immediate early gene expression differ from involuntary alcohol exposure and suggest several brain regions as substrates for alcohol consumption.

Alcohol Drinking↗