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121.
We evaluated the mechanism of capsaicin-mediated ROS generation in pancreatic cancer cells. The generation of ROS was about 4-6 fold more as compared to control and as early as 1 h after capsaicin treatment in BxPC-3 and AsPC-1 cells but not in normal HPDE-6 cells. The generation of ROS was inhibited by catalase and EUK-134. To delineate the mechanism of ROS generation, enzymatic activities of mitochondrial complex-I and complex-III were determined in the pure mitochondria. Our results shows that capsaicin inhibits about 2.5-9% and 5-20% of complex-I activity and 8-75% of complex-III activity in BxPC-3 and AsPC-1 cells respectively, which was attenuable by SOD, catalase and EUK-134. On the other hand, capsaicin treatment failed to inhibit complex-I or complex-III activities in normal HPDE-6 cells. The ATP levels were drastically suppressed by capsaicin treatment in both BxPC-3 and AsPC-1 cells and attenuated by catalase or EUK-134. Oxidation of mitochondria-specific cardiolipin was substantially higher in capsaicin treated cells. BxPC-3 derived ρ(0) cells, which lack mitochondrial DNA, were completely resistant to capsaicin mediated ROS generation and apoptosis. Our results reveal that the release of cytochrome c and cleavage of both caspase-9 and caspase-3 due to disruption of mitochondrial membrane potential were significantly blocked by catalase and EUK-134 in BxPC-3 cells. Our results further demonstrate that capsaicin treatment not only inhibit the enzymatic activity and expression of SOD, catalase and glutathione peroxidase but also reduce glutathione level. Over-expression of catalase by transient transfection protected the cells from capsaicin-mediated ROS generation and apoptosis. Furthermore, tumors from mice orally fed with 2.5 mg/kg capsaicin show decreased SOD activity and an increase in GSSG/GSH levels as compared to controls. Taken together, our results suggest the involvement of mitochondrial complex-I and III in capsaicin-mediated ROS generation and decrease in antioxidant levels resulting in severe mitochondrial damage leading to apoptosis in pancreatic cancer cells. 相似文献
122.
T.K. Sasikumar Li Qiang Duane A. Burnett William J. Greenlee Cheng Li Larry Heimark Birendra Pramanik Mariagrazia Grilli Rosalia Bertorelli Gianluca Lozza Angelo Reggiani 《Bioorganic & medicinal chemistry letters》2009,19(12):3199-3203
Introduction of small unsaturated alkylamino groups at the 4-position of the A-ring of the tricyclic framework (triazafluorenone) afforded extremely potent and selective mGluR1 antagonists with desirable properties. Compounds 11q and 11s are active in the SNL pain model with ED50s 3.3 and 6.4 mg/kg respectively. Metabolic outcome of propargyl amino moiety was studied. 相似文献
123.
Zhang FL Luo L Gustafson E Lachowicz J Smith M Qiao X Liu YH Chen G Pramanik B Laz TM Palmer K Bayne M Monsma FJ 《The Journal of biological chemistry》2001,276(11):8608-8615
P2Y receptors are a class of G protein-coupled receptors activated primarily by ATP, UTP, and UDP. Five mammalian P2Y receptors have been cloned so far including P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11. P2Y1, P2Y2, and P2Y6 couple to the activation of phospholipase C, whereas P2Y4 and P2Y11 couple to the activation of both phospholipase C and the adenylyl cyclase pathways. Additional ADP receptors linked to Galpha(i) have been described but have not yet been cloned. SP1999 is an orphan G protein-coupled receptor, which is highly expressed in brain, spinal cord, and blood platelets. In the present study, we demonstrate that SP1999 is a Galpha(i)-coupled receptor that is potently activated by ADP. In an effort to identify ligands for SP1999, fractionated rat spinal cord extracts were assayed for Ca(2+) mobilization activity against Chinese hamster ovary cells transiently transfected with SP1999 and chimeric Galpha subunits (Galpha(q/i)). A substance that selectively activated SP1999-transfected cells was identified and purified through a series of chromatographic steps. Mass spectral analysis of the purified material definitively identified it as ADP. ADP was subsequently shown to inhibit forskolin-stimulated adenylyl cyclase activity through selective activation of SP1999 with an EC(50) of 60 nM. Other nucleotides were able to activate SP1999 with a rank order of potency 2-MeS-ATP = 2-MeS-ADP > ADP = adenosine 5'-O-2-(thio)diphosphate > 2-Cl-ATP > adenosine 5'-O-(thiotriphosphate). Thus, SP1999 is a novel, Galpha(i)-linked receptor for ADP. 相似文献
124.
