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Biomedical subjects

J Chen

Publications and source records attributed to J Chen.

At least 1,099 records · Page 61Linked to original sources
PubMed1999

Neuroprotective effects of progesterone after transient middle cerebral artery occlusion in rat.

Treatment of focal cerebral ischemia in the rat with intraperitoneal administration of progesterone dissolved in dimethyl sulfoxide (DMSO) has demonstrated therapeutic efficacy. In the present study we test whether iv administration of water soluble progesterone 2 h after the onset of middle cerebral artery occlusion provides therapeutic benefit for the treatment of stroke. In addition, we perform a battery of functional tests: rotarod, adhesive-backed somatosensory, and neurological score, as well as a dose-response study. The data indicate that iv administration of progesterone at a dose of 8 mg/kg significantly reduces the volume of cerebral infarction and significantly improves outcome on the array of functional measures employed. Treatment with 4 mg/kg or 32 mg/kg of progesterone failed to provide any therapeutic benefit. Progesterone, a non toxic, clinically employed, pluripotent therapeutic agent which targets both neuroprotective as well as neuroregenerative strategies, may have important therapeutic benefits for the treatment of stroke.

Animals↗
PubMed1999

Combination therapy with the farnesyl protein transferase inhibitor SCH66336 and SCH58500 (p53 adenovirus) in preclinical cancer models.

SCH66336 is a p.o.-active, farnesyl protein transferase inhibitor. SCH66336 inhibits farnesylation of RAS and other proteins in tumor cells and suppresses tumor growth in human xenograft and transgenic mouse cancer models in vivo. SCH58500 is a replication-deficient, recombinant adenovirus, which expresses the human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a wide range of human tumor types containing nonfunctional p53 and enhanced activity in combination with many chemotherapeutic drugs. Here we report that combination therapy with SCH66336 and SCH58500 has synergistic or additive antiproliferative effects on a panel of tumor cells lines in vitro. The efficacy of the three-drug combination of SCH66336, SCH58500, and paclitaxel was also examined in vitro. Each two-drug interaction displayed such marked synergy, the addition of a third drug to the statistical model could only yield additivity. Greater combined efficacy for SCH66336 and SCH58500 was also observed in vivo in the DU-145 human prostate and wap-ras/F transgenic mouse cancer models.

Adenocarcinoma↗
PubMed1999

Early beta-blocker therapy for acute myocardial infarction in elderly patients.

BACKGROUND: Despite the evidence supporting the importance of early beta-blocker therapy, this intervention has received little attention as an indicator of quality of care. OBJECTIVES: To determine how often beta-blockers are administered as early treatment of acute myocardial infarction in patients 65 years of age or older, to identify predictors of the decision to use beta-blockers, and to evaluate the association between the early use of beta-blockers and in-hospital mortality. DESIGN: Observational study. SETTING: Nongovernment, acute care hospitals in the United States. PATIENTS: Medicare beneficiaries who were 65 years of age or older, were hospitalized with an acute myocardial infarction in 1994 and 1995, and did not have a contraindication to beta-blocker therapy. MEASUREMENTS: Medical chart review to obtain information about the use of beta-blockers, contraindications to these drugs, patient demographics, and clinical factors. RESULTS: Of the 58 165 patients (from a total of 4414 hospitals), 28 256 (49%) received early beta-blocker therapy. Patients with the highest risk for in-hospital death were the least likely to receive therapy. Patients who received beta-blockers had a lower in-hospital mortality rate than patients who did not receive beta-blockers (odds ratio, 0.81 [95% CI, 0.75 to 0.87]), even after adjustment for baseline differences in demographic, clinical, and treatment characteristics between the two groups. CONCLUSIONS: Early beta-blocker therapy was not used for 51% of elderly patients who were hospitalized with an acute myocardial infarction and did not have a contraindication to this therapy. Increasing the early use of beta-blockers for these patients would provide an excellent opportunity to improve their care and outcomes.

