Biomedical subjects

Zhiming Zhang

Publications and source records attributed to Zhiming Zhang.

At least 19 recordsLinked to original sources

PubMed2006

Magnetic properties of conducting polymer nanostructures.

Magnetic susceptibility measurements on conducting polyaniline and polypyrrole nanostructures with different dopant type and doping level as functions of temperature and magnetic field are reported. The susceptibility data cannot be simply described as Curie-like susceptibility at lower temperatures and temperature-independent Pauli-like susceptibility at higher temperatures; some unusual transitions are observed in the temperature dependence of susceptibility, for example, paramagnetic susceptibility decreases gradually with lowering temperature, which suggests the coexistence of polarons and spinless bipolarons and possible formation of bipolarons with changing temperature or doping level. In particular, it is found that the direct current magnetic susceptibilities are strongly dependent on applied magnetic field, dopant type, and doping level.

Journal Article↗

PubMed2006

SAR studies of 6-(arylamino)-4,4-disubstituted-1-methyl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones as progesterone receptor antagonists.

We previously disclosed that 6-aryl benzoxazin-2-ones were PR modulators. In a continuation of this work we examined the SAR of new 6-arylamino benzoxazinones and found the targets 1-25, with an extra amino linker between the pendent 6-aryl groups and benzoxazinone or benzoxazine-2-thione core, were PR antagonists. A series of compounds with substituents at the 1- and 4-positions as well as different 6-aryl groups were prepared and tested in the T47D cell alkaline phosphatase assay. Interestingly, the SAR unveiled from the 6-arylamino benzoxazinones was quite different from those of their parent compounds. For example, in contrast to the 6-aryl benzoxazinones, methyl substitution at the 1-position significantly increased the potency of 6-arylamino benzoxazinones. Several 6-arylamino benzoxazinones (e.g., 12, IC(50)=5.0 nM) had low nanomolar in vitro potency as PR antagonists in the T47D cell alkaline phosphatase assay.

Benzoxazines↗

PubMed2006

Point source concentration of GDNF may explain failure of phase II clinical trial.

Significant differences have been reported in results from three clinical trials evaluating intraputamenal infusion of glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease. To determine if problems in drug bioavailability could have contributed to the discrepancies between studies, we have analyzed the distribution of intraputamenally infused GDNF in the rhesus monkey brain using the delivery system and infusion protocol followed in a phase 2 clinical trial that failed to achieve its primary endpoint. I125-GDNF was unilaterally infused into the putamen of three adult rhesus monkeys for 7 days. Three age- and sex-matched animals received vehicle infusions following identical procedures. GDNF levels in the brain, peripheral organs, blood and CSF were quantified and mapped by GDNF immunocytochemistry, GDNF ELISAs and I125 measurements. Infused GDNF was found to be unevenly concentrated around the catheter, with tissue levels dropping exponentially with increasing distance from the point source of the single opening in the catheter tip. The volume of distribution of GDNF around the catheter, as determined by immunocytochemistry, varied over four-fold between animals ranging from 87 to 369 mm3. The concentration of GDNF around the catheter tip and limited diffusion into surrounding brain parenchyma support the hypothesis that drug bioavailability was limited to a small portion (2-9%) of the human putamen in the clinical trial using this catheter and infusion protocol.

Animals↗

PubMed2006

Assessing nigrostriatal dysfunctions by pharmacological MRI in parkinsonian rhesus macaques.

New imaging techniques are needed to longitudinally monitor the development, progression and treatment of Parkinson's disease. The present study was designed to test whether the blood oxygenation level-dependent (BOLD) response to dopaminergic stimulation as measured by pharmacological MRI (phMRI) correlated to specific histological and behavioral features of the parkinsonian state. Nine adult rhesus monkeys were rendered hemiparkinsonian by intracarotid administration of MPTP. Three months after MPTP treatment, the trained, MRI-adapted awake animals were scanned with a phMRI technique while being administered a presynaptic (D-amphetamine) or postsynaptic (apomorphine) dopamine stimulating agents. The primary findings were (1) the putamen and substantia nigra (SN) but not the caudate nucleus displayed significant BOLD responses to these dopaminergic drugs; (2) a significant relationship was found between amphetamine-evoked activation and the number of surviving dopamine neurons in the SN, which was also correlated with bradykinesia; and (3) inverse relationships were seen in response to apomorphine and amphetamine stimulation between the MPTP-lesioned and unlesioned putamen and SN. The results suggest that phMRI may prove useful for longitudinally monitoring the progression and treatment of PD.

