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Biomedical subjects

J Xie

Publications and source records attributed to J Xie.

At least 271 records · Page 15Linked to original sources
PubMed1991

A cyclopeptidic suicide substrate preferentially inactivates urokinase-type plasminogen activator.

c[Arg-aB-(CH2+SCH3 phi)-Gly4] was designed and studied as a mechanism-based inactivator (suicide substrate) for plasminogen activators (u-PA and t-PA) and plasmin. This compound inhibited u-PA and fulfills criteria expected for the involvement of an enzyme-activated inhibitor: first-order and irreversible process, saturation kinetics, protection by substrate. The limiting first-order rate constant kinact and the apparent enzyme-inhibitor dissociation constant KI were 0.021 s-1 and 9 microM, respectively at pH 7.5 and 25 degrees C. The activation of plasminogen by u-PA is compromised after this enzyme has been treated by the reagent. Plasmin and t-PA were inactivated 40- and 2330-fold less efficiently than u-PA, respectively.

Amino Acid Sequence↗
PubMed1991

Lymphokine-activated killer (LAK) cells modulate the effects of IL-2 on a T cell-mediated immune response.

The ability of LAK cells and/or IL-2 to affect the course of an established T cell response was examined in a delayed-type hypersensitivity (DTH) model. IL-2 greatly increased the magnitude of the response at 24 h, while LAK cells alone had no effect. The administration of LAK cells and IL-2 together also had no effect on the magnitude of the DTH response, demonstrating that LAK cells were able to remove the enhancement seen with IL-2 alone. The presence of LAK cells reduced the serum half-life of IL-2 significantly, but not to an extent able to account for the observed loss of IL-2 induced DTH enhancement. IL-2 administration influenced cell phenotypes in the spleen and draining lymph nodes (DLN), as well as increasing splenic weight; the additional presence of LAK cells markedly altered these effects of IL-2 in the spleen (but not the DLN). Taken together, these results suggest that LAK cells interact with activated T-cells within the immune system and modulate their function.

Animals↗
PubMed1991

The effect of thromboxane on contraction of canine mesenteric and lingual arteries.

Thromboxane A2 (TXA2), a potent vasoconstrictor agent, is released from platelets and smooth muscle during inflammation and trauma. TXA2 may cause lingual artery (LA) contraction, leading to lingual paresthesia. The effects of U-46619, a TxA2 mimetic, on isolated rings of canine LA and mesenteric artery (MA) were examined. U-46619 (1 nmol/L to 1 mumol/L) caused a triphasic contraction of LA and MA; a rapid, phasic contraction; a slow, sustained contraction; and, upon washout of U-46619, a maintained contraction. The MA relaxed slowly, but the LA remained contracted for at least three h after washout. Decreasing extracellular calcium ion (Ca2+o) to less than 0.1 mumol/L with 2 mmol/L EGTA relaxed MA, but not LA. EGTA (4 mmol/L) partially relaxed the maintained contraction of LA. Inhibition of protein kinase C with amphotericin B or staurosporine inhibited the phasic and sustained contractions of LA, but did not affect the maintained contraction in the presence or absence of EGTA. Thus, CA2+o was required for the initial contraction of the LA by U-46619, but did not appear to be required for the maintained contraction following washout of U-46619. The data support the conclusion that following a brief exposure to U-46619, maintained contraction of LA persists by a unique mechanism that may be independent of Ca2+ and protein kinase C. Sustained LA contraction after exposure to endogenous TXA2 during inflammation and trauma may contribute to impaired lingual blood flow and orofacial tissue injury.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Effect of hypoxia on the pulmonary beta and alpha 1 adrenoceptors in rats.

The present study was designed to investigate the effect of hypoxia on the pulmonary adrenoceptors in rats. The density and distribution of pulmonary adrenoceptors were studied by using radioligand binding techniques and autoradiography. The beta adrenoceptors in lung homogenates were found to decrease by 24 h of hypoxia, and to unexpectedly increase at 1 week of hypoxia. Exposure to hypoxia for 2 and 4 weeks led to another decrease in beta adrenoceptors. In contrast, the alpha 1 adrenoceptors were increased markedly at 24 h and 4 weeks of hypoxia. A somewhat higher density of alpha 1 adrenoceptors was also found at 1 week and 7 weeks of hypoxia. The affinity of beta and alpha 1 adrenoceptors did not change. Using a computer image analysis system, beta adrenoceptors were found to be present in higher density in bronchioles than in pulmonary blood vessels before and during hypoxia, while the reverse was true of alpha 1 adrenoceptors. Both beta and alpha 1 adrenoceptors were found in high densities in the parenchyma.

