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11.
Nirogi RV Deshpande AD Kambhampati R Badange RK Kota L Daulatabad AV Shinde AK Ahmad I Kandikere V Jayarajan P Dubey PK 《Bioorganic & medicinal chemistry letters》2011,21(1):346-349
N1-Arylsulfonyl-3-piperazinyl indole derivatives were designed and identified as a novel class of 5-HT6 receptors ligands. All the compounds have high affinity and antagonist activity towards 5-HT6 receptor. The compound 7a (Ki = 3.4 nM, functional assay IC50 = 310 nM) shows enhanced cognitive effect when tested in NORT and Morris water maze models. Synthesis, SAR and PK profile of these novel compounds constitute the subject matter of this Letter. 相似文献
12.
Herpesvirus-specific CD8 T cell immunity in old age: cytomegalovirus impairs the response to a coresident EBV infection 总被引:9,自引:0,他引:9
Khan N Hislop A Gudgeon N Cobbold M Khanna R Nayak L Rickinson AB Moss PA 《Journal of immunology (Baltimore, Md. : 1950)》2004,173(12):7481-7489
Aging in humans is associated with increased infections and the reduced proliferative capacity of T cells, part of the more global phenomenon termed immune senescence. The etiology of immune senescence is unknown but the accumulation of virus-specific memory T cells may be a contributory factor. We have examined CD8 T cell responses to two persistent herpesvirus infections, CMV and EBV, and to a recurrent virus infection, influenza, in different age cohorts of healthy donors using HLA-peptide tetramers and intracellular cytokine detection. Of these, CMV appears to be the most immunogenic, with the CD8 T cell response representing over 10% of the CD8 pool in many elderly donors. Interestingly, the effect of age upon EBV-specific responses depends upon donor CMV sero-status. In CMV seropositive donors, the magnitude of the EBV-specific immune response is stable with age, but in CMV seronegative donors, the response to EBV increases significantly with age. By contrast, the influenza-specific CD8 T cell immune response decreases with age, independent of CMV status. The functional activity of the herpesvirus-specific immune response decreases in elderly donors, although the characteristic phenotypes of CMV- and EBV-specific memory populations are retained. This demonstrates that aging is associated with a marked accumulation of CMV-specific CD8 T cells together with a decrease in immediate effector function. Moreover, infection with CMV can reduce prevailing levels of immunity to EBV, another persistent virus. These results suggest that carriage of CMV may be detrimental to the immunocompetent host by suppressing heterologous virus-specific immunity during aging. 相似文献
13.
14.
Kamal A Laxman N Ramesh G Srinivas O Ramulu P 《Bioorganic & medicinal chemistry letters》2002,12(15):1917-1919
The design and facile synthesis of C-8 alkylamino substituted pyrrolo[2,1-c][1,4]benzodiazepines is described. These have been prepared by linking the amines at C-8 position with propane spacer to improve solubility in water, and their in vitro cytotoxicity studies have been carried out. 相似文献
15.
Subczynski WK Raguz M Widomska J Mainali L Konovalov A 《The Journal of membrane biology》2012,245(1):51-68
The most unique feature of the eye lens fiber-cell plasma membrane is its extremely high cholesterol content. Cholesterol
saturates the bulk phospholipid bilayer and induces formation of immiscible cholesterol bilayer domains (CBDs) within the
membrane. Our results (based on EPR spin-labeling experiments with lens-lipid membranes), along with a literature search,
have allowed us to identify the significant functions of cholesterol specific to the fiber-cell plasma membrane, which are
manifest through cholesterol–membrane interactions. The crucial role is played by the CBD. The presence of the CBD ensures
that the surrounding phospholipid bilayer is saturated with cholesterol. The saturating cholesterol content in fiber-cell
membranes keeps the bulk physical properties of lens-lipid membranes consistent and independent of changes in phospholipid
composition. Thus, the CBD helps to maintain lens-membrane homeostasis when the membrane phospholipid composition changes
significantly. The CBD raises the barrier for oxygen transport across the fiber-cell membrane, which should help to maintain
a low oxygen concentration in the lens interior. It is hypothesized that the appearance of the CBD in the fiber-cell membrane
is controlled by the phospholipid composition of the membrane. Saturation with cholesterol smoothes the phospholipid-bilayer
surface, which should decrease light scattering and help to maintain lens transparency. Other functions of cholesterol include
formation of hydrophobic and rigidity barriers across the bulk phospholipid-cholesterol domain and formation of hydrophobic
channels in the central region of the membrane for transport of small, nonpolar molecules parallel to the membrane surface.
In this review, we provide data supporting these hypotheses. 相似文献
16.
