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Biomedical subjects

Jian Qiu

Publications and source records attributed to Jian Qiu.

At least 19 recordsLinked to original sources
PubMed2006

Estrogen upregulates T-type calcium channels in the hypothalamus and pituitary.

Low voltage-activated (T-type) Ca2+ channels are responsible for generating low-threshold spikes (LTS) that facilitate burst firing and transmitter release in neurons. The T-type Ca2+ channels contain a regulatory alpha1 subunit, and several isoforms of the alpha1 subunit (Cav3.1, 3.2, 3.3) have been cloned. The Cav 3.1 alpha1 subunit is abundantly expressed in the hypothalamus. Previously, we found that 17 beta-estradiol (E2) increased the number of arcuate neurons expressing LTS. Therefore, we used an ovariectomized female guinea pig model to measure the distribution and regulation of Cav3.1 mRNA expression by E2. Guinea pig Cav3.1 alpha1 subunit sequences, which were cloned by PCR, were used in ribonuclease protection (RPA) and in situ hybridization assays to evaluate mRNA expression. Based on a RPA, E2 significantly increased the mRNA expression of Cav3.1 alpha1 subunit in the mediobasal hypothalamus and the pituitary. In situ hybridization analysis revealed that E2 significantly increased Cav 3.1 mRNA expression in medial preoptic nuclei, bed nuclei stria terminalis, and the arcuate nucleus. Whole-cell patch recordings in arcuate neurons revealed that E2 treatment significantly increased the peak T-type Ca2+ current density by twofold without affecting the activation/inactivation characteristics and augmented the rebound excitation by threefold to fourfold. These results suggest that estrogen regulates the mRNA expression of T-type calcium channels, which leads to increased functional expression of the channel. Increased expression of T-type channels could be one mechanism by which estrogen augments burst firing and transmitter release in hypothalamic neurons.

Animals↗
PubMed2006

Cerebellar interposed nucleus lesions suppress lymphocyte function in rats.

We previously reported that the cerebellar fastigial nucleus, output nucleus of the spinocerebellum, modulates lymphocyte function. To further explore the role of the cerebellum in neuroimmunomodulation, we here lesioned bilaterally the cerebellar interposed nuclei (IN) of rats with kainic acid (KA) injections. On days 8, 16 and 32 after IN lesions, lymphocyte percentage in peripheral white blood cells was examined. Furthermore, proliferation of lymphocytes from mesenteric lymph nodes induced by concanavalin A, sheep red blood cell-specific IgM antibody in the serum and cytotoxicity of natural killer cells from spleen against YAC-1 cells were measured by methyl-thiazole-tetrazolium assay, enzyme-linked immunosorbent assay and flow cytometric assay, respectively. On days 8, 16 and 32 after KA injection in the IN, the lymphocyte percentage in the peripheral white blood cells was notably diminished with respect to control rats injected with saline in the IN. Concanavalin A-induced lymphocyte proliferation, serum sheep red blood cell-specific IgM antibody and natural killer cell toxicity of the IN-lesioned rats were significantly attenuated with respect to IN-saline control rats at all the post-lesion time points. The findings reveal that KA-induced neuronal loss in the IN of both sides exerts an inhibitory effect on number and functions of T, B and natural killer lymphocytes, and indicate that the cerebellar IN participates in regulating immune function. Thus, the data suggest that the cerebellum may be an important brain area for neuroimmunomodulation, besides its well-known role in motor control.

Animals↗
PubMed2006

A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis.

Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The critical role of 17beta-estradiol (E2) is evident in hypoestrogenic states (e.g., postmenopause) in which many of these functions go awry. The actions of E2 in the brain have been attributed to the activation of estrogen receptors alpha and beta through nuclear, cytoplasmic, or membrane actions. However, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABAB and mu-opioid receptors in guinea pig and mouse hypothalamic proopiomelanocortin neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Galphaq-coupled phospholipase C-protein kinase C-protein kinase A pathway, and have established that STX is more potent than E2 in mediating this desensitization in an ICI 182, 780-sensitive manner in both guinea pig and mouse neurons. Both E2 and STX were fully efficacious in estrogen receptor alpha,beta knock-out mice. Moreover, in vivo treatment with STX, similar to E2, attenuated the weight gain in hypoestrogenic female guinea pigs. Therefore, this membrane-delimited signaling pathway plays a critical role in the control of energy homeostasis and may provide a novel therapeutic target for treatment of postmenopausal symptoms and eating disorders in females.

