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61.
Robert W. Schwenk Graham P. Holloway Joost J.F.P. Luiken Arend Bonen Jan F.C. Glatz 《Prostaglandins, leukotrienes, and essential fatty acids》2010,82(4-6):149-154
Transport of long-chain fatty acids across the cell membrane has long been thought to occur by passive diffusion. However, in recent years there has been a fundamental shift in understanding, and it is now generally recognized that fatty acids cross the cell membrane via a protein-mediated mechanism. Membrane-associated fatty acid-binding proteins (‘fatty acid transporters’) not only facilitate but also regulate cellular fatty acid uptake, for instance through their inducible rapid (and reversible) translocation from intracellular storage pools to the cell membrane. A number of fatty acid transporters have been identified, including CD36, plasma membrane-associated fatty acid-binding protein (FABPpm), and a family of fatty acid transport proteins (FATP1–6). Fatty acid transporters are also implicated in metabolic disease, such as insulin resistance and type-2 diabetes. In this report we briefly review current understanding of the mechanism of transmembrane fatty acid transport, and the function of fatty acid transporters in healthy cardiac and skeletal muscle, and in insulin resistance/type-2 diabetes. Fatty acid transporters hold promise as a future target to rectify lipid fluxes in the body and regain metabolic homeostasis. 相似文献
62.
Kevin K.-C. Liu Bruce A. Lefker Mark A. Dombroski Phoebe Chiang Peter Cornelius Terrell A. Patterson Yuan Zeng Stephanie Santucci Elizabeth Tomlinson Colleen P. Gibbons Ravi Marala Janice A. Brown Jimmy X. Kong Eunsun Lee Wendy Werner Zane Wenzel Craig Giragossian Hou Chen Steven B. Coffey 《Bioorganic & medicinal chemistry letters》2010,20(7):2365-2369
Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered. 相似文献
63.
Kevin K.-C. Liu Peter Cornelius Terrell A. Patterson Yuan Zeng Stephanie Santucci Elizabeth Tomlinson Colleen Gibbons Tristan S. Maurer Ravi Marala Janice Brown Jimmy X. Kong Eunsun Lee Wendy Werner Zane Wenzel Chandra Vage 《Bioorganic & medicinal chemistry letters》2010,20(1):266-271
Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure–activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose–responsive in vivo efficacy in our pre-clinical food intake model. 相似文献
64.
Kristen L.G. Jones M. Katharine Holloway Hua-Poo Su Steven S. Carroll Christine Burlein Sinoeun Touch Daniel J. DiStefano Rosa I. Sanchez Theresa M. Williams Joseph P. Vacca Craig A. Coburn 《Bioorganic & medicinal chemistry letters》2010,20(14):4065-4068
A series of HIV-1 protease inhibitors containing an epsilon substituted lysinol backbone was synthesized. Two novel synthetic routes using N-boc-l-glutamic acid alpha-benzyl ester and 2,6-diaminopimelic acid were developed. Incorporation of this epsilon substituent enabled access to the S2 pocket of the enzyme, affording high potency inhibitors. Modeling studies and synthetic efforts suggest the potency increase is due to both conformational bias and van der Waals interactions with the S2 pocket. 相似文献
65.
L. M. Tai K. A. Holloway D. K. Male A. J. Loughlin I. A. Romero 《Journal of cellular and molecular medicine》2010,14(5):1101-1112
Vascular dysfunction is emerging as a key pathological hallmark in Alzheimer’s disease (AD). A leaky blood–brain barrier (BBB) has been described in AD patient tissue and in vivo AD mouse models. Brain endothelial cells (BECs) are linked together by tight junctional (TJ) proteins, which are a key determinant in restricting the permeability of the BBB. The amyloid β (Aβ) peptides of 1–40 and 1–42 amino acids are believed to be pivotal in AD pathogenesis. We therefore decided to investigate the effect of Aβ 1–40, the Aβ variant found at the highest concentration in human plasma, on the permeability of an immortalized human BEC line, hCMEC/D3. Aβ 1–40 induced a marked increase in hCMEC/D3 cell permeability to the paracellular tracer 70 kD FITC‐dextran when compared with cells incubated with the scrambled Aβ 1–40 peptide. Increased permeability was associated with a specific decrease, both at the protein and mRNA level, in the TJ protein occludin, whereas claudin‐5 and ZO‐1 were unaffected. JNK and p38MAPK inhibition prevented both Aβ 1–40‐mediated down‐regulation of occludin and the increase in paracellular permeability in hCMEC/D3 cells. Our findings suggest that the JNK and p38MAPK pathways might represent attractive therapeutic targets for preventing BBB dysfunction in AD. 相似文献
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68.