EPR spin-labeling methods were used to investigate the order and fluidity of alkyl chains, the hydrophobicity of the membrane
interior, and the order and motion of cholesterol molecules in coexisting phases and domains, or in a single phase of fluid-phase
cholesterol/egg-sphingomyelin (Chol/ESM) membranes with a Chol/ESM mixing ratio from 0 to 3. A complete set of profiles for
these properties was obtained for the liquid-disordered (l
d) phase without cholesterol, for the liquid-ordered (l
o) phase for the entire region of cholesterol solubility in this phase (from 33 to 66 mol%), and for the l
o-phase domain that coexists with the cholesterol bilayer domain (CBD). Alkyl chains in the l
o phase are more ordered than in the l
d pure ESM membrane. However, fluidity in the membrane center is greater. Also, the profile of hydrophobicity changed from
a bell to a rectangular shape. These differences are enhanced when the cholesterol content of the l
o phase is increased from 33 to 66 mol%, with clear brake-points between the C9 and C10 positions (approximately where the
steroid-ring structure of cholesterol reaches into the membrane). The organization and motion of cholesterol molecules in
the CBD are similar to those in the l
o-phase domain that coexists with the CBD. 相似文献
17.
Pokhrel L Kim Y Nguyen TD Prior AM Lu J Chang KO Hua DH 《Bioorganic & medicinal chemistry letters》2012,22(10):3480-3484
During the last decade, noroviruses have gained media attention as the cause of large scale outbreaks of gastroenteritis on cruise ships, dormitories, nursing homes, etc. Although noroviruses do not multiply in food or water, they can cause large outbreaks because approximately 10-100 virions are sufficient to cause illness in a healthy adult. Recently, it was shown that the activity of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) enzyme may be important in norovirus infection. In search of anti-noroviral agents based on the inhibition of ACAT1, we synthesized and evaluated the inhibitory activities of a class of pyranobenzopyrone molecules containing amino, pyridine, substituted quinolines, or 7,8-benzoquinoline nucleus. Three of the sixteen evaluated compounds possess ED(50) values in the low micrometer range. 2-Quinolylmethyl derivative 3A and 4-quinolylmethyl derivative 4A showed ED(50) values of 3.4 and 2.4 μM and TD(50) values of >200 and 96.4 μM, respectively. The identified active compounds are suitable for further modification for the development of anti-norovirus agents. 相似文献
18.
BP Bandgar LK Adsul HV Chavan SN Shringare BL Korbad SS Jalde SV Lonikar SH Nile AL Shirfule 《Bioorganic & medicinal chemistry》2012,20(18):5649-5657
Claisen-Schmidt condensation of 3-formyl-9-methylcarbazole with various amides of 3-aminoacetophenone afforded N-{3-[3-(9-methyl-9H-carbazol-3-yl)-acryloyl]-phenyl}-benzamide/amide derivatives. All compounds were investigated for their in vitro xanthine oxidase (XO), tyrosinase and melanin production inhibitory activity. Most of the target compounds had more potent XO inhibitory activity than the standard drug (IC(50)=4.3-5.6μM). Interestingly, compound 7q bearing cyclopropyl ring was found to be the most potent inhibitor of XO (IC(50)=4.3μM). Molecular modelling study gave an insight into its binding modes with XO. Compounds 7a, 7d, 7e, 7g, and 7k were found to be potent inhibitors of tyrosinase (IC(50)=14.01-17.52μM). These results suggest the possible use of these compounds for the design and development of novel XO and tyrosinase inhibitors. 相似文献
19.
Minehira K Young SG Villanueva CJ Yetukuri L Oresic M Hellerstein MK Farese RV Horton JD Preitner F Thorens B Tappy L 《Journal of lipid research》2008,49(9):2038-2044
The liver secretes triglyceride-rich VLDLs, and the triglycerides in these particles are taken up by peripheral tissues, mainly heart, skeletal muscle, and adipose tissue. Blocking hepatic VLDL secretion interferes with the delivery of liver-derived triglycerides to peripheral tissues and results in an accumulation of triglycerides in the liver. However, it is unclear how interfering with hepatic triglyceride secretion affects adiposity, muscle triglyceride stores, and insulin sensitivity. To explore these issues, we examined mice that cannot secrete VLDL [due to the absence of microsomal triglyceride transfer protein (Mttp) in the liver]. These mice exhibit markedly reduced levels of apolipoprotein B-100 in the plasma, along with reduced levels of triglycerides in the plasma. Despite the low plasma triglyceride levels, triglyceride levels in skeletal muscle were unaffected. Adiposity and adipose tissue triglyceride synthesis rates were also normal, and body weight curves were unaffected. Even though the blockade of VLDL secretion caused hepatic steatosis accompanied by increased ceramides and diacylglycerols in the liver, the mice exhibited normal glucose tolerance and were sensitive to insulin at the whole-body level, as judged by hyperinsulinemic euglycemic clamp studies. Normal hepatic glucose production and insulin signaling were also maintained in the fatty liver induced by Mttp deletion. Thus, blocking VLDL secretion causes hepatic steatosis without insulin resistance, and there is little effect on muscle triglyceride stores or adiposity. 相似文献
20.
Schwab U Seppänen-Laakso T Yetukuri L Agren J Kolehmainen M Laaksonen DE Ruskeepää AL Gylling H Uusitupa M Oresic M;GENOBIN Study Group 《PloS one》2008,3(7):e2630