Adrenergic beta-Antagonists↗
PubMed1999

Beta-blocker therapy for secondary prevention of myocardial infarction in elderly diabetic patients. Results from the National Cooperative Cardiovascular Project.

OBJECTIVES: We sought to determine the use and association with one-year mortality of beta-blocker therapy for the treatment of acute myocardial infarction (AMI) in elderly diabetic patients and to examine whether beta-blocker therapy was associated with increased rates of hospital readmission for diabetic complications traditionally associated with beta-blockers. BACKGROUND: Although many randomized trials have demonstrated that beta-blockers are effective in reducing mortality after AMI, some experts are concerned about the use of beta-blockers in diabetic patients. Little is known about the effectiveness and complication rate of beta-blocker therapy after AMI for elderly diabetics in community practice settings. METHODS: We conducted a retrospective cohort study using the National Cooperative Cardiovascular Project, which contained data abstracted from hospital medical records of Medicare beneficiaries admitted with an AMI during 1994 and 1995. RESULTS: Out of 45,308 patients without contraindications to beta-blocker therapy, 7.4% were insulin-treated diabetics and 18.5% were non-insulin-treated diabetics. Beta-blockers were prescribed at discharge for 45% of insulin-treated diabetics, 48.1% of non-insulin-treated diabetics and 51% of nondiabetics (p < 0.001). After adjusting for demographic and clinical factors, diabetics continued to be less likely to receive beta-blockers at discharge compared with nondiabetics (odds ratio [OR] for insulin-treated diabetics 0.88, 95% confidence interval [CI] 0.82 to 0.96; OR for non-insulin-treated diabetics 0.93, 95% CI 0.88 to 0.98). After adjusting for potential confounders, beta-blockers were associated with lower one-year mortality for insulin-treated diabetics (hazard ratio [HR] = 0.87, 95% CI 0.72 to 1.07), non-insulin-treated diabetics (HR = 0.77, 95% CI 0.67 to 0.88) and nondiabetics (HR = 0.87, 95% CI 0.80 to 0.94). Beta-blocker therapy was not significantly associated with increased six-month readmission rates for diabetic complications among diabetics and nondiabetics. CONCLUSIONS: Beta-blockers are associated with a lower one-year mortality rate for elderly diabetic patients to a similar extent as for nondiabetics, without increased risk of readmission for diabetic complications. Increasing the use of beta-blockers in elderly diabetic patients represents an opportunity to improve the care and outcomes of these patients after AMI.

Adrenergic beta-Antagonists↗
PubMed1999

NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP.

The inhibitor-of-apoptosis (IAP) family of proteins, originally identified in baculoviruses, regulate programmed cell death in a variety of organisms. IAPs inhibit specific enzymes (caspases) in the death cascade and contain one to three modules of a common 70-amino-acid motif called the BIR domain. Here we describe the nuclear magnetic resonance structure of a region encompassing the second BIR domain (BIR2) of a human IAP family member, XIAP (also called hILP or MIHA). The structure of the BIR domain consists of a three-stranded antiparallel beta-sheet and four alpha-helices and resembles a classical zinc finger. Unexpectedly, conserved amino acids within the linker region between the BIR1 and BIR2 domains were found to be critical for inhibiting caspase-3. The absence or presence of these residues may explain the differences in caspase inhibition observed for different truncated and full-length IAPs. Our data further indicate that these residues may bind to the active site and that the BIR domain may interact with an adjacent site on the enzyme.

Amino Acid Sequence↗
PubMed1999

Structure and function of the mammalian egg zona pellucida.

The zona pellucida is a thick extracellular coat that surrounds all mammalian eggs and preimplantation embryos. The zona pellucida supports communication between oocytes and follicle cells during oogenesis; protects oocytes, eggs, and embryos during development, and regulates interactions between ovulated eggs and free-swimming sperm during and following fertilization. Mutant females that produce eggs that lack a zona pellucida are infertile. The functions of the zona pellucida during fertilization now can be ascribed to certain of its glycoproteins. Here we describe some aspects of zona pellucida structure and function as they relate to mammalian fertilization. J. Exp. Zool. (Mol. Dev. Evol.) 285:251-258, 1999.