We investigated the specific binding of epidermal growth factor (EGF) to its membrane-bound receptors in cultured cells. The specificity of the binding was attested by the consistent displacement of bound rhodamine-labeled EGF (Rh-EGF) following addition of 1000-fold molar excess of unlabeled EGF. The binding specificity of EGF was further confirmed when vascular EGF was unable to displace Rh-EGF binding, demonstrating no cross-reaction. Evidence for the specific interactions was verified by an equilibrium saturation binding experiment. EGF binding to the cell membranes is saturated at nanomolar concentration. The Scatchard plots show a binding process with K(ass) of 1.5 x 10(9) M(-1). The dissociation kinetics follow a single exponential function characteristic for a relatively slow dissociation process with k(diss) = 2.9 x 10(-4) s(-1). The appearance of two binding complexes through the distribution of diffusion times may suggest that these are representatives of two different forms or subtypes of EGF receptors. This study is of pharmaceutical significance as it provides evidence that fluorescence correlation spectroscopy can be used as a rapid technique for studying ligand-receptor interactions in cell cultures. This is a step forward toward large-scale drug screening in cell cultures. 相似文献
125.
Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors 总被引:10,自引:0,他引:10
Issaeva N Bozko P Enge M Protopopova M Verhoef LG Masucci M Pramanik A Selivanova G 《Nature medicine》2004,10(12):1321-1328
In tumors that retain wild-type p53, its tumor-suppressor function is often impaired as a result of the deregulation of HDM-2, which binds to p53 and targets it for proteasomal degradation. We have screened a chemical library and identified a small molecule named RITA (reactivation of p53 and induction of tumor cell apoptosis), which bound to p53 and induced its accumulation in tumor cells. RITA prevented p53-HDM-2 interaction in vitro and in vivo and affected p53 interaction with several negative regulators. RITA induced expression of p53 target genes and massive apoptosis in various tumor cells lines expressing wild-type p53. RITA suppressed the growth of human fibroblasts and lymphoblasts only upon oncogene expression and showed substantial p53-dependent antitumor effect in vivo. RITA may serve as a lead compound for the development of an anticancer drug that targets tumors with wild-type p53. 相似文献
126.
Cell-penetrating peptides (CPPs) are able to mediate the efficient cellular uptake of a wide range of cargoes. Internalization of a number of CPPs requires uptake by endocytosis, initiated by binding to anionic cell surface heparan sulfate (HS), followed by escape from endosomes. To elucidate the endosomal escape mechanism, we have modeled the process for two CPPs: penetratin (pAntp) and the N-terminal signal peptide of the unprocessed bovine prion protein (bPrPp). Large unilamellar phospholipid vesicles (LUVs) were produced encapsulating either peptide, and an ionophore, nigericin, was used to create a transmembrane pH gradient (DeltapH(mem), inside acidic) similar to the one arising in endosomes in vivo. In the absence of DeltapH(mem), no pAntp escape from the LUVs is observed, while a fraction of bPrPp escapes. In the presence of DeltapH(mem), a significant amount of pAntp escapes and an even higher degree of bPrPp escape takes place. These results, together with the differences in kinetics of escape, indicate different escape mechanisms for the two peptides. A minimum threshold peptide concentration exists for the escape of both peptides. Coupling of the peptides to a cargo reduces the fraction escaping, while complexation with HS significantly hinders the escape. Fluorescence correlation spectroscopy results show that during the escape process the LUVs are intact. Taken together, these results suggest a model for endosomal escape of CPPs: DeltapH(mem)-mediated mechanism, following dissociation from HS of the peptides, above a minimum threshold peptide concentration, in a process that does not involve lysis of the vesicles. 相似文献
127.