Animals↗
PubMed1990

A new efficient synthetic method for 2- and 4-hydroxy-17 alpha-ethynylestradiol.

The reaction of ethyl magnesium bromide and 17 alpha-ethynylestradiol with formaldehyde in the presence of triethyl phosphate or hexamethylphosphoramide gave the 2- and 4-formyl-17 alpha-ethynylestradiol in high yield. Treatment of the formyl derivatives with an alkaline solution of hydrogen peroxide in tetrahydrofuran afforded the corresponding catechols in almost quantitative yield. This new synthetic method was far superior to other methods, especially concerning simplicity, selectivity, and high yields.

Estradiol↗
PubMed1989

New kelatorphan-related inhibitors of enkephalin metabolism: improved antinociceptive properties.

In order to improve the in vivo protection of enkephalins from enzymatic degradation, a new series of inhibitors derived from kelatorphan [HONHCOCH2CH(CH2Ph)CONHCH(CH3)COOH], the first-described complete inhibitor of enkephalin metabolism, were designed by modification of the C-terminal amino acid. The progressive lengthening of the chain of this residue shows that a beta-alanine seems to be the best basic model for the conception of such types of compounds. On the other hand, the methylation of the amide bond, which is well accepted by aminopeptidase N (EC 3.4.11.2) and dipeptidylaminopeptidase, induced a significant loss of affinity for neutral endopeptidase -24.11. Starting from these data, compounds containing a variously substituted beta-alanine residue and corresponding to the general formula HONHCOCH2CH(CH2Ph)CONHCH(R1)CH(R2)COOH were synthesized. All these molecules inhibit neutral endopeptidase -24.11 and dipeptidylaminopeptidase in the nanomolar range, and those containing an aromatic chain (compound 7A, R1 = CH2Ph,R2 = H, and compound 8A, R1 = Ph, R2 = H) inhibit the biologically relevant aminopeptidase N, with IC50's around 10(-8) M. Intracerebroventricular injection in mice of these multienzyme inhibitors produced an efficient and naloxone-reversible analgesic response (hot plate test): compounds 7A and 8A were shown to be more potent than kelatorphan in increasing the jump latency time, in agreement with their in vitro properties, and these new compounds were found to increase the forepaw lick latency, a reflex considered as a typical morphine response.

Analgesics↗
PubMed1989

Enkephalin-degrading enzyme inhibitors. Crucial role of the C-terminal residue on the inhibitory potencies of retro-hydroxamate dipeptides.

The retro-inversion of the amide bond in kelatorphan and analogs, the first series of complete inhibitors of enkephalin metabolism, led to compounds highly efficient only against the neutral endopeptidase 24-11 (NEP). In order to increase the recognition of the aminopeptidase N (APN) and dipeptidylaminopeptidase (DAP), without loss of affinity for NEP, the malonyl group of these retro-inhibitors was replaced by diversely substituted succinyl moieties. All the molecules synthesized are highly efficient NEP inhibitors with Ki's in the 0.2-1 nM range, indicating that NEP possesses a relatively large and not very selective S'2 subsite. In contrast, inhibition of DAP activity is crucially dependent on the size and the position of the substituent in the succinyl moiety. Inhibitory potencies in the nanomolar range are obtained with compounds containing a benzyl group in the alpha-position related to the retro amide bond. Finally, a relatively modest inhibition of APN was observed with Ki's in the 0.5-1 microM range for compounds with benzyl or cyclohexyl group in P'2 position. However, these data demonstrate that efficient and complete inhibition of enkephalin degradation can be obtained with hydroxamate dipeptides containing a retro amide bond. The analgesic potency of the most active inhibitors was measured using the hot plate test in mice. Significant antinociceptive responses were obtained but these effects were rather weaker than those expected from the in vitro inhibitory potencies of these compounds on the three enkephalin-degrading enzymes.

Animals↗
PubMed1989

Inhibitors of the enkephalin degrading enzymes. Modulation of activity of hydroxamate containing compounds by modifications of the C-terminal residue.

To further characterize the S'2 subsite of both the neutral endopeptidase (EC 3.4.24.11, NEP) and aminopeptidase N (EC 3.4.11.2, APN), two enzymes physiologically involved in enkephalin metabolism, a new series of hydroxamate inhibitors containing a cyclic amino acid as the P'2 component were synthesized. These amino acids differ by the size of the cycle, the relative position of the functional groups, and their absolute configuration. Highly efficient inhibitors of NEP were obtained whatever the modification on the P'2 component, while for APN inhibition, a cyclic beta-amino acid was preferred. The most active inhibitors contained a trans cyclopentyl beta-amino acid and a cis or a trans cyclohexyl beta-amino acid. When injected intracerebroventricularly in mice, these two latter compounds elicited potent antinociceptive responses on both the jump latency and the fore paw lick times.