Animals↗
PubMed1999

Involvement of peripheral NMDA and non-NMDA receptors in development of persistent firing of spinal wide-dynamic-range neurons induced by subcutaneous bee venom injection in the cat.

To study the roles of peripheral excitatory amino acids receptor subtypes N-methyl-D-aspartate (NMDA) and non-NMDA receptors in persistent nociception, extracellular single unit recording technique was used to assess the effects of a single dose NMDA and non-NMDA receptor antagonists, AP(5) (5-aminophosphonovaleric acid) and CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) or DNQX (6,7-dinitroquinoxaline-2,3-dione), on s.c. bee venom-induced increase in firing of wide-dynamic-range (WDR) neurons in the spinal dorsal horn of the urethane-chloralose anesthetized cats. Subcutaneous bee venom injection into the cutaneous receptive field resulted in a single phase of increased firing of WDR neurons over the background activity for more than 1 h. Local pre-administration of AP(5) (200 microg/100 microl) or CNQX (8.3 microg/100 microl) into the bee venom injection site produced 94% (1.01+/-0.96 spikes/s, n=5) or 76% (2.97+/-0.58 spikes/s, n=4) suppression of the increased neuronal firing when compared with local saline (16.32+/-4.55 spikes/s, n=10) or dimethyl sulfoxide (DMSO) (12.37+/-6.36 spikes/s, n=4) pre-treated group, respectively. Local post-administration of the same dose of AP(5) produced a similar result to the pre-treatment group with a 67% inhibition of the mean firing rate, however, the same treatment with CNQX and even a higher dose of DNQX (100 microg/100 microl) did not produce any inhibition of the neuronal firing induced by s.c. bee venom injection (DNQX vs. DMSO: 23.91+/-0. 25 vs. 22.14+/-0.04 spikes/s, P=0.0298, n=5). In the control experiments, local pre-administration of the same dose of AP(5) or CNQX into a region on the contralateral hindpaw symmetrical to the bee venom injection site produced no significant influence on the increased firing of the WDR neurons [contralateral AP(5) vs. saline: 14.17+/-6.27 spikes/s (n=5) vs. 16.32+/-4.55 spikes/s (n=10), P0.05; contralateral CNQX vs. DMSO: 12.85+/-6.38 spikes/s (n=4) vs. 12. 37+/-6.36 spikes/s (n=4), P0.05], implicating that the suppressive action of local AP(5) or CNQX was not the result of systemic effects. The present results suggest that activation of the peripheral NMDA receptors is involved in both induction and maintenance, while activation of non-NMDA receptors is only involved in induction, but not in the maintenance of persistent firing of the dorsal horn WDR neurons induced by s.c. bee venom injection.

2-Amino-5-phosphonovalerate↗
PubMed1999

Emerging HIV infections with distinct subtypes of HIV-1 infection among injection drug users from geographically separate locations in Guangxi Province, China.

Heroin users from Guangxi province, a southern province of China that borders Vietnam in the south and Yunnan province in China in the west, were studied for prevalence and risk factors for HIV-1 infection. Viral env sequences from HIV-1-positive individuals were also determined for subtypes of HIV-1. The overall HIV prevalence among 227 heroin users was 40%. Most had used drugs for < or = 3 years. Sharing of injection equipment and unprotected sex were significantly associated with HIV-1 infection. Subtypes C and E HIV-1 were detected in infected heroin users and were sharply segregated in two geographic locations: only subtype C was found in a border city with Yunnan province, whereas only subtype E was found in a city bordering northern Vietnam. HIV-1 strains within each subtype were remarkably homogenous, with a mean intersubject DNA distance of 2.32% for subtype E and 1.13% for subtype C, respectively. Phylogenetic analysis of C2-V5 region of Guangxi subtype E env sequences revealed significant clustering with subtype E sequences from southern Vietnam and Cambodia. These results suggest that HIV-1 infection among heroin users in Guangxi represents two emerging epidemics initiated from distinct sources: one from Vietnam and another from Yunnan province. Factors associated with HIV-1 infection were not restricted to injection practices. Unprotected sexual behaviors are likely to increase the probability of HIV transmission beyond this high-risk population. Designing and implementing effective intervention strategies targeted toward both injection drug use and high risk sexual behavior are urgently needed to further reduce HIV-1 spread in China.

