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31.
A Naess H Sjursen I Talstad C O Solberg 《APMIS : acta pathologica, microbiologica, et immunologica Scandinavica》1990,98(12):1135-1138
Two gradient separation techniques were compared with the dextran sedimentation method for the separation of granulocytes from blood. Both techniques gave adequate yield and excellent purity, and flow cytometric analysis of surface membrane markers gave no indication of subset selection during the procedure. Cells separated by the three methods behaved comparably in functional tests including random migration, chemotaxis and chemiluminescence. The gradient separation techniques are rapid and efficient methods for the preparation of near 100% pure granulocyte suspensions for functional studies. 相似文献
32.
The complete sequence determination of the human genome marks the start of a new era in biological science, with focus shifting from sequencing to functional mechanisms of gene products. In addition to effects on gene expression, most of the currently used therapeutic drugs either have enzymes or membrane proteins as their molecular targets of action. These membrane proteins include ion channels and transporters of small molecules, and receptors that convey signals from one side of a membrane to the other. Membrane proteins are thus involved in a variety of cellular processes and have a large potential as targets for new drug discovery. However, detailed structural information is still lacking for the majority of membrane proteins since their association with membrane constituents make NMR (nuclear magnetic resonance) spectroscopic and X-ray diffraction determinations difficult. Molecular modelling by biocomputing is a methodological alternative for structural studies of membrane proteins, but has to be based on experimental structural information in addition to computational techniques. A combination of bioinformatics and experimental techniques was used to model membrane proteins from two different classes, secondary transporters of the sodium:neurotransmitter symporter family (SNF transporters), and G-protein coupled receptors (GPCRs). The protein models were used to examine ligand-protein interactions and signalling/transport mechanisms, and to design experimental site-directed mutagenesis studies. Such studies have provided new insight into the detailed molecular mechanisms of two important classes of membrane proteins, which may be of value in the discovery and development of new pharmaceuticals. 相似文献
33.
Mari Gabrielsen Karol Wołosewicz Anna Zawadzka Jerzy Kossakowski Gabriel Nowak Małgorzata Wolak Katarzyna Stachowicz Agata Siwek Aina W. Ravna Irina Kufareva Lech Kozerski Elżbieta Bednarek Jerzy Sitkowski Wojciech Bocian Ruben Abagyan Andrzej J. Bojarski Ingebrigt Sylte Zdzisław Chilmonczyk 《Chemical biology & drug design》2013,81(6):695-706
Twelve alkyl analogues ( 1–12 ) of the high‐affinity serotonin transporter (SERT) inhibitor 6‐nitroquipazine (6‐NQ) were synthesized and studied using in vitro radioligand competition binding assays to determine their binding affinity (Ki). The putative antidepressant activity of five of the binders with the highest SERT binding affinities was studied by the forced swim and locomotor activity mouse tests. The three‐dimensional (3D) structures of 8 and 9 were determined using NOE NMR technique. Flexible docking of the compounds was undertaken to illustrate the binding of the compounds in the SERT model. Our results showed that several of the 6‐NQ analogues are high‐affinity SERT inhibitors and indicated that the octyl ( 8 ), decyl ( 10 ) and dodecyl ( 12 ) 6‐NQ analogues exhibit moderate antidepressant activity. 相似文献
34.
Refractory myelomatosis treated with mitoxantrone in combination with vincristine and prednisone (NOP-regimen): a phase II study 总被引:1,自引:0,他引:1
Peter Gimsing Ole W. Bjerrum Eystein Brandt Josrgen Ellegaard Stein A. Evensen Mogens Mosrk Hansen Michael Hedenus Erik Hippe Nina Keldsen Ilmari Palva Stig Roudjer Ingebrigt Talstad Jan Westin Finn Wislosff 《British journal of haematology》1991,77(1):73-79
In a phase II study, patients with refractory myelomatosis were treated with a combination chemotherapy (NOP regimen): mitoxantrone (bolus injection of 4 mg/m2 on days 1-4), vincristine (continuous infusion of 0.4 mg/24 h on days 1-4) and prednisone (250 mg/d on days 1-4 and 17-20). The treatment was repeated every 4 weeks. Ninety-two patients were treated after they were found refractory to treatment with melphalan and prednisone (and occasionally vincristine) (n = 50) or more intensive treatment regimens (n = 42) including anthracyclines (n = 18). Response (greater than or equal to 50% reduction of M protein) was obtained in 23 patients and minor response (clinical improvement but less than 50% reduction in M protein) in 22 patients. The median duration of the response was 7.5 months. Equal response rates were observed irrespective of the type of previous treatment. The major toxicity was myelosuppression with severe granulocytopenia and infections. However, the frequency decreased throughout the cycles. The NOP treatment is recommended in refractory myelomatosis, especially in patients refractory to other intensive regimens. Patients in a poor clinical condition or with thrombocytopenia before treatment should have a reduced mitoxantrone dose in the first treatment cycles. 相似文献
35.
