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991.
Bäck M Dahlén SE Drazen JM Evans JF Serhan CN Shimizu T Yokomizo T Rovati GE 《Pharmacological reviews》2011,63(3):539-584
The seven-transmembrane G protein-coupled receptors activated by leukotrienes are divided into two subclasses based on their ligand specificity for either leukotriene B(4) or the cysteinyl leukotrienes (LTC(4), LTD(4), and LTE(4)). These receptors have been designated BLT and CysLT receptors, respectively, and a subdivision into BLT(1) and BLT(2) receptors and CysLT(1) and CysLT(2) receptors has been established. However, recent findings have also indicated the existence of putative additional leukotriene receptor subtypes. Furthermore, other ligands interact with the leukotriene receptors. Finally, leukotrienes may also activate other receptor classes, such as purinergic receptors. The aim of this review is to provide an update on the pharmacology, expression patterns, and pathophysiological roles of the leukotriene receptors as well as the therapeutic developments in this area of research. 相似文献
992.
993.
Shahinaz M. Gadalla Arun Rajan Ruth Pfeiffer Sigurdur Y. Kristinsson Magnus Björkholm Giuseppe Giaccone 《International journal of cancer. Journal international du cancer》2011,128(11):2688-2694
Thymomas are rare tumors of the mediastinum; a limited number of small studies have evaluated the outcomes in these patients. We identified 668 patients with thymoma from the Swedish Cancer Registry, and 2,719 population‐based matched controls. We obtained information on autoimmunity from the nationwide inpatient/outpatient hospital discharge Registry. We constructed Kaplan‐Meier curves for survival analysis, conditional regression and Cox proportional hazards models to evaluate the association between thymoma and autoimmune diseases, and standardized incidence ratios (SIRs) to evaluate the risk for second cancers following thymoma. Compared with controls, patients with benign or malignant thymoma had a poorer (p < 0.001) 5‐year (79%, 53% vs. 91%), 10‐year (65%, 39% vs. 78%) and 20‐year (43%, 18% vs. 55%) overall survival. For thymoma patients, younger age at diagnosis and being diagnosed in recent years were associated with a better survival. Compared with controls, thymoma patients were more likely to have an autoimmune disease at some point during their lives (32.7% vs. 2.4%, respectively, p < 0.001), most frequently myasthenia gravis (24.5%), systemic lupus erythematosus (2.4%) and red cell aplasia (1.2%). Thymoma patients had twofold excess risk for second cancers compared with the general population, most notably: non‐melanoma skin cancer (SIR = 10.6, 95% confidence intervals (CI) = 6.0–17.3), non‐Hodgkin lymphoma (SIR = 6.8, 95% CI = 3.00–13.0), and cervical (SIR = 6.9, 95% CI = 1.4–20.1), endocrine (SIR = 4.7, 95% CI = 1.3–12.0), and prostate cancer (SIR = 3.0, 95% CI = 1.7–4.8). Despite the improved survival for thymoma patients over time, they have worse survival than controls. Thymoma patients are in need for follow‐up to detect and manage autoimmune diseases and cancer. 相似文献
994.
Rusert P Krarup A Magnus C Brandenberg OF Weber J Ehlert AK Regoes RR Günthard HF Trkola A 《The Journal of experimental medicine》2011,208(7):1419-1433
The HIV-1 envelope trimer adopts a quaternary conformation that effectively shields neutralization-sensitive domains and thus represents a major obstacle for natural and vaccine-elicited antibody responses. By using a structure-function analysis based on a specifically devised mathematical model, we demonstrate in this study that protection from neutralization is enforced by intersubunit contact between the variable loops 1 and 2 (V1V2) and domains of neighboring gp120 subunits in the trimer encompassing the V3 loop. Our data are consistent with an interaction of the V1V2 and V3 loop at the spike apex as proposed by cryoelectron tomography experiments. By defining the orientation of the V1V2 loop within the trimer toward the neighboring gp120 subunit's V3 loop, our data close an important gap in the understanding of the architecture of the trimeric spike. Knowledge on how the V1V2 barrier functions in the context of the trimer to mask conserved epitopes on gp120 may aid future vaccine design. 相似文献
995.
Wu X Ohrngren P Joshi AA Trejos A Persson M Arvela RK Wallberg H Vrang L Rosenquist A Samuelsson BB Unge J Larhed M 《Journal of medicinal chemistry》2012,55(6):2724-2736
In an effort to identify a new class of druglike HIV-1 protease inhibitors, four different stereopure β-hydroxy γ-lactam-containing inhibitors have been synthesized, biologically evaluated, and cocrystallized. The impact of the tether length of the central spacer (two or three carbons) was also investigated. A compound with a shorter tether and (3R,4S) absolute configuration exhibited high activity with a K(i) of 2.1 nM and an EC(50) of 0.64 μM. Further optimization by decoration of the P1' side chain furnished an even more potent HIV-1 protease inhibitor (K(i) = 0.8 nM, EC(50) = 0.04 μM). According to X-ray analysis, the new class of inhibitors did not fully succeed in forming two symmetric hydrogen bonds to the catalytic aspartates. The crystal structures of the complexes further explain the difference in potency between the shorter inhibitors (two-carbon spacer) and the longer inhibitors (three-carbon spacer). 相似文献
996.
