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991.
Cosi C Mannaioni G Cozzi A Carlà V Sili M Cavone L Maratea D Moroni F 《Neuropharmacology》2011,60(7-8):1227-1231
G-protein coupled receptor 35 (GPR35) is a former "orphan receptor" expressed in brain and activated by either kynurenic acid or zaprinast. While zaprinast has been studied as a phosphodiesterase inhibitor, kynurenic acid (KYNA) is a tryptophan metabolite and has been proposed as the endogenous ligand for this receptor. In the present work, we showed that GPR35 is present in the dorsal root ganglia and in the spinal cord and in order to test the hypothesis that GPR35 activation could cause analgesia, we administered suitable doses of zaprinast or we increased the local concentration of KYNA by administering a precursor (kynurenine) or by inhibiting its disposal from the CNS (with probenecid). We used the "writhing test" induced by acetic acid i.p. injection in mice. KYNA and kynurenine plasma and spinal cord levels were measured with HPLC techniques. Kynurenine (30, 100, 300 mg/kg s.c.) increased plasma and spinal cord levels of KYNA and decreased the number of writhes in a dose dependent manner. Similarly, probenecid was able to increase KYNA levels in plasma and spinal cord, to reduce the number of writes and to amplify kynurenine effects. Furthermore, zaprinast had antinociceptive effects in the writhing test without affecting KYNA levels. In agreement with its affinity for GPR35 receptor (approximately 10 times higher than that of KYNA), zaprinast action occurred at relatively low doses. No additive actions were obtained when kynurenine and zaprinast were administered at maximally active doses. Our results suggest that GPR35 could be an interesting target for innovative pharmacological agents designed to reduce inflammatory pain. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. 相似文献
992.
Johnson S Barile E Farina B Purves A Wei J Chen LH Shiryaev S Zhang Z Rodionova I Agrawal A Cohen SM Osterman A Strongin A Pellecchia M 《Chemical biology & drug design》2011,78(2):211-223
It has been estimated that nearly one-third of functional proteins contain a metal ion. These constitute a wide variety of possible drug targets including metalloproteinases, dehydrogenases, oxidoreductases, hydrolases, deacetylases, or many others in which the metal ion is either of catalytic or of structural nature. Despite the predominant role of a metal ion in so many classes of drug targets, current high-throughput screening techniques do not usually produce viable hits against these proteins, likely due to the lack of proper metal-binding pharmacophores in the current screening libraries. Herein, we describe a novel fragment-based drug discovery approach using a metal-targeting fragment library that is based on a variety of distinct classes of metal-binding groups designed to reliably anchor the fragments at the target's metal ions. We show that the approach can effectively identify novel, potent and selective agents that can be readily developed into metalloprotein-targeted therapeutics. 相似文献
993.
Riganti C Voena C Kopecka J Corsetto PA Montorfano G Enrico E Costamagna C Rizzo AM Ghigo D Bosia A 《Molecular pharmaceutics》2011,8(3):683-700
The most frequent drawback of doxorubicin is the onset of drug resistance, due to the active efflux through P-glycoprotein (Pgp). Recently formulations of liposome-encapsulated doxorubicin have been approved for the treatment of tumors resistant to conventional anticancer drugs, but the molecular basis of their efficacy is not known. To clarify by which mechanisms the liposome-encapsulated doxorubicin is effective in drug-resistant cancer cells, we analyzed the effects of doxorubicin and doxorubicin-containing anionic liposomal nanoparticles ("Lipodox") on the drug-sensitive human colon cancer HT29 cells and on the drug-resistant HT29-dx cells. Interestingly, we did not detect any difference in drug accumulation and toxicity between free doxorubicin and Lipodox in HT29 cells, but Lipodox was significantly more effective than doxorubicin in HT29-dx cells, which are rich in Pgp. This effect was lost in HT29-dx cells silenced for Pgp and acquired by HT29 cells overexpressing Pgp. Lipodox was less extruded by Pgp than doxorubicin and inhibited the pump activity. This inhibition was due to a double effect: the liposome shell per se altered the composition of rafts in resistant cells and decreased the lipid raft-associated amount of Pgp, and the doxorubicin-loaded liposomes directly impaired transport and ATPase activity of Pgp. The efficacy of Lipodox was not increased by verapamil and cyclosporin A and was underwent interference by colchicine. Binding assays revealed that Lipodox competed with verapamil for binding Pgp and hampered the interaction of colchicine with this transporter. Site-directed mutagenesis experiments demonstrated that glycine 185 is a critical residue for the direct inhibitory effect of Lipodox on Pgp. Our work describes novel properties of liposomal doxorubicin, investigating the molecular bases that make this formulation an inhibitor of Pgp activity and a vehicle particularly indicated against drug-resistant tumors. 相似文献
994.