China↗
PubMed1999

Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways.

The proinflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha are produced within the CNS, and, similar to the periphery, they have pleotrophic and overlapping functions. We have shown previously that TNF-alpha increases neuronal survival to a toxic influx of calcium mediated through neuronal N-methyl-d -aspartic acid (NMDA) glutamate-gated ion channels. This process, termed excitotoxicity, is a major contributor to neuronal death following ischemia or stroke. Neuroprotection by this cytokine requires both activation of the p55/TNF receptor type I and the release of TNF-alpha from neurons, and it is inhibited by the plant alkaloid nicotine. Here, we report that other inflammatory cytokines (IL-1 alpha, IL-1 beta, and IL-6) are also neuroprotective to excessive NMDA challenge in our system. Neuroprotection provided by IL-1 is distinct from TNF-alpha because it is inhibited by IL-1 receptor antagonist; it is not antagonized by nicotine, but it is inhibited by a neutralizing Ab to nerve growth factor (NGF). Similar to IL-1, IL-6-mediated neuroprotection is also antagonized by pretreatment with IL-1 receptor antagonist and it is not affected by nicotine. However, neutralizing anti-NGF only partially blocks IL-6-mediated protection. These studies support an important role for distinct but overlapping neuroprotective cytokine effects in the CNS.

Animals↗
PubMed1999

[Effects of tea on DMBA-induced oral carcinogenesis in hamsters].

The preventive effects of green tea, tea pigments and mixed tea (a composite of whole water extract from green tea, tea polyphenols, and tea pigments) on 7, 12-dimethylbenz(a) anthracene(DMBA)-induced oral carcinogenesis in golden Syrian hamsters were studied. The hamsters were divided into five groups. i.e. the positive control group(the right buccal pouches of animal was topically treated with 0.5% DMBA in acetone three times per week for 15 weeks), three tea treated groups(1.5% green tea, 0.1% tea pigments and 0.5% mixed tea as the sole source of drinking water from two weeks before starting the DMBA treatment to the end of the experiment) and the negative control group(acetone applied topically). The results showed that in the 1.5% green tea, 0.1% tea pigments and 0.5% mixed tea groups, the inhibitory rates of the average number of tumor per hamster were 42.6%, 50.8% and 67.2% respectively, and the mean tumor burdens were 79% 89% and 95% respectively, compared with the positive control group. In the three tea groups, the frequency of micronucleated cells, the number of silver-stained nucleolar organizer regions (AgNOR), labeling index of proliferating cell nuclear antigen(PCNA) and the level of epidermal growth factor receptor(EGFR) expression in the oral mucosa cells were also less than those in the positive control group. These results clearly indicated that the mixed tea could effectively inhibit DMBA-induced oral carcinogenesis in hamsters. The mixed tea was more effective than green tea or tea pigments in this animal model. Protection of DNA from damage by carcinogen and suppression of cell proliferation was considered as important mechanisms of the anticarcinogenic effects of the mixed tea preparations.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

[Inhibitory effects of tea polyphenols and tea pigments on liver precancerous lesions in rats].