Animals↗

PubMed2006

Development of a mouse model of mammary gland versus uterus tissue selectivity using estrogen- and progesterone-regulated gene markers.

We have identified mRNA markers of estradiol and progesterone action in the mouse mammary gland and uterus to establish an in vivo model for the evaluation of novel and potentially tissue selective estrogens and progestins. Gene chip analysis of mRNA from ovariectomized (OVX) mice treated with vehicle (V), 17beta-estradiol (E2), progesterone (P) or E2+P for 7 days identified defensinbeta1 (Defbeta1) and indoleamine-pyrrole 2,3 dioxygenase (INDO) as markers of E2 and P action in the mammary gland, and serine protease inhibitor, Kazal type 3 (Spink3) and G protein-coupled receptor 105 (GPR105) as markers in the uterus. Defbeta1 and Spink3 are both upregulated by E2+P, whereas INDO and GPR105 have a complementary profile of upregulation by E2 alone and suppression of the E2 effect by P. Quantitative RT-PCR analysis of mammary gland markers was concordant with histological changes. Using this model, medroxyprogesterone acetate (MPA) and tanaproget (TNPR), a novel nonsteroidal progesterone receptor agonist, were evaluated and found to have no marked tissue selectivity relative to progesterone. In addition, the ERalpha selective ligand propyl pyrazole triol (PPT) and the ERbeta selective ligands ERB-041 and WAY-202196 were evaluated on the mammary gland endpoints of histology and Defbeta1 mRNA expression, and showed that ERalpha stimulation is necessary and sufficient for eliciting estradiol-mediated changes in the mammary gland.

Animals↗

PubMed2006

Synthesis, characterization, and crystal structures of two novel high-nuclear nickel-substituted dimeric polyoxometalates.

Two novel high-nuclear Ni-substituted polyoxometalates Na9K[Ni7(OH)4(H2O)(CO3)2(HCO3)(A-alpha-SiW9O34)(beta-SiW10O37)].5H3O.18H2O (1) and K6Na4[{Ni6(H2O)4(mu2-H2O)4(mu3-OH)2}(x-SiW9O34)2].17.5H2O (2) have been obtained by reaction of K(8)[gamma-SiW10O36] with NiCl2.2H2O in basic conditions. Compounds 1 and 2 all represent the first polyoxometalates substituted by seven and six Ni centers, respectively. Also, compound 1 exhibits a novel asymmetric dimeric structure, composed of [A-alpha-SiW9O34]10- and [beta-SiW10O37]10- units linked by a Ni7 cluster and three carbonates, which exhibit tri- and bidentate coordination modes in 1.

Journal Article↗

PubMed2006

fMRI in alert, behaving monkeys: an adaptation of the human infant familiarization novelty preference procedure.

Functional magnetic resonance imaging (fMRI) is increasingly used in non-human primate research. In the present study, we adapt the familiarization-novelty preference (FNP) procedure used in human infant research to examine visual behavior in alert, unanaesthetized rhesus monkeys that were acclimated to the fMRI environment, but did not undergo behavioral training. In keeping with the typical FNP paradigm, we recorded eye movements (looking time and number of fixations) while monkeys viewed a series of four identical pictures (familiarization phase) followed by two different pictures (novelty phase). Number of fixations and looking time both increased during the novelty phase, thereby demonstrating visual discrimination of the new from the old picture. Importantly, discrimination did not occur on catch trials in which six identical pictures were presented. Moreover, brain activation in the amygdala was more strongly associated with the novelty phase than with the familiarization phase. In addition, magnitude of brain activation in the amygdala was correlated with the behavioral effect of visual discrimination. These findings demonstrate the feasibility of using eye movements as an index of visual discrimination in untrained monkeys during fMRI scanning. This methodological approach helps to extend the repertoire of research tools for fMRI in non-human primates.

Adaptation, Physiological↗

PubMed2006

Iron accumulation in the striatum predicts aging-related decline in motor function in rhesus monkeys.