Nahorski MS Reiman A Lim DH Nookala RK Seabra L Lu X Fenton J Boora U Nordenskjöld M Latif F Hurst LD Maher ER 《Human mutation》2011,32(8):921-929
Germline mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome, familial spontaneous pneumothorax, or apparently nonsyndromic inherited RCC. The vast majority of reported FLCN mutations are predicted to result in a truncated/absent gene product and so infrequent missense and inframe-deletion (IFD) FLCN mutations might indicate critical functional domains. To investigate this hypothesis we (1) undertook an in silico evolutionary analysis of the FLCN sequence and (2) investigated in vitro the functional effects of naturally occurring FLCN missense/IFD mutations. The folliculin protein sequence evolved more slowly and was under stronger purifying selection than the average gene, most notably at a region between codons 100 and 230. Pathogenic missense and IFD FLCN mutations that impaired folliculin tumor suppressor function significantly disrupted the stability of the FLCN gene product but two missense substitutions initially considered to be putative mutations did not impair protein stability, growth suppression activity, or intracellular localization of folliculin. These findings are consistent with the distribution of FLCN mutations throughout the coding sequence, and suggest that multiple protein domains contribute to folliculin stability and tumor suppressor activity. In vitro assessment of protein stability and tumor suppressor activity provides a practical strategy for assessing the pathogenicity of potential FLCN mutations. 相似文献
997.
Che MM Song J Oguntayo S Doctor BP Rezk P Perkins MW Sciuto AM Nambiar MP 《Toxicology mechanisms and methods》2012,22(4):250-259
Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities were measured in the blood and tissues of animals that are treated with a number of endotracheally aerosolized therapeutics for protection against inhalation toxicity to sarin. Therapeutics included, aerosolized atropine methyl bromide (AMB), scopolamine or combination of AMB with salbutamol, sphingosine 1-phosphate, keratinocyte growth factor, adenosine A1 receptor antisense oligonucleotide (EPI2010), 2,3-diacetyloxybenzoic acid (2,3 DABA), oxycyte, and survanta. Guinea pigs exposed to 677.4?mg/m(3) or 846.5?mg/m(3) (1.2 LCt(50)) sarin for 4?min using a microinstillation inhalation exposure technique and treated 1?min later with the aerosolized therapeutics. Treatment with all therapeutics significantly increased the survival rate with no convulsions throughout the 24?h study period. Blood AChE activity determined using acetylthiocholine as substrate showed 20% activity remaining in sarin-exposed animals compare to controls. In aerosolized AMB and scopolamine-treated animals the remaining AChE activity was significantly higher (45-60%) compared to sarin-exposed animals (p?0.05). Similarly, treatment with all the combination therapeutics resulted in significant increase in blood AChE activity in comparison to sarin-exposed animals although the increases varied between treatments (p?0.05). BChE activity was increased after treatment with aerosolized therapeutics but was lesser in magnitude compared to AChE activity changes. Various tissues showed elevated AChE activity after therapeutic treatment of sarin-exposed animals. Increased AChE and BChE activities in animals treated with nasal therapeutics suggest that enhanced breathing and reduced respiratory toxicity/lung injury possibly contribute to rapid normalization of chemical warfare nerve agent inhibited cholinesterases. 相似文献
998.
999.
Bladder pain syndrome is a deceptively intricate symptom complex that is diagnosed on the basis of chronic pelvic pain, pressure, or discomfort perceived to be related to the urinary bladder, accompanied by at least one other urinary symptom. It is a diagnosis of exclusion in a patient who has experienced the symptoms for at least 6 weeks in the absence of any confusable diseases that may give rise to the symptoms. Symptoms compatible with the diagnosis are now thought to affect up to 3% of the female population in the United States with a 5:1 female-to-male preponderance. Diagnosis and treatment can be challenging, and misdiagnosis as a psychological problem, overactive bladder, or chronic urinary infection has plagued patients with the problem. 相似文献
1000.
Choe CU Lewerenz J Gerloff C Magnus T Donzelli S 《Antioxidants & redox signaling》2011,14(9):1699-1711
Nitroxyl (HNO) is the one-electron-reduced and protonated congener of nitric oxide (NO). Compared to NO, it is far more reactive with thiol groups either in proteins or in small antioxidant molecules either converting those into sulfinamides or inducing disulfide bond formation. HNO might mediate cytoprotective changes of protein function through thiol modifications. However, HNO is a strong oxidant that in vitro reacts with glutathione to form glutathione disulfide and glutathione sulfinamide. The resulting oxidative stress might aggravate tissue damage in inflammatory diseases. In this review, we will summarize the current knowledge of how exogenous HNO affects the central nervous system, especially nerve cells and glia in health and disease. Unlike most other organs, the brain is separated from the circulation by the blood-brain barrier, which limits access of many pharmacological compounds. Given that, we will review what is known about the ability of currently used HNO donors to cross the blood-brain barrier. Moreover, considering that the physiology and composition of the brain has unique properties, for example, expression of brain-specific enzymes like neuronal NO synthase, its high iron content, and increased energy metabolism, we will discuss possible sources of endogenous HNO in the brain. 相似文献