995.
Laura C. Hautala Dario Greco Riitta Koistinen Tuomas Heikkinen Päivi Heikkilä Kristiina Aittomäki Carl Blomqvist Hannu Koistinen Heli Nevanlinna 《Breast cancer research and treatment》2011,128(1):85-95
Glycodelin (encoded by PAEP gene) is a secreted lipocalin protein mainly expressed in reproductive tissues, but also in several tumour types. In the
breast, glycodelin is expressed both in normal epithelial and cancerous tissue. To investigate the association of glycodelin
with clinicopathological features of breast cancer and outcome of patients we evaluated the protein expression of glycodelin
in a large series of breast tumours. Immunohistochemical analysis of tissue microarrays was used to study glycodelin expression
on 399 sporadic and 436 familial non-BRCA1/2 tumours with strong family history. Gene expression analysis was used to define genes co-expressed with PAEP in sporadic and familial non-BRCA1/2 breast tumours. In the sporadic series, the glycodelin expression associated with low proliferation rate (P < 0.001), with a tendency towards well-differentiated tumours (grades 1 and 2, P = 0.012) and high cyclin D1 (P = 0.034) expression. However, in familial non-BRCA1/2 cases with strong family history glycodelin expression associated with a less favourable phenotype, i.e. positive lymph node
status (P = 0.003) and HER2-positive tumours (P = 0.009). Moreover, the patients with glycodelin-positive tumours had an increased risk for distant metastases (P = 0.001) and in multivariate analysis glycodelin expression was an independent predictor of metastasis (hazard ratio (HR) = 2.22,
95% confidence interval (95% CI) = 1.22–4.03, P = 0.009) in familial non-BRCA1/2 breast cancer. Gene expression analysis further revealed different gene expression profiles correlating with the PAEP expression in the sporadic and familial non-BRCA1/2 breast cancers. Our findings suggest differential progression pathways in the sporadic and familial non-BRCA1/2 breast tumours expressing glycodelin. 相似文献
996.
Lucchini R Carnelli D Ponzoni M Bertarelli E Gastaldi D Vena P 《Journal of the Mechanical Behavior of Biomedical Materials》2011,4(8):1852-1863
The aim of this paper is to show that damage mechanisms can account for the response of lamellar bone to nanoindentation tests, with particular regards to the decrease of indentation stiffness with increasing penetration depth and to the loss of contact stiffness during the unloading phase of the test. For this purpose, indentation experiments on bovine cortical bone samples along axial and transverse directions have been carried out at five penetration depths from 50 to 450 nm; furthermore, a continuum damage model has been implemented into finite element analyses, which are able to simulate indentation experiments. Experiments along the axial direction have shown a decrease of about 20% of the indentation modulus with indentation depth; a similar trend was found along the transverse direction. All unloading branches of the force-displacement indentation curves exhibited relevant stiffness loss (curve concavity). The numerical model with damage was able to correctly predict the indentation stiffness and hardness at 300 nm penetration depth along both axial and transverse directions. Furthermore, stiffness loss during unloading was simulated with both qualitative and quantitative agreement with experiments. A final validation has been provided by simulating axial indentation experiments at the remaining penetration depths using the same set of constitutive parameters as those used to simulate the experiments at 300 nm depth. These results support the hypothesis that damage plays a relevant role in the mechanics of lamellar bone and should be taken into account when studying bone mechanical properties at multiple scales. 相似文献
997.
