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91.
92.
Irreversible AE1 tyrosine phosphorylation leads to membrane vesiculation in G6PD deficient red cells
Pantaleo A Ferru E Carta F Mannu F Simula LF Khadjavi A Pippia P Turrini F 《PloS one》2011,6(1):e15847
Background
While G6PD deficiency is one of the major causes of acute hemolytic anemia, the membrane changes leading to red cell lysis have not been extensively studied. New findings concerning the mechanisms of G6PD deficient red cell destruction may facilitate our understanding of the large individual variations in susceptibility to pro-oxidant compounds and aid the prediction of the hemolytic activity of new drugs.Methodology/Principal Findings
Our results show that treatment of G6PD deficient red cells with diamide (0.25 mM) or divicine (0.5 mM) causes: (1) an increase in the oxidation and tyrosine phosphorylation of AE1; (2) progressive recruitment of phosphorylated AE1 in large membrane complexes which also contain hemichromes; (3) parallel red cell lysis and a massive release of vesicles containing hemichromes. We have observed that inhibition of AE1 phosphorylation by Syk kinase inhibitors prevented its clustering and the membrane vesiculation while increases in AE1 phosphorylation by tyrosine phosphatase inhibitors increased both red cell lysis and vesiculation rates. In control RBCs we observed only transient AE1 phosphorylation.Conclusions/Significance
Collectively, our findings indicate that persistent tyrosine phosphorylation produces extensive membrane destabilization leading to the loss of vesicles which contain hemichromes. The proposed mechanism of hemolysis may be applied to other hemolytic diseases characterized by the accumulation of hemoglobin denaturation products. 相似文献93.
Cristina Bolzati Davide Carta Valentina Gandin Cristina Marzano Nicolò Morellato Nicola Salvarese Mariangela Cantore Nicola Antonio Colabufo 《Journal of biological inorganic chemistry》2013,18(5):523-538
[99mTc(N)(DBODC)(PNP5)]+ [DBODC is bis(N-ethoxyethyl)dithiocarbamato; PNP5 is bis(dimethoxypropylphosphinoethyl)ethoxyethylamine], abbreviated as 99mTc(N)-DBODC(5), is a lipophilic cationic mixed compound investigated as a myocardial imaging agent. The findings that this tracer accumulates in mitochondrial structures through a mechanism mediated by the negative mitochondrial membrane potential and that the rapid efflux of 99mTc(N)-DBODC(5) from nontarget tissues seems to be associated with the multidrug resistance (MDR) P-glycoprotein (P-gp) transport function open up the possibility to extend its clinical applications to tumor imaging and noninvasive MDR studies. The rate of uptake at 4 and 37 °C of 99mTc(N)-DBODC(5) was evaluated in vitro in selected human cancer cell lines and in the corresponding sublines before and after P-gp and/or MDR-associated protein (MRP) modulator/inhibitor treatment using 99mTc-sestamibi as a reference. The results indicated that (1) the uptake of both 99mTc(N)-DBODC(5) and 99mTc-sestamibi is correlated to metabolic activity of the cells and (2) the cellular accumulation is connected to the level of P-gp/MRP expression; in fact, an enhancement of uptake in resistant cells was observed after treatment with opportune MDR inhibitor/modulator, indicating that the selective blockade of P-gp/MRP prevented efflux of the tracers. This study provides a preliminary indication of the applicability of 99mTc(N)-DBODC(5) in tumor imaging and in detecting P-gp/MRP-mediated drug resistance in human cancer. In addition, the possibility to control the hydrophobicity and pharmacological activity of this heterocomplex through the variation of the substituents on the ligands backbone without affecting the P2S2 coordinating sphere makes 99mTc(N)-DBODC(5) a suitable scaffold for the preparation of a molecular probe for single photon emission computed tomography of MDR. 相似文献
94.
Murat Bozdag Tobias Dreker Christophe Henry Paolo Tosco Maura Vallaro Roberta Fruttero Andrea Scozzafava Fabrizio Carta Claudiu T. Supuran 《Bioorganic & medicinal chemistry letters》2013,23(3):715-719
Protein arginin deaminase 4 (PAD4) is a calcium dependent enzyme which catalyses the conversion of peptidyl-arginine into peptidyl-citrulline and is implicated in several diseases such as rheumatoid arthritis (RA) and cancer. Herein we report the discovery of novel small-molecule, non peptidic PAD4 inhibitors incorporating primary/secondary guanidine moieties. 相似文献
95.
Leo Syrjänen Martti E.E. Tolvanen Mika Hilvo Daniela Vullo Fabrizio Carta Claudiu T. Supuran Seppo Parkkila 《Bioorganic & medicinal chemistry》2013,21(6):1516-1521
Carbonic anhydrases (CAs) are essential and ubiquitous enzymes. Thus far, there are no articles on characterization of Drosophila melanogaster α-CAs. Data from invertebrate CA studies may provide opportunities for anti-parasitic drug development because α-CAs are found in many parasite or parasite vector invertebrates. We have expressed and purified D. melanogaster CAH1 and CAH2 as proteins of molecular weights 30 kDa and 28 kDa. CAH1 is cytoplasmic whereas CAH2 is a membrane-attached protein. Both are highly active enzymes for the CO2 hydration reaction, being efficiently inhibited by acetazolamide. CAH2 in the eye of D. melanogaster may provide a new animal model for CA-related eye diseases. A series of dithiocarbamates were also screened as inhibitors of these enzymes, with some representatives showing inhibition in the low nanomolar range. 相似文献
96.