Changes in the nigrostriatal system may be involved with the motor abnormalities seen in aging. These perturbations include alterations in dopamine (DA) release, regulation and transport in the striatum and substantia nigra, striatal atrophy and elevated iron levels in the basal ganglia. However, the relative contribution of these changes to the motor deficits seen in aging is unclear. Thus, using the rhesus monkey as a model, the present study was designed to examine several of these key alterations in the basal ganglia in order to help elucidate the mechanisms contributing to age-related motor decline. First, 32 female rhesus monkeys ranging from 4 to 32 years old were evaluated for their motor capabilities using an automated hand-retrieval task. Second, non-invasive MRI methods were used to estimate brain composition and to indirectly measure relative iron content in the striatum and substantia nigra. Third, in vivo microdialysis was used to evaluate basal and stimulus-evoked levels of DA and its metabolites in the striatum and substantia nigra of the same monkeys. Our results demonstrated significant decreases in motor performance, decreases in striatal DA release, and increases in striatal iron levels in rhesus monkeys as they age from young adulthood. A comprehensive statistical analysis relating age, motor performance, DA release, and iron content indicated that the best predictor of decreases in motor ability, above and beyond levels of performance that could be explained by age alone, was iron accumulation in the striatum. This suggests that striatal iron levels may be a biomarker of motor dysfunction in aging; and as such, can be monitored non-invasively by longitudinal brain MRI scans. The results also suggest that treatments aimed at reducing accumulation of excess iron in the striatum during normal aging may have beneficial effects on age-related deterioration of motor performance.

Aging↗

PubMed2006

Down-regulation of endometrial matrix metalloproteinase-3 and -7 expression in vitro and therapeutic regression of experimental endometriosis in vivo by a novel nonsteroidal progesterone receptor agonist, tanaproget.

CONTEXT: Endometriosis, the growth of endometrial tissue outside the uterus, is principally an estrogen-dependent disease. In contrast, exposure to progesterone during pregnancy or therapeutically has been shown to provide benefit to some women with this disease. However, recent research suggests that the presence of endometriosis impairs the capacity of the eutopic endometrium to respond to endogenous progesterone. OBJECTIVE: Reduced progesterone responsiveness results in an elevated endometrial expression of matrix metalloproteinases (MMPs) during the secretory phase of the menstrual cycle in women with endometriosis. Although cyclic MMP expression is critical for endometrial growth and remodeling, the failure of progesterone to down-regulate MMPs may impair nidation and promote the invasive establishment of endometriosis. In the current study we examined the ability of a newly developed progesterone receptor (PR) agonist, tanaproget (TNPR), to down-regulate endometrial MMP expression in vitro and regress experimental endometriosis in vivo. SETTING: This study was performed at a university-based medical center. PARTICIPANTS: Asymptomatic volunteers and patients with endometriosis were studied. MAIN OUTCOME MEASURES: We examined the ability of TNPR to down-regulate endometrial MMP expression in vitro compared with that of natural progesterone and two currently marketed synthetic steroidal progestins. Using a human/mouse model of endometriosis, we also tested the in vivo ability of TNPR to regress ectopic lesions established by tissues with reduced progesterone sensitivity. RESULTS: TNPR effectively down-regulated MMP expression in vitro and induced significant reduction of lesions in mice with disease established by tissues from endometriosis patients. CONCLUSION: Given the positive preclinical pharmacological profile of TNPR that has recently been reported, additional development of this compound for the treatment of endometriosis is warranted.

Adolescent↗

PubMed2005

Synthesis and structure-activity relationship of novel 6-aryl-1,4-dihydrobenzo[d][1,3]oxazine-2-thiones as progesterone receptor modulators leading to the potent and selective nonsteroidal progesterone receptor agonist tanaproget.

Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.

Alkaline Phosphatase↗

PubMed2005

SAR studies of 6-aryl-1,3-dihydrobenzimidazol-2-ones as progesterone receptor antagonists.

We have previously reported that the aryl substituted benzimidazolones, benzoxazinones, and oxindoles (e.g., 1-3) are progesterone receptor (PR) antagonists and have recently disclosed that the nature of 5- and 6-aryl moieties played a critical role in PR functional activity in the oxindole and benzoxazinone templates. For example, replacing the phenyl group of PR antagonists 2 and 3 with a 5'-cyanopyrrol-2'-yl moiety switched their functional activity to PR agonist activity (2a and 3a). These findings prompted us to examine if there is a similar effect of the 6-aryl moieties on the PR functional activity for the benzimidazolone template. Numerous analogs, such as 5, showed potent PR antagonist activity with about a 10-fold increase in potency as compared to those reported earlier in the same series. More interestingly, pyrrole-containing benzimidazolones 24-27 remained as PR antagonists in contrast to the PR agonist activity switch for oxindole and benzoxazinone scaffolds when a 5'-cyanopyrrol-2'-yl group was installed as a pendant aryl group.

Benzimidazoles↗

PubMed2005

Molecular and pharmacological properties of a potent and selective novel nonsteroidal progesterone receptor agonist tanaproget.