A liver precancerous model in rats was established with diethylnitorsamine(DEN) injected intraperitoneally as initiator and promoted by partial hepatectomy and injection of CCl4. The model was used to study the chemopreventive effect of tea polyphenols and tea pigments. A water solution of 0.1% tea polyphenols or tea pigments was given to Wistar rats as drinking water during the 56-day experiment period. A stable and sensitive early marker of liver cancer--GST-Pi positive foci or nodule was measured by a immunohistochemical method. Both tea polyphenols and tea pigments decreased the density and area of the GST-Pi foci. The expression of GST-Pi mRNA in chemical induced precancerous liver tissue was measured by Northern Blotting technique, and the expression of GST-Pi isoenzyme in liver tissue was detected by Western Blotting method. The results showed that both tea polyphenols and tea pigments effectively reduced the GST-Pi expression at both transcription and translation level. It is concluded that the inhibition of tea polyphenols and tea pigments on GST-Pi overexpression induced by chemical carinogen may be one of the mechanisms of their inhibition on the occurrence and progression of liver precancerous lesions in rats.

Animals↗
PubMed1999

Postmortem diffusion of autoradiographic blood flow tracers.

The heterogeneity of blood flow in the brain under normo- and pathophysiological conditions, as well as during functional activation, has stimulated an interest in the use of autoradiography as a technique for the measurement of local cerebral blood flow. [14C]iodoantipyrine is the most prevalent tracer for the autoradiographic measurement of local cerebral blood flow since it is inert, nonvolatile, and is readily diffusible through the blood-brain barrier. The ability to diffuse freely in cerebral tissue, however, can lead to significant errors if the time duration between when the animal is sacrificed and when the tissue is frozen becomes appreciable, leading to significant postmortem diffusion of the tracer. Using an in vitro technique, the bulk diffusion coefficient for [14C]iodoantipyrine was measured in brain tissue (2.1 x 10(-6) cm(2)/s). Cerebral blood flow was measured with [14C]iodoantipyrine in anesthetized rats. At the end of the radiotracer infusion, the brain was freeze-captured using a device consisting of two rapidly spinning stainless steel blades that were pneumatically driven through the head, freezing the tissue several hundred milliseconds following sacrifice. Autoradiograms from these brains exhibit considerable heterogeneity in blood flow. Computer simulations of the effect of tracer diffusion on these autoradiograms show significant degradation of the images highlighting the importance of very rapid postmortem freezing.

Algorithms↗
PubMed1999

Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine.

Acute exposure to cocaine transiently induces several Fos family transcription factors in the nucleus accumbens, a region of the brain that is important for addiction. In contrast, chronic exposure to cocaine does not induce these proteins, but instead causes the persistent expression of highly stable isoforms of deltaFosB. deltaFosB is also induced in the nucleus accumbens by repeated exposure to other drugs of abuse, including amphetamine, morphine, nicotine and phencyclidine. The sustained accumulation of deltaFosB in the nucleus accumbens indicates that this transcription factor may mediate some of the persistent neural and behavioural plasticity that accompanies chronic drug exposure. Using transgenic mice in which deltaFosB can be induced in adults in the subset of nucleus accumbens neurons in which cocaine induces the protein, we show that deltaFosB expression increases the responsiveness of an animal to the rewarding and locomotor-activating effects of cocaine. These effects of deltaFosB appear to be mediated partly by induction of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole) glutamate receptor subunit GluR2 in the nucleus accumbens. These results support a model in which deltaFosB, by altering gene expression, enhances sensitivity to cocaine and may thereby contribute to cocaine addiction.

Animals↗
PubMed1999

Kinetics of visual pigment regeneration in excised mouse eyes and in mice with a targeted disruption of the gene encoding interphotoreceptor retinoid-binding protein or arrestin.