998.
Domitrovi? R Jakovac H Marchesi VV ?ain I Romi? ? Raheli? D 《Pharmacological research》2012,65(4):451-464
Olives and olive products, an inevitable part of the Mediterranean diet, possess various beneficial effects, such as a decreased risk of cardiovascular disease and cancer. Oleuropein is a non-toxic secoiridoid found in the leaves and fruits of olive (Olea europaea L.). In this study, we have investigated the hepatoprotective activity of oleuropein in carbon tetrachloride (CCl(4))-induced liver injury in male BALB/cN mice. Oleuropein in doses of 100 and 200mg/kg was administered intraperitoneally (ip) once daily for 3 consecutive days, prior to CCl(4) administration (the preventive treatment), or once daily for 2 consecutive days 6h after CCl(4) intoxication (the curative treatment). CCl(4) intoxication resulted in a massive hepatic necrosis and increased plasma transaminases. Liver injury was associated with oxidative/nitrosative stress evidenced by increased nitrotyrosine formation as well as a significant decrease in superoxide dismutase activity and glutathione levels. CCl(4) administration triggered inflammatory response in mice livers by inducing expression of nuclear factor-kappaB, which coincided with the induction of tumor necrosis factor-alpha, cyclooxygenase-2 and inducible nitric oxide synthase. In both treatment protocols, oleuropein significantly attenuated oxidative/nitrosative stress and inflammatory response and improved histological and plasma markers of liver damage. Additionally, in the curative regimen, oleuropein prevented tumor necrosis factor-beta1-mediated activation of hepatic stellate cells, as well as the activation of caspase-3. The hepatoprotective activity of oleuropein was, at least in part, achieved through the NF-E2-related factor 2-mediated induction of heme oxygenase-1. The present study demonstrates antioxidant, anti-inflammatory, antiapoptotic, and antifibrotic activity of oleuropein, with more pronounced therapeutic than prophylactic effects. 相似文献
999.
M Nebbioso M Evangelista A Librando D Di Blasio N Pescosolido 《Expert opinion on pharmacotherapy》2012,13(13):1829-1835
Objective: The purpose of this study was to verify the ocular comfort of a fixed topical combination of brinzolamide 1% plus timolol 0.5% suspension vs. dorzolamide 2% plus timolol 0.5% solution, both preserved with benzalkonium chloride (BAK), in patients with primary open-angle glaucoma (POAG) through subjective and objective methods. BAK is the most commonly used preservative in topical glaucoma medications. Methods: 62 subjects were examined and included in the analysis. Each patient was asked to complete a questionnaire on symptoms (Ocular Surface Disease Index) and then underwent a series of examinations. The Ocular Protection Index evaluated the risk of damage to the ocular surface, and was expressed as the ratio between fluorescein breakup time and blinking interval. These and other analyses were repeated 30 days after instillation of the new eye drop treatment. Results: The results demonstrated that patients enrolled with the preserved fixed combination of dorzolamide or brinzolamide represented a subgroup of patients in which the discomfort symptoms were supposedly justified by the presence of BAK used chronically in antihypertensive drops. Ocular discomfort scores were significantly higher with dorzolamide/timolol than brinzolamide/timolol (p < 0.0001). Conclusions: This work shows the better tolerability of brinzolamide 1% plus timolol 0.5% suspension, compared with dorzolamide 2% plus timolol 0.5% solution. Fortunately, some of the adverse reactions induced by preserved eye drop glaucoma medication are reversible after removing the preservatives. Both the potential for added benefit and patient compliance should be considered when selecting ocular hypotensive therapy. 相似文献