Animals↗
PubMed2006

SSALN: an alignment algorithm using structure-dependent substitution matrices and gap penalties learned from structurally aligned protein pairs.

In template-based modeling of protein structures, the generation of the alignment between the target and the template is a critical step that significantly affects the accuracy of the final model. This paper proposes an alignment algorithm SSALN that learns substitution matrices and position-specific gap penalties from a database of structurally aligned protein pairs. In addition to the amino acid sequence information, secondary structure and solvent accessibility information of a position are used to derive substitution scores and position-specific gap penalties. In a test set of CASP5 targets, SSALN outperforms sequence alignment methods such as a Smith-Waterman algorithm with BLOSUM50 and PSI_BLAST. SSALN also generates better alignments than PSI_BLAST in the CASP6 test set. LOOPP server prediction based on an SSALN alignment is ranked the best for target T0280_1 in CASP6. SSALN is also compared with several threading methods and sequence alignment methods on the ProSup benchmark. SSALN has the highest alignment accuracy among the methods compared. On the Fischer's benchmark, SSALN performs better than CLUSTALW and GenTHREADER, and generates more alignments with accuracy >50%, >60% or >70% than FUGUE, but fewer alignments with accuracy >80% than FUGUE. All the supplemental materials can be found at http://www.cs.cornell.edu/ approximately jianq/research.htm.

Algorithms↗
PubMed2006

Heat-shocked tumor cell lysate-pulsed dendritic cells induce effective anti-tumor immune response in vivo.

AIM: To study whether heat-shocked tumor cells could enhance the effect of tumor cell lysate-pulsed dendritic cells (DCs) in evoking anti-tumor immune response in vivo. METHODS: Mouse undifferentiated colon cancer cells (CT-26) were heated at 42 degrees Celsius for 1 h and then frozen-thawed. The bone marrow-derived DCs pulsed with heat-shocked CT-26 cell lysate (HSCT-26 DCs) were recruited to immunize syngeneic naive BALB/c mice. The cytotoxic activity of tumor specific cytotoxic T lymphocytes (CTLs) in mouse spleen was evaluated by IFN-enzyme-linked immunospot (ELISpot) and LDH release assay. The immunoprophylactic effects induced by HSCT-26 DCs in mouse colon cancer model were compared to those induced by single CT-26 cell lysate-pulsed DCs (CT-26 DCs) on tumor volume, peritoneal metastasis and survival time of the mice. RESULTS: Heat-treated CT-26 cells showed a higher hsp70 protein expression. Heat-shocked CT-26 cell lysate pulsing elevated the co-stimulatory and MHC-II molecule expression of bone marrow-derived DCs as well as interleukin-12 p70 secretion. The IFN-gamma secreting CTLs induced by HSCT-26 DCs were significantly more than those induced by CT-26 DCs (P=0.002). The former CTLs' specific cytotoxic activity was higher than the latter CTLs' at a serial E/T ratio of 10:1, 20:1, and 40:1. Mouse colon cancer model showed that the tumor volume of HSCT-26 DC vaccination group was smaller than that of CT-26 DC vaccination group on tumor volume though there was no statistical difference between them (24 mm3 vs 8 mm3, P=0.480). The median survival time of mice immunized with HSCT-26 DCs was longer than that of those immunized with CT-26 DCs (57 d vs 43 d, P=0.0384). CONCLUSION: Heat-shocked tumor cell lysate-pulsed DCs can evoke anti-tumor immune response in vivo effectively and serve as a novel DC-based tumor vaccine.

Animals↗
PubMed2006

Synthesis and biological evaluation of SERMs with potent nongenomic estrogenic activity.