Photoisomerization of 11-cis-retinal to all-trans-retinal and reduction to all-trans-retinol occur in photoreceptor outer segments whereas enzymatic esterification of all-trans-retinol, isomerization to 11-cis-retinol, and oxidation to 11-cis-retinal occur in adjacent cells. The processes are linked into a visual cycle by intercellular diffusion of retinoids. Knowledge of the mechanistic aspects of the visual cycle is very limited. In this study, we utilize chemical analysis of visual cycle retinoids to assess physiological roles for components inferred from in vitro experiments and to understand why excised mouse eyes fail to regenerate their bleached visual pigment. Flash illumination of excised mouse eyes or eyecups, in which regeneration of rhodopsin does not occur, produced a block in the visual cycle after all-trans-retinal formation; constant illumination of eyecups produced a block in the cycle after all-trans-retinol formation; and constant illumination of whole excised eyes resulted in a block of the cycle after formation of all-trans-retinyl ester. These blocks emphasize the role of cellular metabolism in the visual cycle. Interphotoreceptor retinoid-binding protein (IRBP) has been postulated to play a role in intercellular retinoid transfer in the retina; however, the rates of recovery of 11-cis-retinal and of regeneration of rhodopsin in the dark in IRBP-/- mice were very similar to those found with wild-type (wt) mice. Thus, IRBP is necessary for photoreceptor survival but is not essential for a normal rate of visual pigment turnover. Arrestin forms a complex with activated rhodopsin, quenches its activity, and affects the release of all-trans-retinal in vitro. The rate of recovery of 11-cis-retinal in arrestin-/- mice was modestly delayed relative to wt, and the rate of rhodopsin recovery was approximately 80% of that observed with wt mice. Thus, the absence of arrestin appeared to have a minor effect on the kinetics of the visual cycle.

Animals↗
PubMed1999

Synthesis and structure activity relationships of novel small molecule cathepsin D inhibitors.

Cathepsin D, a lysosomal aspartyl protease, has been implicated in the pathology of Alzheimer's disease as well as breast and ovarian cancer. A weakly active cathepsin D inhibitor was identified by high throughput screening. Subsequent optimization led to the discovery of a new class of small molecule inhibitors of this enzyme, culminating with the sulfonamide 13 (IC50 = 250 nM).

Cathepsin D↗
PubMed1999

Sequences of European wheat mosaic virus and oat golden stripe virus and genome analysis of the genus furovirus.

The complete nucleotide sequences of both RNAs of oat golden stripe virus (OGSV) and a wheat-infecting furovirus isolate from France, previously thought to be soil-borne wheat mosaic virus (SBWMV), have been determined. Both viruses had a similar genomic organisation to SBWMV and Chinese wheat mosaic virus, the two other furoviruses previously sequenced but had <70% nucleotides identical to them. The French isolate has been named European wheat mosaic virus (EWMV). Phylogenetic analyses supported the recognition of these isolates as distinct viruses in the genus Furovirus. Analysis of the coat protein readthrough domain on RNA2 of all furoviruses strongly predicts two mutually compatible conserved transmembrane domains that may be significant for fungus transmission. The second of these regions is eliminated by a deletion in the isolate of OGSV studied. Leaky opal (UGA) stop codons occur on both RNAs of all four furoviruses characterised and, in common with most other leaky opal codons identified in plant viruses, they are followed by a CGG codon.

Amino Acid Sequence↗
PubMed1999

Effect of species differences on stromelysin-1 (MMP-3) inhibitor potency. An explanation of inhibitor selectivity using homology modeling and chimeric proteins.

For an animal model to predict a compound's potential for treating human disease, inhibitor interactions with the cognate enzymes of separate species must be comparable. Rabbit and human isoforms of stromelysin-1 are highly homologous, yet there are clear and significant compound-specific differences in inhibitor potencies between these two enzymes. Using crystal structures of discordant inhibitors complexed with the human enzyme, we generated a rabbit enzyme homology model that was used to identify two unmatched residues near the active site that could explain the observed disparities. To test these observations, we designed and synthesized three chimeric mutants of the human enzyme containing the single (H224N and L226F) and double (H224N/L226F) mutations. A comparison of inhibitor potencies among the mutant and wild-type enzymes shows that the mutation of a single amino acid in the human enzyme, histidine 224 to asparagine, is sufficient to change the selectivity profile of the mutant to that of the rabbit isoform. These studies emphasize the importance of considering species differences, which can result from even minor protein sequence variations, for the critical enzymes in an animal disease model. Homology modeling provides a tool to identify key differences in isoforms that can significantly affect native enzyme activity.

Amino Acid Sequence↗