Progesterone receptor (PR) agonists have several important applications in women's health, such as in oral contraception and post-menopausal hormone therapy. Currently, all PR agonists used clinically are steroids. Because of their interactions with other steroid receptors, steroid-metabolizing enzymes, or other steroid-signaling pathways, these drugs can pose significant side effects in some women. Efforts to discover novel nonsteroidal PR agonists with improved biological properties led to the discovery of tanaproget (TNPR). TNPR binds to the PR from various species with a higher relative affinity than reference steroidal progestins. In T47D cells, TNPR induces alkaline phosphatase activity with an EC(50) value of 0.1 nm, comparable with potent steroidal progestins such as medroxyprogesterone acetate (MPA) and trimegestone (TMG), albeit with a reduced efficacy ( approximately 60%). In a mammalian two-hybrid assay to measure PR agonist-induced interaction between steroid receptor co-activator-1 and PR, TNPR showed similar potency (EC(50) value of 0.02 nm) and efficacy to MPA and TMG. Importantly, in key animal models such as the rat ovulation inhibition assay, TNPR demonstrates full efficacy and an enhanced progestational potency (30-fold) when compared with MPA and TMG. Furthermore, TNPR has relatively weak interactions with other steroid receptors and binding proteins and little effect on cytochrome P450 metabolic pathways. Finally, the three-dimensional crystal structure of the PR ligand binding domain with TNPR has been delineated to demonstrate how this nonsteroidal ligand achieves its high binding affinity. Therefore, TNPR is a structurally novel and very selective PR agonist with an improved preclinical pharmacological profile.

Alkaline Phosphatase↗

PubMed2005

Trophic factor distribution predicts functional recovery in parkinsonian monkeys.

Glial cell line-derived neurotrophic factor (GDNF) promotes the survival, growth, and regeneration of dopamine neurons in the midbrain that degenerate in Parkinson's disease. However, translating successful animal studies into effective clinical therapy for Parkinson's disease has proved difficult. In this article, using pulsed infusion for convection-enhanced delivery of GDNF, we have analyzed two variables hypothesized to be important for achieving efficacy: dose and GDNF distribution in the target tissue. Motor functions were significantly improved in rhesus monkeys with unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism that received midbrain infusion of GDNF for 10 weeks. The volume of distribution of GDNF in the five trophic factor recipients varied more than fivefold, from 59 to 325 mm3, and significantly correlated with motor function improvements. Significant increases were evident in the number of midbrain dopamine neurons immunopositive for tyrosine hydroxylase in both the substantia nigra and ventral tegmental area. Based on neurochemical and quantitative morphological measures, GDNF administration promoted recovery of both the nigrostriatal and ventral tegmental area-nucleus accumbens dopaminergic pathways without producing evident side effects. Increasing the dose threefold did not increase efficacy, suggesting that after achieving a critical threshold, GDNF tissue distribution is more important than dose for trophic stimulation of dopamine neurons.

Analysis of Variance↗

PubMed2005

Correlation of R2 with total iron concentration in the brains of rhesus monkeys.

PURPOSE: To estimate the relationship between R2 = 1/T2 as measured with a double echo spin echo sequence and total iron concentration in gray matter structures in the brains of aging rhesus monkeys. MATERIALS AND METHODS: Using a 1.5-T magnetic resonance (MR) imager, we collected double echo spin echo images of the brains of 12 female rhesus monkeys aged between 9 and 23 years. From the double echo images, the transverse relaxation rate R2 = 1/T2 was calculated in selected gray matter regions. After the animals were euthanized, their brains were excised and tissue punches were taken of the substantia nigra, globus pallidus, and gray matter regions of the cerebellum. Some of the tissue punches were assayed for total iron using atomic absorption spectroscopy. RESULTS: The range of tissue iron concentration spanned from 15 to 450 microg/g wet weight, with the highest levels in the globus pallidus and the lowest levels in the cerebellum. The results show that R2 was highly correlated with the total iron concentration and that the relationship between R2 and tissue iron concentration appeared to depend upon the iron concentration. For concentrations above approximately 150 microg/g wet weight, R2 increased with a sensitivity of 0.0484 +/- 0.0023 second(-1)(microg/g)(-1). In contrast, where the iron concentration was below 150 microg/g, R2 increased at 0.0013 +/- 0.0073 second(-1)(microg/g)(-1). The bilinear behavior may reflect changes with age in the relative amounts of iron distributed diffusely and in granular form in the globus pallidus and substantia nigra. Histological sections of the tissues stained for iron and ferritin support this hypothesis and indicate that the distribution of ferritin is similar to the distribution of iron. CONCLUSION: This study reaffirms the value of measuring the MR relaxation rate R2 for a noninvasive estimate of iron content in the brain and identified limitations in the relationship at low tissue iron concentrations.