We have synthesized novel SERMs that activate a rapid response in CNS neurons, but which lack the ability to bind to the nuclear estrogen receptors (ERalpha and ERbeta). These compounds are analogues of 4-hydroxytamoxifen, but unlike 4-hydroxytamoxifen, they do not exist as a mixture of E/Z isomers. They contain a carboxamide insertion between the olefin and basic phenyl side chain, which results in more stable geometric isomers. The amide insertion also eliminates their ability to bind to the nuclear estrogen receptors, and hence, they are unable to modulate ER-mediated gene transcription as do classical estrogens and SERMs. We show that one of these analogues, ST-X, elicits a potent nongenomic estrogen response in the CNS by rapidly inhibiting GIRK activation in hypothalamic gamma-aminobutyric acid (GABA) and proopiomelanocortin (POMC) neurons. To our knowledge, ST-X is the only SERM that modulates rapid estrogen responses, but which lacks nuclear ER activity.

Estrogens↗
PubMed2006

[Clinical features of patients with atypical coronary artery spasm].

OBJECTIVE: This study is aimed to compare the clinical characteristics of patients with typical and atypical coronary artery spasm. METHODS: Out of 64 patients with chest pain at rest and without significant coronary artery stenosis, coronary artery spasm was provoked by intracoronary injection of acetylcholine in 46 patients, including 12 with ST segment elevation (typical coronary artery spasm group) and 34 without ST segment elevation (atypical coronary artery spasm group). The demographic data, coronary angiographic findings, treadmill electrocardiogram, dipyridamole and rest thallium-201 myocardial perfusion computed tomography, and the follow-up clinical data of the two groups were compared. RESULTS: The patients with typical coronary artery spasm were younger (47 +/- 6 vs. 58 +/- 12, P < 0.05) than patients with atypical coronary artery spasm group. Hyperlipidemia were more common in atypical coronary artery spasm group (74% vs. 33%, P < 0.05) and myocardial bridging was more common in patients with typical coronary artery spasm group (67% vs. 32%, P < 0.01). Focal coronary spasm during acetylcholine provocation was seen in 92% patients with typical coronary spasm and in 32% patients with a atypical coronary artery spasm (P < 0.01) while diffuse coronary spasm was seen in 8% patients with typical coronary spasm and in 68% patients with a atypical coronary artery spasm (P < 0.01). All patients with coronary artery spasm were treated with aspirin, calcium channel blockers, long-acting nitroglycerine, with or without lipid-lowering drugs, 2 patients with typical coronary spasm and 4 patients with atypical coronary spasm were rehospitalized due to chest pain and rest of the patients remained free of chest pain during the median follow-up period of 18 +/- 14 months. CONCLUSION: Atypical coronary artery spasm is common in patients with rest angina and diffuse coronary microvascular spasm might be the cause of chest pain in these patients.

Acetylcholine↗
PubMed2005

Atomically detailed potentials to recognize native and approximate protein structures.

Atomically detailed potentials for recognition of protein folds are presented. The potentials consist of pair interactions between atoms. One or three distance steps are used to describe the range of interactions between a pair. Training is carried out with the mathematical programming approach on the decoy sets of Baker, Levitt, and some of our own design. Recognition is required not only for decoy-native structural pairs but also for pairs of decoy and homologous structures. Performance is tested on the targets of CASP5 using templates from the Protein Data Bank, on two test ab initio decoy sets from Skolnick's laboratory, and on decoy sets from Moult's laboratory. We conclude that the newly derived potentials have significant recognition capacity, comparable to the best models derived from other techniques. The new potentials require a significantly smaller number of parameters. The enhanced recognition capacity extends primarily to the identification of structures generated by ab initio simulation and less to the recognition of approximate shapes created by homology.

Computational Biology↗
PubMed2005

Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABA(C) receptors.