David J. Holloway 《Palaeontology》2004,47(4):1015-1036
The Monorakinae is a subfamily of the Pterygometopidae characterised by the fusion of L2 and L3 in the glabella. The resulting bicomposite lobe is expanded backwards to reach the occipital furrow, displacing L1 from contact with the axial furrow and causing the realignment of S1 to a markedly oblique orientation. The bicomposite lobe is commonly bounded adaxially by a longitudinal furrow containing three pairs of apodemal pits. The Monorakinae was probably derived from the Pterygometopinae, and includes the genera and subgenera Monorakos , Carinopyge , Ceratevenkaspis , Elasmaspis , Evenkaspis ( Evenkaspis ) and E . ( Parevenkaspis ), of which Carinopyge , Elasmaspis and Evenkaspis ( Parevenkaspis ) are known only from limited parts of the exoskeleton. Monorakines have a stratigraphical range of Caradoc–Ashgill. Their known geographical distribution in the Siberian Platform, Taimyr, the Russian Far East, and the Seward Peninsula of Alaska is restricted to areas that in the Ordovician were part of the palaeocontinents of Siberia and Arctida, which must have been connected or situated close together at that time. The occurrence of monorakines in the Taimyr Peninsula but their absence from Baltica does not support the suggestion of some workers that Taimyr was part of Baltica in the Ordovician. 相似文献
69.
Photoacoustic calorimetry and transient absorption spectroscopy were used to study conformational dynamics associated with CO photodissociation from horse heart myoglobin (Mb) reconstituted with either Fe protoporphyrin IX dimethylester (FePPDME), Fe octaethylporphyrin (FeOEP), or with native Fe protoporphyrin IX (FePPIX). The volume and enthalpy changes associated with the Fe-CO bond dissociation and formation of a transient deoxyMb intermediate for the reconstituted Mbs were found to be similar to those determined for native Mb (DeltaV1 = -2.5+/-0.6 ml mol(-1) and DeltaH1 = 8.1+/-3.0 kcal mol(-1)). The replacement of FePPIX by FeOEP significantly alters the conformational dynamics associated with CO release from protein. Ligand escape from FeOEP reconstituted Mb was determined to be roughly a factor of two faster (tau=330 ns) relative to native protein (tau=700 ns) and accompanying reaction volume and enthalpy changes were also found to be smaller (DeltaV2 = 5.4+/-2.5 ml mol(-1) and DeltaH2 = 0.7+/-2.2 kcal mol(-1)) than those for native Mb (DeltaV2 = 14.3+/-0.8 ml mol(-1) and DeltaH2 = 7.8+/-3.5 kcal mol(-1)). On the other hand, volume and enthalpy changes for CO release from FePPIX or FePPDME reconstituted Mb were nearly identical to those of the native protein. These results suggest that the hydrogen bonding network between heme propionate groups and nearby amino acid residues likely play an important role in regulating ligand diffusion through protein matrix. Disruption of this network leads to a partially open conformation of protein with less restricted ligand access to the heme binding pocket. 相似文献
70.
Geiser F Holloway JC Körtner G 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》2007,177(5):495-501
Most studies on animal physiology and behaviour are conducted in captivity without verification that data are representative
of free-ranging animals. We provide the first quantitative comparison of daily torpor, thermal biology and activity patterns,
conducted on two groups of sugar gliders (Petaurus breviceps, Marsupialia) exposed to similar thermal conditions, one in captivity and the other in the field. Our study shows that activity
in captive gliders in an outdoor aviary is restricted to the night and largely unaffected by weather, whereas free-ranging
gliders omit foraging on cold/wet nights and may also forage in the afternoon. Torpor occurrence in gliders was significantly
lower in captivity (8.4% after food deprivation; 1.1% for all observations) than in the field (25.9%), mean torpor bout duration
was shorter in captivity (6.9 h) than in the field (13.1 h), and mean body temperatures during torpor were higher in captivity
(25.3°C) than in the field (19.6°C). Moreover, normothermic body temperature as a function of air temperature differed between
captive and free-ranging gliders, with a >3°C difference at low air temperatures. Our comparison shows that activity patterns,
thermal physiology, use of torpor and patterns of torpor may differ substantially between the laboratory and field, and provides
further evidence that functional and behavioural data on captive individuals may not necessarily be representative of those
living in the wild. 相似文献