Amino Acids↗
PubMedDate not supplied

Comparative effects of chelating agents on pulmonary toxicity of systemic nickel in mice.

N-Benzyl-D-glucaminedithiocarbamate (BGD), diethyldithiocarbamate (DDTC), dihydroxyethyldithiocarbamate (DHED), trans-1,2-cyclohexanediamine N,N,N',N'-tetraacetic acid (CDTA) and meso-2,3-dimercaptosuccinic acid (DMSA) were studied for their protective effects against the pulmonary toxicity in mice induced by acute exposure to nickel. Nickel injection increased lipid peroxidation, lactate dehydrogenase (LDH) activity and the concentrations of protein, phospholipids (PL) and essential metals such as Ca, Fe and Zn and decreased the reduced glutathione (GSH) concentration and alkaline phosphatase (ALP) activity in the lungs. At 30 min after Ni treatment, DMSA, BGD and DDTC effectively depressed Ni concentration in the lungs. At 24 h after Ni treatment, DMSA and BGD were effective in mobilizing Ni from the lungs. Both DMSA and BGD significantly prevented increases in lipid peroxidation and in the concentrations of PL, Ca, Fe and Zn, and decreases in GSH concentration and ALP activity in the lungs of mice caused by Ni injection. Treatment with DMSA or BGD was more effective than that with other chelating agents in decreasing the pulmonary Ni concentration and preventing other changes caused by acute exposure to Ni, resulting in effective protection against Ni-induced pulmonary damage.

Alkaline Phosphatase↗
PubMedDate not supplied

Ethanol relaxes pulmonary artery by release of prostaglandin and nitric oxide.

Acute-intake of ethanol is associated with vasodilation of vascular smooth muscle (VSM). Relaxation of VSM is dependent, in part, on the actions of nitric oxide (NO) and prostaglandin (PG) produced by endothelial cells (EC) lining the VSM. We examined the effects of endothelium rubbing and inhibition of EC synthesis of NO and PG on ethanol-induced relaxation of bovine pulmonary artery (BPA) and pulmonary vein (BPV) in vitro. Rings of isolated BPA and BPV were mounted in muscle chambers for the isometric recording of force development. Blood vessels were precontracted with an EC50 concentration of the thromboxane receptor mimetic U46619. Ethanol (0.01, 0.02, 0.04, 0.08, 0.16, 0.32, 0.64, and 1.28% (w/v) produced concentration-dependent relaxation of BPA and BPV. Ethanol-induced relaxation was attenuated in BPA with rubbed EC and by the NO synthase inhibitors, L-NG monomethylarginine (LNMMA, 50 microM) and L-nitroarginine (NOLA, 10 microM), and the prostaglandin cyclooxygenase inhibitor, ibuprofen (10 microM). In contrast, ethanol-induced relaxation of BPV was not affected by endothelium rubbing or by NOLA or LNMMA, but was partially attenuated by ibuprofen. Nitric oxide was measured with the chemiluminescence technique. Ethanol increased the content of NO released under basal conditions by the BPA but did not effect basal NO release from BPV. However, ethanol enhanced bradykinin-induced release of NO from BPA and BPV and, at low concentrations, augmented bradykinin-induced relaxation of both BPA and BPV.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

Escherichia coli-induced inhibition of endothelium-dependent relaxation and gene expression and release of nitric oxide is attenuated by chronic alcohol ingestion.

We examined the effect of chronic administration of ETOH on Escherichia coli-mediated suppression of relaxation and nitric oxide (NO) production by the rat thoracic aorta (RTA) and gene expression for constitutive NO synthase (cNOS) by the adrenal gland. Chronic alcoholic rats ("alcoholic") were fed a diet containing ETOH as 36% of the caloric intake for 8-10 weeks. Nonalcoholic control rats ("control") were fed an isocaloric equivalent diet containing 36% dextrin. Alcoholic rats were given an injection of approximately approximately 10(10) live E. coli through a dorsal SC catheter 24 and 19 h before experimentation ("alcoholic-septic"), and control rats were treated in an identical manner ("septic"). The next day the rats were anesthetized with ketamine-xylazine (0.1 ml/100 g rat) and rings of RTA were mounted in muscle chambers for isometric recording of force development. Rings of RTA were precontracted with an EC50 concentration of phenylephrine, and relaxation to acetylcholine (ACh), A23187, and nitroglycerin were obtained. A23187- and ACh-induced relaxation was attenuated in RTA obtained from septic rats, whereas the relaxation to nitroglycerin was slightly enhanced. Chronic administration of ETOH attenuated the effects of E. coli on endothelium-dependent relaxation in alcoholic-septic rats. NO was measured with ozone chemiluminescence. Basal and stimulated NO production was attenuated in RTA obtained from septic rats and unaffected in RTA obtained from alcoholic or alcoholic-septic rats. cNOS was unmeasurable in adrenals from septic rats. ETOH increased mRNA for cNOS, an effect amplified in alcoholic-septic rats. Thus, E. coli inhibits endothelium-dependent relaxation and NO production, and ETOH attenuates these effects of E. coli on the endothelium-NO system, possibly by upregulating gene expression for cNOS.