The effects of the enantiomers of a number of flexible and cis-constrained GABA analogues were tested on GABA(C) receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp electrophysiology. (1S,2R)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((+)-CAMP), a potent and full agonist at the rho1 (EC(50) approximately 40 microM, I(max) approximately 100%) and rho 2 (EC(50) approximately 17 microM, I(max) approximately 100%) receptor subtypes, was found to be a potent partial agonist at rho3 (EC(50) approximately 28 microM, I(max) approximately 70%). (1R,2S)-cis-2-Aminomethylcyclopropane-1-carboxylic acid ((-)-CAMP), a weak antagonist at human rho1 (IC(50) approximately 890 microM) and rho2 (IC(50) approximately 400 microM) receptor subtypes, was also found to be a moderately potent antagonist at rat rho3 (IC(50) approximately 180 microM). Similarly, (1R,4S)-4-aminocyclopent-2-ene-1-carboxylic acid ((+)-ACPECA) was a full agonist at rho1 (EC(50) approximately 135 microM, I(max) approximately 100%) and rho2 (EC(50) approximately 60 microM, I(max) approximately 100%), but only a partial agonist at rho3 (EC(50) approximately 112 microM, I(max) approximately 37%), while (1S,4R)-4-aminocyclopent-2-ene-1-carboxylic acid ((-)-ACPECA) was a weak antagonist at all three receptor subtypes (IC(50)>>300 microM). 4-Amino-(S)-2-methylbutanoic acid ((S)-2MeGABA) and 4-amino-(R)-2-methylbutanoic acid ((R)-2MeGABA) followed the same trend, with (S)-2MeGABA acting as a full agonist at the rho1 (EC(50) approximately 65 microM, I(max) approximately 100%), and rho2 (EC(50) approximately 20 microM, I(max) approximately 100%) receptor subtypes, and a partial agonist at rho3 (EC(50) approximately 25 microM, I(max) approximately 90%). (R)-2MeGABA, however, was a moderately potent antagonist at all three receptor subtypes (IC(50) approximately 16 microM at rho1, 125 microM at rho2 and 35 microM at rho3). On the basis of these expanded biological activity data and the solution-phase molecular structures obtained at the MP2/6-31+G* level of ab initio theory, a rationale is proposed for the genesis of this stereoselectivity effect.

Animals↗
PubMed2005

Rapid activation of JNK and p38 by glucocorticoids in primary cultured hippocampal cells.

Rapid activation of JNK and p38 and their translocation to the cell nucleus by glucocorticoids, corticosterone (Cort), and bovine serum-conjugated corticosterone (Cort-BSA) were studied in primary cultured hippocampal cells by using immunoblotting and immunofluorescence confocal microscopy. The rapid activation occurred 5 min after stimulation and was maintained at plateau for as long as 2-4 hr; i.e., the response persisted for 2 hr after washing out the 15-min application of Cort-BSA. The activation occurred at a minimal concentration of 10(-9) M for Cort and 10(-8) M for Cort-BSA. GDPbetaS blocked the activation, but RU38486, a nuclear glucocorticoid receptor antagonist, could not block the activation, indicating the involvement of the membrane-delineated receptor in this reaction. The protein kinase C (PKC) inhibitor Go6976 blocked the response, whereas the protein kinase A inhibitor H89 could not, implying the involvement of PKC in the intracellular signal transduction pathway. The nongenomic nature of the responses and the transduction pathway and the significance of persistent action and biological significance are discussed.

Analysis of Variance↗
PubMed2005

Estrogen signaling in the hypothalamus.

Estrogen has multifaceted effects on the hypothalamus that regulate a number of homeostatic functions including reproduction, temperature, energy balance, stress, and motivated behaviors. Estrogen targets all of the major hypothalamic neuroendocrine and autonomic cellular groups to activate multiple signaling pathways. Originally it was thought that all of these actions of estrogen could be ascribed to its binding to its "classical" intracellular receptor and to alterations in gene transcription. However, we now know that this steroid hormone activates multiple signaling pathways to affect neuronal excitability and gene transcription. Although the "classical" genomic signaling pathway has been recognized for almost half a century, until recently little attention has been paid to the rapid membrane-initiated signaling by estrogen in neurons. It has been known since the 1970s that estrogen can rapidly alter neuronal firing within seconds, indicating that some cellular effects of estrogen could occur via rapid, non-transcriptional mechanisms. Therefore, this chapter reviews the current status of estrogen signaling in the hypothalamus via membrane-initiated and nuclear-mediated events that affect the excitability of hypothalamic neurons and, ultimately, neuroendocrine and autonomic functions.

