排序方式: 共有39条查询结果,搜索用时 15 毫秒
1.
Subasinghe S Unabia S Barrow CJ Mok SS Aguilar MI Small DH 《Journal of neurochemistry》2003,84(3):471-479
Accumulation of beta amyloid (Abeta) in the brain is central to the pathogenesis of Alzheimer's disease. Abeta can bind to membrane lipids and this binding may have detrimental effects on cell function. In this study, surface plasmon resonance technology was used to study Abeta binding to membranes. Abeta peptides bound to synthetic lipid mixtures and to an intact plasma membrane preparation isolated from vascular smooth muscle cells. Abeta peptides were also toxic to vascular smooth muscle cells. There was a good correlation between the toxic effect of Abeta peptides and their membrane binding. 'Ageing' the Abeta peptides by incubation for 5 days increased the proportion of oligomeric species, and also increased toxicity and the amount of binding to lipids. The toxicities of various Abeta analogs correlated with their lipid binding. Significantly, binding was influenced by the concentration of cholesterol in the lipid mixture. Reduction of cholesterol in vascular smooth muscle cells not only reduced the binding of Abeta to purified plasma membrane preparations but also reduced Abeta toxicity. The results support the view that Abeta toxicity is a direct consequence of binding to lipids in the membrane. Reduction of membrane cholesterol using cholesterol-lowering drugs may be of therapeutic benefit because it reduces Abeta-membrane binding. 相似文献
2.
Rudolph MJ Illig CR Subasinghe NL Wilson KJ Hoffman JB Randle T Green D Molloy CJ Soll RM Lewandowski F Zhang M Bone R Spurlino JC Deckman IC Manthey C Sharp C Maguire D Grasberger BL DesJarlais RL Zhou Z 《Bioorganic & medicinal chemistry letters》2002,12(3):491-495
A study of the S1 binding of lead 5-methylthiothiophene amidine 3, an inhibitor of urokinase-type plasminogen activator, was undertaken by the introduction of a variety of substituents at the thiophene 5-position. The 5-alkyl substituted and unsubstituted thiophenes were prepared using organolithium chemistry. Heteroatom substituents were introduced at the 5-position using a novel displacement reaction of 5-methylsulfonylthiophenes and the corresponding oxygen or sulfur anions. Small alkyl group substitution at the 5-position provided inhibitors equipotent with but possessing improved solubility. 相似文献
3.
Travins JM Ali F Huang H Ballentine SK Khalil E Hufnagel HR Pan W Gushue J Leonard K Bone RF Soll RM DesJarlais RL Crysler CS Ninan N Kirkpatrick J Cummings MD Huebert N Molloy CJ Gaul M Tomczuk BE Subasinghe NL 《Bioorganic & medicinal chemistry letters》2008,18(5):1603-1606
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described. 相似文献
4.
Li X Han X Llano J Bole M Zhou X Swan K Anandaiah A Nelson B Patel NR Reinach PS Koziel H Tachado SD 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(11):6052-6058
TLR-4-mediated signaling is significantly impaired in macrophages from HIV(+) persons, predominantly owing to altered MyD88-dependent pathway signaling caused in part by constitutive activation of PI3K. In this study we assessed in these macrophages if the blunted increase in TLR-4-mediated TNF-α release induced by lipid A (LA) is associated with PI3K-induced upregulation of mammalian target of rapamycin (mTOR) activity. mTOR inhibition with rapamycin enhanced TLR-4-mediated TNF-α release, but suppressed anti-inflammatory IL-10 release. Targeted gene silencing of mTOR in macrophages resulted in LA-induced TNF-α and IL-10 release patterns similar to those induced by rapamycin. Rapamycin restored MyD88/IL-1R-associated kinase interaction in a dose-dependent manner. Targeted gene silencing of MyD88 (short hairpin RNA) and mTOR (RNA interference) inhibition resulted in TLR-4-mediated 70-kDa ribosomal protein S6 kinase activation and enhanced TNF-α release, whereas IL-10 release was inhibited in both silenced and nonsilenced HIV(+) macrophages. Furthermore, mTOR inhibition augmented LA-induced TNF-α release through enhanced and prolonged phosphorylation of ERK1/2 and JNK1/2 MAPK, which was associated with time-dependent MKP-1 destabilization. Taken together, impaired TLR-4-mediated TNF-α release in HIV(+) macrophages is attributable in part to mTOR activation by constitutive PI3K expression in a MyD88-dependent signaling pathway. These changes result in MAPK phosphatase 1 stabilization, which shortens and blunts MAPK activation. mTOR inhibition may serve as a potential therapeutic target to upregulate macrophage innate immune host defense responsiveness in HIV(+) persons. 相似文献
5.
Subasinghe NL Illig C Hoffman J Rudolph MJ Wilson KJ Soll R Randle T Green D Lewandowski F Zhang M Bone R Spurlino J DesJarlais R Deckman I Molloy CJ Manthey C Zhou Z Sharp C Maguire D Crysler C Grasberger B 《Bioorganic & medicinal chemistry letters》2001,11(11):1379-1382
The serine protease urokinase plasminogen activator (uPA) is thought to play a central role in tumor metastasis and angiogenesis. Molecular modeling studies suggest that 5-thiomethylthiopheneamidine inhibits uPA by binding at the S1 pocket of the active site. Further structure based elaboration of this residue resulted in a novel class of potent and selective inhibitors of uPA. 相似文献
6.