I Talstad 《American journal of clinical pathology》1985,83(3):378-381
A linear relation between heparin concentrations and the dosage of heparin/kg body weight (r = 0.91, N = 47) was found after bolus injections of 2,500, 5,000, or 10,000 U heparin; the heparin concentrations agreed with plasma distribution. The maintenance therapy showed linearity between heparin concentrations and the dosage of heparin/kg body weight and 24 hours; however, the sensitivity for maintenance therapy differed between patients. The mean dosage required for maintaining heparin at 0.5 U/mL was 400 but ranged between 250 and 600 U heparin/kg body weight and 24 hours. A bolus dose of 75 U heparin/kg body weight, followed by a maintenance dose of 400 U heparin/kg body weight and 24 hours, showed therapeutic heparin response in 78% of patients, however, heparin monitoring two times daily is necessary for adjustment of dosage. 相似文献
36.
Chilmonczyk Z Cybulski M Iskra-Jopa J Chojnacka-Wójcik E Tatarczyńska E Kłodzińska A Leś A Bronowska A Sylte I 《Il Farmaco; edizione pratica》2002,57(4):285-301
In the present paper, we describe affinities to 5-HT1A and 5-HT2A receptors of several new 1,2,4-trisubstituted piperazine derivatives. The affinities were compared with those described earlier for 1,4-disubstituted piperazines and the influence of the third (methyl) substituent on the affinity to both receptors is discussed. The difference between two- and three-substituted derivatives was rationalised in terms of molecular modelling of the respective ligand-receptor complexes. Additionally, the functional activity of some 1,2,4-trisubstituted piperazines for 5-HT1A receptor was examined in behavioural and biochemical models. The obtained results have shown that some trisubstituted compounds exhibited a higher affinity to 5-HT2A receptors than their respective disubstituted analogues (with the affinity to 5-HT1A receptors remaining the same or somewhat improving). The molecular dynamics simulations suggested that the presence of the third substituent in the piperazine ring of those compounds may induce stabilising effect on the ligand-receptor complexes. The results of the in vivo studies have shown that some of the examined trisubstituted piperazines (10-13, 16, 17) exhibited properties of postsynaptic 5-HT1A partial agonists. Moreover, compounds 13 and 16 exhibited features of 5-HT1A presynaptic agonists in in vitro test, and compound 16 also in in vivo tests. 相似文献
37.
Structures and models of transporter proteins 总被引:2,自引:0,他引:2
Dahl SG Sylte I Ravna AW 《The Journal of pharmacology and experimental therapeutics》2004,309(3):853-860
Transporter proteins in biological membranes may be divided into channels and carriers. Channels function as selective pores that open in response to a chemical or electrophysiological stimulus, allowing movement of a solute down an electrochemical gradient. Active carrier proteins use an energy producing process to translocate a substrate against a concentration gradient. Secondary active transporters use the movement of a solute down a concentration gradient to drive the translocation of another substrate across a membrane. ATP-binding cassette (ABC) transporters couple hydrolysis of adenosine triphosphate (ATP) to the translocation of various substrates across cell membranes. High-resolution three-dimensional structures have now been reported from X-ray crystallographic studies of six different transporters, including two ATP-binding cassette (ABC) transporters. These structures have explained the results from many previous biochemical and biological studies and shed new light on their functional mechanisms. All these transporters have alpha-helical structures of the membrane-spanning domains, as suggested from many previous studies, and some of the helices have irregular shapes with kinks and bends. Together these crystal structures demonstrate the large flexibility of transporter proteins and that substantial movements take place during the substrate translocation process, which to a certain extent may distinguish active carriers from channel proteins. These structures and other low-resolution structures of membrane proteins have served as a basis for construction of three-dimensional protein models that have provided insight into functional mechanisms and molecular structures and enabled formulation of new hypotheses regarding transporter structure and function, which may be experimentally validated. 相似文献
38.