Aging↗

PubMed2005

Differential effects of estrogens and progestins on the anticoagulant tissue factor pathway inhibitor in the rat.

Oral contraceptives (OC) and postmenopausal hormone therapy (HT) modulate plasma levels of proteins that regulate blood coagulation. It remains unclear whether the progestin component contributes to these changes. The present study was designed to determine whether progestins modulate two essential plasma anticoagulants, antithrombin (AT) and tissue factor pathway inhibitor (TFPI), in an animal model. Ovariectomized rats were treated orally with three progestins, norethindrone acetate (NETA), trimegestone (TMG), or drospirenone (DSP), either alone or combined with 17alpha-ethyinylestradiol (EE). Plasma AT levels were unchanged. However, TFPI activity was reduced by EE alone (10-100 microg/kg/day) in a dose-dependent manner; NETA (3 or 10 mg/kg/day) reduced TFPI by approximately 40 or approximately 80%, respectively, while TMG and DSP had no effect. NETA and EE effects were blocked by co-administration of ICI-182,780, an estrogen receptor antagonist, suggesting that both responses were likely estrogen receptor-mediated. Reduced TFPI after NETA or EE treatment was not accompanied by changes in TFPI mRNA levels in tissues that express TFPI, but there was a positive correlation between plasma TFPI and total cholesterol. Sex hormone effects on TFPI in this model and as reported in women may help to shift the coagulation balance to a more prothrombotic state. Progestins such as TMG and DSP that lack estrogenic activity could potentially have an improved clinical profile.

Androstenes↗

PubMed2005

Nonsteroidal progesterone receptor modulators: structure activity relationships.

Progesterone, acting primarily via the progesterone receptor (PR), plays an essential role in the regulation of female reproduction. Steroidal progestins (i.e., PR agonists) are commonly used in women's health, such as in contraception and hormone therapy and for the treatment of gynecological disorders. Recent studies in women and in nonhuman primates also indicate that PR antagonists may have potential applications in contraception and for the treatment of reproductive disorders such as fibroids and endometriosis. Currently, all clinically available PR agonists and antagonists are steroidal compounds. They often cause various side effects due to their functional interactions with other steroid receptors or because of effects associated with their steroidal metabolites. In an effort to identify more receptor-selective and structurally diverse compounds that may render clinical advantages over steroidal PR ligands, numerous receptor-selective novel nonsteroidal PR agonists and antagonists have been discovered. This review focuses on the structure activity relationships and the biological profile of the nonsteroidal PR modulators discovered in the last decade.

Animals↗

PubMed2005

[Expression of eotaxin gene in nasal mucosa of allergic rhinitis in the guinea pig sensitized by fungal allergen].

OBJECTIVE: To study the expression and significance of Eotaxin gene in nasal mucosa of guinea pig sensitized by fungal allergen. METHOD: Alternaria alternata sensitized guinea pigs used as animal model of allergic rhinitis (AR). The changes in the nasal mucosa were studied by pathological method and the Eotaxin gene were studied by In Situ Hybridization. RESULT: The behavior science score of experimental group was significant higher than the controls group. Plenty eosinophils were found in lamina propria of nasal mucosa of experimental group. Eotaxin gene is expressed in lamina propria of nasal mucosa of experimental group. The controls group had not positive expression. CONCLUSION: Eotaxin gene is expressed at high levels in nasal mucosa of fungal allergic rhinitis in the guinea pig. Plenty eosinophils were found in nasal mucosa. We considered that Eotaxin gene and eosinophils could play a key role in fungal allergic rhinitis.

Alternaria↗

PubMed2004

Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson's disease.

We report that a low-calorie diet can lessen the severity of neurochemical deficits and motor dysfunction in a primate model of Parkinson's disease. Adult male rhesus monkeys were maintained for 6 months on a reduced-calorie diet [30% caloric restriction (CR)] or an ad libitum control diet after which they were subjected to treatment with a neurotoxin to produce a hemiparkinson condition. After neurotoxin treatment, CR monkeys exhibited significantly higher levels of locomotor activity compared with control monkeys as well as higher levels of dopamine (DA) and DA metabolites in the striatal region. Increased survival of DA neurons in the substantia nigra and improved manual dexterity were noted but did not reach statistical significance. Levels of glial cell line-derived neurotrophic factor, which is known to promote the survival of DA neurons, were increased significantly in the caudate nucleus of CR monkeys, suggesting a role for glial cell line-derived neurotrophic factor in the anti-Parkinson's disease effect of the low-calorie diet.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