Animals↗
PubMed2005

Multivesicular liposome formulations for the sustained delivery of interferon alpha-2b.

AIM: To develop and optimize a sustained release multivesicular liposome (MVL) formulation of interferon (IFN) alpha-2b. METHODS: IFN alpha-2b MVL were prepared using a typical double-emulsion procedure. The sustained release effects of IFN alpha-2b MVL were investigated by monitoring the blood IFN alpha-2b concentration using an enzyme-linked immunosorbent assay test after subcutaneous administration to healthy mice. RESULTS: IFN alpha-2b was successfully encapsulated in MVL with high efficiency, and the integrity of encapsulated protein was maintained. After subcutaneous injection, the MVL slowly released IFN alpha-2b into systemic circulation in a sustained manner. The estimated serum half-life of IFN alpha-2b was approximately 30 h. In addition, varying the size of the MVL preparations could further modify the in vivo release profile. CONCLUSION: IFN alpha-2b MVL may be a useful sustained release formulation in the clinical treatment of viral diseases.

Animals↗
PubMed2005

[Cardioprotective effects of K(ATP) channel opener nicorandil during ischemia/ reperfusion in dogs].

OBJECTIVE: To further confirm the effect of nicorandil in reducing the area of myocardial infarct is through the mediation of activation of the KATP channel but not by its nitrate-like properties, and to determine whether the protective effect is the same or not when the drug is either given immediate after infarction or after reperfusion. METHODS: Thirty-five dogs were randomly divided into five groups as follows. Ischemia/reperfusion (IR) group: the dogs were subjected to 90 minutes of left anterior descending coronary artery(LAD) occlusion followed by 120 minutes reperfusion. Pre-nicorandil (PNIC) group: nicorandil(NIC) 100 microg/kg was administrated by intravenous injection 10 minutes before occlusion, followed by infusion of 10 microg x kg(-1) x min (-1) of the drug till the end of reperfusion. Ischemia nicorandil(INIC) group: NIC 100 microg/kg was administered by intravenous injection 15 minutes after occlusion and 10 microg x kg(-1) x min (-1) of drug intravenously till the end of reperfusion. In the Onset reperfusion treated with nicorandil(RNIC) group: NIC 100 microg/kg was administered intravenously at the onset of reperfusion followed by 10 microg x kg(-1) x min (-1)of drug intravenously up to the end of reperfusion. Glibenclamide(GLIB)+INIC group: before NIC was administered, dogs were pretreated with GLIB 0.3 mg/kg for 10 minutes, and other treatment was the same as INIC group. Hemodynamics data were determined as baseline, 60 minutes post-occlusion, and 120 minutes post-reperfusion. By using 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, the infarct areas were analyzed with image analyzer. RESULTS: The results showed that at 60 minutes post-occlusion, cardiac output (CO) was reduced in every group compared with baseline (all P<0.01), CO value recovered at 120 minutes after reperfusion in both PNIC and INIC group (P>0.05). There were no significant differences in heart rate (HR), mean artery pressure(MAP), mean pulmonary artery pressure(MPAP), pulmonary capillary wedge pressure(PCWP) values among all the groups. A marked reduction in the infarct area was found in PNIC group and INIC group (P<0.01) compared with IR group. Administration of GLIB before INIC shows to have no protective effect (P>0.05). CONCLUSION: Our study shows that nicorandil which is a K ATP channel activator, could mimic the effect of ischemic pre-conditioning of the myocardium, by reducing the area of myocardial infarct.

Animals↗
PubMed2005

[Construction of eukaryotic expression vectors of two mutants of hypoxia-inducible factor-1 and their expressions in human microvascular endothelial cells].