Acetylcholine↗
PubMedDate not supplied

Ethanol suppresses LPS-induced mRNA for nitric oxide synthase II in alveolar macrophages in vivo and in vitro.

Alcohol abuse increases the incidence and severity of opportunistic lung infections and pneumonias. Inducible nitric oxide (NO) synthase (iNOS II) and NO may be a pivotal system in the intracellular bactericidal activity of macrophages. We tested the hypothesis that acute administration of ethanol (ETOH) suppressed Escherichia coli endotoxin lipopolysaccharide (LPS) mediated upregulation of the iNOS II system in the lung of the rat, in vivo. We also tested the effect of ETOH on alveolar macrophage (AM) production of free NO using microelectrodes. Male Sprague-Dawley rats were given ETOH (5.5 g/kg, IP) 30 min. before giving intratracheal sterile phosphate buffered saline solution (PBS, 0.5 ml) or LPS (1 mg/kg in a total volume of 0.5 ml PBS). The isolated lungs were subjected to bronchoalveolar lavage (BAL) 3.5 hr. later. Aliquots of the BAL fluid were assayed for tumor necrosis factor alpha TNF alpha and reactive nitrogen intermediates (nitrate and nitrite) (RNI) with chemiluminescence. Aliquots of AM were incubated 1 hr ex vivo for spontaneous production of RNI or frozen and assayed for iNOS II mRNA with competitor exchange reverse transcriptase polymerase chain reaction (cERT-PCR). The lung was homogenized and assayed for RNI. LPS increased BAL fluid TNF alpha and RNI, lung RNI, and the spontaneous production of RNI by AM, ex vivo. These effects were inhibited by in vivo administration of inhibitors of iNOS II. LPS increased iNOS mRNA in AM. This was unaffected by iNOS inhibitors. ETOH suppressed LPS-induced BAL fluid TNF, iNOS mRNA and RNI production by AM and the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMedDate not supplied

A mild and efficient solid-support synthesis of novel oligonucleotide conjugates.

Conjugates of oligodeoxyribonucleotide phosphorothioate (ODN-PS) with folic acid, retinoic acid, arachidonic acid, and methoxypoly(ethylene glycol)propionic acid have been synthesized. The procedure involved the initial solid-phase preparation of 5'-amino-functionalized ODN-PS using N-pent-4-enoyl-derived (PNT) nucleoside phosphoramidites followed by conjugation of the oligonucleotide either to the ligand acids, using 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide as a coupling reagent, or to their corresponding succinimidyl derivatives. Subsequent exposure of the support to aqueous ammonium hydroxide (28%, 2 h, 55 degrees C) resulted in the release of the fully deprotected ODN conjugates, which were purified by reversed-phase HPLC or by preparative polyacrylamide gel electrophoresis. The identity of the oligonucleotide conjugates was confirmed by MALDI-TOF mass spectral analysis.

Ammonium Hydroxide↗
PubMedDate not supplied

SNAP-25 deficit and hippocampal connectivity in schizophrenia.

Regional abnormalities of brain connectivity may be an important substrate for the expression of schizophrenia, a severe form of mental illness. Brain imaging and postmortem morphometric studies indicate hippocampal structure is abnormal in schizophrenia. To study molecular components of hippocampal connectivity the presynaptic proteins SNAP-25 and synaptophysin were assayed in postmortem samples. Immunocytochemical studies indicated reduced SNAP-25 immunoreactivity in schizophrenia compared to controls, particularly in the terminal fields of entorhinal cortex projections. Although there were no overall changes in synaptophysin immunoreactivity, in the granule cell layer of the dentate gyrus synaptophysin immunoreactivity was increased in schizophrenia. These results indicate that disconnection of a subset of hippocampal circuitry from the entorhinal cortex, as well as intrinsic changes in hippocampal connectivity, may contribute to the mechanism of illness in schizophrenia.

Adult↗