The relationship between the erythrocyte sedimentation rate (ESR) and plasma proteins in clinical materials and models 总被引:1,自引:0,他引:1
I Talstad H F Haugen 《Scandinavian journal of clinical and laboratory investigation》1979,39(6):519-524
The relationship between the erythrocyte sedimentation rate (ESR) and plasma proteins was studied within homogenous clinical material and in vitro models. In acute phase reactions, fibrinogen was the likely cause of the ESR-elevation, but there were significant associations between the ESR and the concentrations of alpha 1-antitrypsin, C3, haptoglobin and albumin. In chronic diseases, the ESR-elevation was probably caused by fibrinogen, mono- or polyclonal increase of IgG, IgA, IgM alone or in combinations. In multiple myeloma of the IgG and IgA subtypes, significant correlations were found between the ESR and the monoclonal proteins or between the ESR and the percentage of plasma cells in bone marrow. Model studies showed that the ESR increased linearly with the concentrations of fibrinogen or gammaglobulin (IgG) when these exceeded normal thresholds. The ESR was slightly decreased by increasing concentrations of albumin. Albumin had a synergistic effect on the ESR together with gamma-globulin, but not together with fibrinogen. 相似文献
39.
The complete sequence determination of the human genome marks the start of a new era in biological science, with focus shifting from sequencing to functional mechanisms of gene products. In addition to effects on gene expression, most of the currently used therapeutic drugs either have enzymes or membrane proteins as their molecular targets of action. These membrane proteins include ion channels and transporters of small molecules, and receptors that convey signals from one side of a membrane to the other. Membrane proteins are thus involved in a variety of cellular processes and have a large potential as targets for new drug discovery. However, detailed structural information is still lacking for the majority of membrane proteins since their association with membrane constituents make NMR (nuclear magnetic resonance) spectroscopic and X-ray diffraction determinations difficult. Molecular modelling by biocomputing is a methodological alternative for structural studies of membrane proteins, but has to be based on experimental structural information in addition to computational techniques. A combination of bioinformatics and experimental techniques was used to model membrane proteins from two different classes, secondary transporters of the sodium:neurotransmitter symporter family (SNF transporters), and G-protein coupled receptors (GPCRs). The protein models were used to examine ligand-protein interactions and signalling/transport mechanisms, and to design experimental site-directed mutagenesis studies. Such studies have provided new insight into the detailed molecular mechanisms of two important classes of membrane proteins, which may be of value in the discovery and development of new pharmaceuticals. 相似文献
40.
Peroxisome proliferator-activated receptor gamma belongs to the nuclear receptor superfamily and is activated by the antidiabetic drugs rosiglitazone and pioglitazone. Ligand-independent constitutive activity of peroxisome proliferator-activated receptor gamma is also demonstrated. X-ray crystallographic structures show that the active or inactive conformations of the receptor are determined by the position of helix 12 in the C-terminal end. In this study, molecular dynamics simulations were used to gain molecular insight into the activation process and the structural stability of inactive and active peroxisome proliferator-activated receptor gamma receptor structure. The simulations showed: (i) during molecular dynamics simulations without agonist at the active site, the receptor structure with helix 12 in a position corresponding to activated receptor structure was structurally more stable than with helix 12 in a position corresponding to inactive receptor structure, which may contribute to the constitutive activity of the receptor; (ii) docosahexenoic acid stabilized the active receptor conformation more efficiently than the glitazones; (iii) docosahexenoic acid, but not glitazones, induced structural changes into the inactive receptor structure such that helix 12 was shifted into a position more similar to that of an active receptor structure, which indicate that docosahexenoic acid is a more effective peroxisome proliferator-activated receptor gamma agonist than the glitazones. 相似文献