Harun M. Said Carsten Hagemann Fabrizio Carta Astrid Katzer Bülent Polat Adrian Staab Andrea Scozzafava Jelena Anacker Giles H. Vince Michael Flentje Claudiu T. Supuran 《Bioorganic & medicinal chemistry》2013,21(13):3949-3957
HIF-1α regulated genes are mainly responsible for tumour resistance to radiation- and chemo-therapy. Among these genes, carbonic anhydrase isoform IX (CA9) is highly over expressed in many types of cancer especially in high grade brain cancer like Glioblastoma (GBM). Inhibition of the enzymatic activity by application of specific chemical CA9 inhibitor sulphonamides (CAI) like Acetazolamide (Aza.), the new sulfonamide derivative carbonic anhydrase inhibitor (SU.D2) or indirect inhibitors like the HIF-1α inhibitor Chetomin or molecular inhibitors like CA9-siRNA are leading to an inhibition of the functional role of CA9 during tumorigenesis. Human GBM cells were treated with in vitro hypoxia (1, 6, or 24 h at 0.1%, O2). Aza. application was at a range between 250 and 8000 nM and the HIF-1α inhibitor Chetomin at a concentration range of 150–500 nM. Cell culture plates were incubated for 24 h under hypoxia (0.1% O2). Further, CA9-siRNA constructs were transiently transfected into GBM cells exposed to extreme hypoxic aeration conditions. CA9 protein expression level was detectable in a cell-type specific manner under normoxic conditions. Whereas U87-MG exhibited a strong aerobic expression, U251 and U373 displayed moderate and GaMG very weak normoxic CA9 protein bands. Aza. as well as SU.D2 displayed inhibitory characteristics to hypoxia induced CA9 expression in the four GBM cell lines for 24 h of hypoxia (0.1% O2) at concentrations between 3500 and 8000 nM, on both the protein and mRNA level. Parallel experiments using CA9-siRNA confirmed these results. Application of 150–500 nM of the glycolysis inhibitor Chetomin under similar oxygenation conditions led to a sharply reduced expression of both CA IX protein and CA9 mRNA levels, indicating a clear glucose availability involvement for the hypoxic HIF-1α and CA9 expression in GBM cells. Hypoxia significantly influences the behaviour of human tumour cells by activation of genes involved in the adaptation to hypoxic stress. The main objective in malignant GBM therapy is either to eradicate the tumour or to convert it into a controlled, quiescent chronic disease. Aza., SU.D2, Chetomin or CA9-siRNA possesses functional CA9 inhibitory characteristics when applied against human cancers with hypoxic regions like GBM. They may be used as alternative or in conjunction with other direct inhibitors possessing similar functionality, thereby rendering them as potential optimal tools for the development of an optimized therapy in human brain cancer treatment. 相似文献
97.
Crocus ilvensis sp. nov. (sect. Crocus,Iridaceae), endemic to Elba Island (Tuscan Archipelago,Italy)
A new species of Crocus sect. Crocus is described as an endemic of Elba Island (Tuscan Archipelago, Italy): C. ilvensis Peruzzi & Carta sp. nov. (2n=8). The new species was wrongly referred to C. corsicus Vanucchi (2n=18), C. etruscus Parl. (2n=8) or C. vernus Hill. subsp. vernus (2n=8, 16) by previous authors. Its karyotype structure, asymmetry and chromosome dimensions show affinity with C. etruscus, and no clear relations with other related taxa. From a morphological point of view, C. ilvensis appears intermediate between C. etruscus and C. vernus subsp. vernus, showing however a peculiar combination of character‐states. The new species is completely allopatric with other Crocus sect. Crocus taxa and its possible role in the origin of tetraploid races of C. vernus is discussed. 相似文献
98.
99.
McKay PB Peters MB Carta G Flood CT Dempsey E Bell A Berry C Lloyd DG Fayne D 《Bioorganic & medicinal chemistry letters》2011,21(11):3335-3341
We describe the application of ligand based virtual screening technologies towards the discovery of novel plasmepsin (PM) inhibitors, a family of malarial parasitic aspartyl proteases. Pharmacophore queries were used to screen vendor libraries in search of active and selective compounds. The virtual hits were biologically assessed for activity and selectivity using whole cell Plasmodium falciparum parasites and on target in PM II, PM IV and the closely related human homologue, Cathepsin D assays. Here we report the virtual screening highlights, structures of the hits and their demonstrated biological activity. 相似文献
100.
Pacchiano F Carta F Vullo D Scozzafava A Supuran CT 《Bioorganic & medicinal chemistry letters》2011,21(1):102-105
A series of sulfonamides was prepared by reaction of sulfanilamide with aryl/alkyl isocyanates. The ureido-substituted benzenesulfonamides showed a very interesting profile for the inhibition of several carbonic anhydrases (CAs, EC 4.2.1.1) such as the human hCA II and three β-CAs from pathogenic fungal or bacterial species. The Candida albicans enzyme was inhibited with potencies in the range of 3.4-3970 nM, whereas the Mycobacterium tuberculosis enzymes Rv1284 and Rv3273 were inhibited with Kis in the range of 4.8-6500 nM and of 6.4-6850 nM, respectively. The structure-activity relationship for this class of inhibitors is rather complex, but the main features associated with effective inhibition of both α- and β-CAs investigated here have been delineated. The nature of the moiety substituting the second ureido nitrogen is the determining factor in controlling the inhibitory power, probably due to the flexibility of the ureido linker and the possibility of this moiety to orientate in different subpockets of the active site cavities of these enzymes. 相似文献