Mark J. Wall Nalin L. Subasinghe Michael P. Winters Mary Lou Lubin Michael F.A. Finley Ning Qin Michael R. Brandt Michael P. Neeper Craig R. Schneider Raymond W. Colburn Christopher M. Flores Zhihua Sui 《Bioorganic & medicinal chemistry letters》2018,28(23-24):3780-3783
A novel series of pyrazolyltetrahydropyran N-type calcium channel blockers are described. Structural modifications of the series led to potent compounds in both a cell-based fluorescent calcium influx assay and a patch clamp electrophysiology assay. Representative compounds from the series were bioavailable and showed efficacy in the rat CFA and CCI models of inflammatory and neuropathic pain. 相似文献
7.
The role of crustacean fisheries and aquaculture in global food security: past, present and future 总被引:2,自引:0,他引:2
Bondad-Reantaso MG Subasinghe RP Josupeit H Cai J Zhou X 《Journal of invertebrate pathology》2012,110(2):158-165
The 1996 World Food Summit defined food security as "Food security exists when all people, at all times, have physical and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life". This paper looks at the status of production from both shrimp capture fisheries and shrimp aquaculture, as well as trade, in order to understand the contribution of the crustacean sector to overall fish production and thus to global food security. This paper also examines some sustainability issues that will potentially affect the contribution of the crustacean sector (particularly shrimp) to food security. These include sustainable shrimp capture fisheries, sustainable shrimp trade and sustainable shrimp aquaculture. The paper concludes that crustaceans are an important source of aquatic food protein. Production (as food and ornamental) and trade are extremely important for developing countries. It provides both economic development and empowerment in terms of contribution to GDP, consumption, employment, catch value and exports. The crustacean sector generates high value export products which enables producers to buy lower value products in the world market - thus a positive contribution to food security in both producing and exporting countries. 相似文献
8.
NL Subasinghe E Khalil JM Travins F Ali SK Ballentine HR Hufnagel W Pan K Leonard RF Bone RM Soll CS Crysler N Ninan J Kirkpatrick MX Kolpak KA Diloreto SH Eisennagel ND Huebert CJ Molloy BE Tomczuk MD Gaul 《Bioorganic & medicinal chemistry letters》2012,22(16):5303-5307
Complement C1s protease inhibitors have potential utility in the treatment of diseases associated with activation of the classical complement pathway such as humorally mediated graft rejection, ischemia-reperfusion injury (IRI), vascular leak syndrome, and acute respiratory distress syndrome (ARDS). The utility of biphenylsulfonyl-thiophene-carboxamidine small-molecule C1s inhibitors are limited by their poor in vivo pharmacokinetic properties. Pegylation of a potent analog has provided compounds with good potency and good in vivo pharmacokinetic properties. 相似文献
9.
Robert M. Weston Kamani R. Subasinghe Vasiliki Staikopoulos Bevyn Jarrott 《Neurochemical research》2009,34(10):1816-1823
Physical or chemical damage to peripheral nerves can result in neuropathic pain which is not easily alleviated by conventional
analgesic drugs. Substantial evidence has demonstrated that voltage-gated Na+ channels in the membrane of damaged nerves play a key role in the establishment and maintenance of pathological neuronal
excitability not only of these peripheral nerves but also in the second- and third-order neurons in the pain pathway to the
cerebral cortex. Na+ channel blocking drugs have been used in treating neuropathic pain with limited success mainly because of a preponderance
of side-effects. We have developed an analogue of mexiletine which is approximately 80 times more potent than mexiletine in
competing with the radioligand, 3H-batrachotoxinin for binding to Na+ channels in rat brain membranes and also it is much more lipophilic than mexiletine which should enhance its uptake into
the brain to block the increased expression of Na+ channels on second- and third-order neurons of the pain pathway. This analogue, HFI-1, has been tested in three different
rat models of neuropathic pain (formalin paw model, ligated spinal nerve model and contusive spinal cord injury model) and
found to be more effective in reducing pain behaviours than mexiletine. 相似文献
10.
Carroll J Raththagala M Subasinghe W Baguzis S D'amico Oblak T Root P Spence D 《Molecular bioSystems》2006,2(6-7):305-311
A novel microflow technique is used to demonstrate that a weakened oxidant defense system found in diabetic erythrocytes leads to decreased levels of deformation-induced release of adenosine triphosphate (ATP) from erythrocytes. Addition of an oxidant to rabbit erythrocytes resulted in a 63% decrease in deformation-induced ATP release before eventually recovering to a value that was statistically equivalent to the initial value. Inhibition of glucose-6-phosphate dehydrogenase prevents recovery from the oxidant attack. Finally, results indicated that the ATP release from the erythrocytes of type II diabetics (91 nM +/- 10 nM) was less than half of that measured from the erythrocytes of healthy controls (190 +/- 10 nM). These data suggest that the antioxidant status of erythrocytes is a critical determinant in the ability of these cells to release ATP, a known nitric oxide stimulus. 相似文献