Microwave-enhanced enzyme reaction for protein mapping by mass spectrometry: a new approach to protein digestion in minutes 总被引:1,自引:0,他引:1
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Pramanik BN Mirza UA Ing YH Liu YH Bartner PL Weber PC Bose AK 《Protein science : a publication of the Protein Society》2002,11(11):2676-2687
Accelerated proteolytic cleavage of proteins under controlled microwave irradiation has been achieved. Selective peptide fragmentation by endoproteases trypsin or lysine C led to smaller peptides that were analyzed by matrix-assisted laser desorption ionization (MALDI) or liquid chromatography-electrospray ionization (LC-ESI) techniques. The efficacy of this technique for protein mapping was demonstrated by the mass spectral analyses of the peptide fragmentation of several biologically active proteins, including cytochrome c, ubiquitin, lysozyme, myoglobin, and interferon alpha-2b. Most important, using this novel approach digestion of proteins occurs in minutes, in contrast to the hours required by conventional methods. 相似文献
128.
Debadrito Das Divya Vishambhar Kumbhakar Bapi Ghosh Ankita Pramanik Sudha Gupta 《Journal of Plant Interactions》2018,13(1):182-194
The present study highlights the nanoimpact of cadmium sulfide quantum dots on a plant system (Sesamum indicum L.) encompassing uptake of nanoparticles (NPs), subsequent translocation following root to leaf transportation pathway using both water- and food-conducting elements and deposition in nucleus and cytoplasm with no preferential subcellular localization. Nanocrystal agglomeration, mucilaginous sheathing and vesicularization studied are the host toxicity minimization attempt. Cellular stress due to NPs is recorded in the form of elevated production of hydrogen peroxide and malondialdehyde. However, non-synchronous activation of ascorbate peroxidase-monodehydroascorbate reductase-glutathione reductase-glutathione S-transferase enzyme system contributes to failure of anti-oxidative response and persistence of stress environment. Flow cytometric assessment reveals changes in cellular metabolic event along with blockage of cell division at G1 phase and enhances apoptotic cell death. Nuclear internalization along with oxidative burst results in generation of DNA double-strand break which can be the focal point of genome alteration and subsequent gene mutation. 相似文献
129.
A.?Pramanik A.?K.?DattaEmail author D.?Das D.?V.?Kumbhakar B.?Ghosh A.?Mandal S.?Gupta A.?Saha S.?Sengupta 《Cytology and Genetics》2018,52(4):299-308
Present investigation deals with cytogenetical consequences (using attributes namely, seed germination, seedling length, mitotic index, mitotic and meiotic abnormalities and pollen grain sterilities) of cadmium sulphide (CdS) and copper oxide (CuO) nanoparticles (NPs) treatment in Coriandrum sativum L. (Family: Apiaceae, spice of commerce). Ethyl methanesulphonate (EMS), a conventional mutagen is used as positive control. Results suggest that both CdS- and CuO-NPs can induce growth inhibition and cause cytological aberrations in both mitotic and meiotic cells in the studied species. EMS also responds similarly as that of NPs. Study highlights that rooted plant species can be effectively used as model for assessment of nanotoxicity considering cytogenetical parameters. 相似文献
130.
Quantification of retinoic acid by gas-liquid chromatography-mass spectrometry: total versus all-trans-retinoic acid in human plasma 总被引:4,自引:0,他引:4
J L Napoli B C Pramanik J B Williams M I Dawson P D Hobbs 《Journal of lipid research》1985,26(3):387-392
An assay based on negative ion chemical ionization mass spectrometry has been developed to quantify retinoic acid in plasma or serum. The lower limit of detection is 75 pg (240 fmol); normal values of retinoic acid can be determined on as little as 40 microliters of human plasma. The plasma concentrations of total retinoic acid in 12 healthy male volunteers taking no medication or vitamin supplementation ranged from 2.8 to 6.6 ng/ml; the mean was 4.9 ng/ml. The assay can be manipulated to measure all-trans-retinoic acid alone; about 75% of retinoic acid in human plasma or rat serum is all-trans-retinoic acid. Both retinol and retinoic acid can be quantified on the same 0.1-ml sample; the concentration of retinoic acid in human plasma or rat serum is at least 150-fold less than that of retinol. 相似文献