OBJECTIVE: To construct eukaryotic expression vectors of two mutants of hypoxia-inducible factor-1 (HIF-1alpha) and study their expressions in human microvascular endothelial cells (HMVECs). METHODS: Site-directed mutagenesis was performed to induce the mutation of the codons for the residue Pro564 (ccc) in HIF-1alpha into gcc (Ala) in pcDNA3.1(+)-HIF-1alphato obtain single-site-mutated vector pcDNA3.1(+)-HIF-1alpha-564Ala, which was then subjected to a second site-directed mutagenesis to convert the codons for Asn803 into that of Ala (gct) to acquire double-site-mutated pcDNA3.1(+)-HIF-1alpha-564Ala-803Ala. After lipofectin-mediated transient transformation of HMVECs with the 3 recombinant plasmids including the two plasmids containing the mutations and the one without mutation, respectively, the expression levels of HIF-1alpha mRNA and protein were determined using RT-PCR, immunofluorescent staining and Western blotting. RESULTS: DNA sequence analysis demonstrated success of the two-step mutagenesis and the two plasmids of pcDNA3.1+-HIF-1alpha-564Ala and pcDNA3.1(+)-HIF-1alpha-564Ala- 803Ala were obtained, both of which could produce HIF-1alpha protein resistant to oxidation degradation in HMVECs as compared with the non-mutated one. CONCLUSION: The recombinant plasmids pcDNA3.1(+)-HIF-1alpha-564Ala and pcDNA3.1(+)-HIF-1alpha- 564Ala-803Ala have been successfully constructed with efficient expressions in HMVECs.

Cloning, Molecular↗
PubMed2004

Mechanistic crystallography. Mechanism of inactivation of gamma-aminobutyric acid aminotransferase by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid as elucidated by crystallography.

(1R,3S,4S)-3-Amino-4-fluorocyclopentane-1-carboxylic acid (7) was previously shown to be a mechanism-based inactivator of gamma-aminobutyric acid aminotransferase (GABA-AT) [Qiu, J. and Silverman, R. B. (2000) J. Med. Chem. 43, 706-720]. Two mechanisms were considered as reasonable possibilities, a Michael addition mechanism and an enamine mechanism. On the basis of a variety of chemical studies, including tedious radiolabeling experiments, it was concluded that inactivation by 7 proceeds by a Michael addition mechanism. Here, a crystal structure of 7 bound to pig liver GABA-AT is reported, which clearly demonstrates that the adduct formed is derived from an enamine mechanism. This represents another example of how crystallography is an important tool for elucidation of inactivation mechanisms.

4-Aminobutyrate Transaminase↗
PubMed2004

[Identification of different lac with infrared spectrum].

Fourier infrared spectrum was used to differentiate raw lac, bleached las and lac mixed with resin. The results indicate that the infrared spectra of raw lac and lac mixed with resin are similar, so the authors can differentiate them by the following items: (1) the position and the shape of absorbing peak between 3500 and 2500 cm(-1), (2) the difference of the vibration peak at 1700 cm(-1) for C=O, (3) characteristic peak between 1200 and 1400 cm(-1), (4) the number of peaks and the change in the position of peak. But with bleached and graft copolymerization lacs the properties have been changed by chemical processing. Graft copolymerization of lac is made from methyl-acrylic acid-methyl fat by using potassium permanganate as stimulant. Their main differences are: the change of vibration peak of 1700 cm(-1) for C=O, a sharp small peak at 1558 cm(-1), a peak with middle strength at 681 cm(-1), and spliting to two small peaks at 1151 cm(-1). The experiment shows that the method of infrared spectrum is more scientific and effective than traditional method.

English Abstract↗
PubMed2003

Design, synthesis, and biological activity of a difluoro-substituted, conformationally rigid vigabatrin analogue as a potent gamma-aminobutyric acid aminotransferase inhibitor.

Previously it was found that a conformationally rigid analogue (2) of the epilepsy drug vigabatrin (1) did not inactivate gamma-aminobutyric acid aminotransferase (GABA-AT). A cyclic compound with an exocyclic double bond (6) was synthesized and was found to inactivate GABA-AT, but only in the absence of 2-mercaptoethanol. The corresponding difluoro-substituted analogue (14) was synthesized and was shown to be a very potent time-dependent inhibitor, even in the presence of 2-mercaptoethanol.

4-Aminobutyrate Transaminase↗