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1.
K. Usha Deniz P. S. Parvathanathan Geeta Datta C. L. Khetrapal K. V. Ramanathan N. Suryaprakash S. Raghotama 《Journal of biosciences》1990,15(3):117-123
The influence of the sulfone drugs, diamino diphenyl sulfone and diamino monophenyl sulfone on the phase transitions and dynamics
of dipalmitoyl phosphatidyl choline-H2O/D2O vesicles have been investigated using differential scanning calorimetry and nuclear magnetic resonance. Our results show
that diamino diphenyl sulfone interacts quite strongly with the headgroups of dipalmitoyl phosphatidyl choline whereas the
diamino monophenyl sulfone-dipalmitoyl phosphatidyl choline interaction is quite weak. This is attributed to the difference
in the structure and hydrophobic character of the two drugs. 相似文献
2.
Exploring polyethylenimine-mediated DNA transfection and the proton sponge hypothesis 总被引:6,自引:0,他引:6
BACKGROUND: The relatively high transfection efficiency of polyethylenimine (PEI) vectors has been hypothesized to be due to their ability to avoid trafficking to degradative lysosomes. According to the proton sponge hypothesis, the buffering capacity of PEI leads to osmotic swelling and rupture of endosomes, resulting in the release of the vector into the cytoplasm. METHODS: The mechanism of PEI-mediated DNA transfer was investigated using quantitative methods to study individual steps in the overall transfection process. In addition to transfection efficiency, the cellular uptake, local pH environment, and stability of vectors were analyzed. N-Quaternized (and therefore non-proton sponge) versions of PEI and specific cell function inhibitors were used to further probe the proton sponge hypothesis. RESULTS: Both N-quaternization and the use of bafilomycin A1 (a vacuolar proton pump inhibitor) reduced the transfection efficiency of PEI by approximately two orders of magnitude. Chloroquine, which buffers lysosomes, enhanced the transfection efficiency of N-quaternized PEIs and polylysine by 2-3-fold. In contrast, chloroquine did not improve the transfection efficiency of PEI. The measured average pH environment of PEI vectors was 6.1, indicating that they successfully avoid trafficking to acidic lysosomes. Significantly lower average pH environments were observed for permethyl-PEI (pH 5.4), perethyl-PEI (pH 5.1), and polylysine (pH 4.6) vectors. Cellular uptake levels of permethyl-PEI and perethyl-PEI vectors were found to be 20 and 90% higher, respectively, than that of parent PEI vectors, indicating that the reduction in transfection activity of the N-quaternized PEIs is due to a barrier downstream of cellular uptake. A polycation/DNA-binding affinity assessment showed that the more charge dense N-quaternized PEIs bind DNA less tightly than PEI, demonstrating that poor vector unpackaging was not responsible for the reduced transfection activity of the N-quaternized PEIs. CONCLUSIONS: The results obtained are consistent with the proton sponge hypothesis and strongly suggest that the transfection activity of PEI vectors is due to their unique ability to avoid acidic lysosomes. 相似文献
3.
Wei Shen Tan Pramit Khetrapal Wei Phin Tan Simon Rodney Marisa Chau John D. Kelly 《PloS one》2016,11(11)
BackgroundThe number of robotic assisted radical cystectomy (RARC) procedures is increasing despite the lack of Level I evidence showing any advantages over open radical cystectomy (ORC). However, several systematic reviews with meta-analyses including non-randomised studies, suggest an overall benefit for RARC compared to ORC. We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) to evaluate the perioperative morbidity and efficacy of RARC compared to ORC in patients with bladder cancer.MethodsLiterature searches of Medline/Pubmed, Embase, Web of Science and clinicaltrials.gov databases up to 10th March 2016 were performed. The inclusion criteria for eligible studies were RCTs which compared perioperative outcomes of ORC and RARC for bladder cancer. Primary objective was perioperative and histopathological outcomes of RARC versus ORC while the secondary objective was quality of life assessment (QoL), oncological outcomes and cost analysis.ResultsFour RCTs (from 5 articles) met the inclusion criteria, with a total of 239 patients all with extracorporeal urinary diversion. Patient demographics and clinical characteristics of RARC and ORC patients were evenly matched. There was no significant difference between groups in perioperative morbidity, length of stay, positive surgical margin, lymph node yield and positive lymph node status. RARC group had significantly lower estimated blood loss (p<0.001) and wound complications (p = 0.03) but required significantly longer operating time (p<0.001). QoL was not measured uniformly across trials and cost analysis was reported in one RCTs. A test for heterogeneity did highlight differences across operating time of trials suggesting that surgeon experience may influence outcomes.ConclusionsThis study does not provide evidence to support a benefit for RARC compared to ORC. These results may not have inference for RARC with intracorporeal urinary diversion. Well-designed trials with appropriate endpoints conducted by equally experienced ORC and RARC surgeons will be needed to address this. 相似文献
4.
5.
Francesca Orlandi Marcella Coronnello Cristina Bellucci Silvia Dei Luca Guandalini Dina Manetti Cecilia Martelli Maria Novella Romanelli Serena Scapecchi Milena Salerno Hayette Menif Ivan Bello Enrico Mini Elisabetta Teodori 《Bioorganic & medicinal chemistry》2013,21(2):456-465
As a continuation of previous research on a new series of potent and efficacious P-gp-dependent multidrug resistant (MDR) reversers with a N,N-bis(cyclohexanol)amine scaffold, we have designed and synthesized several analogs by modulation of the two aromatic moieties linked through ester functions to the N,N-bis(cyclohexanol)amine, aiming to optimize activity and to extend structure–activity relationships (SAR) within the series. This scaffold, when esterified with two different aromatic carboxylic acids, gives origin to four geometric isomers (cis/trans, trans/trans, cis/cis and trans/cis).The new compounds were tested on doxorubicin-resistant erythroleukemia K562 cells (K562/DOX) in the pirarubicin uptake assay. Most of them resulted in being potent modulators of the extrusion pump P-gp, showing potency values ([I]0.5) in the submicromolar and nanomolar range. Of these, compounds 2b, 2c, 3d, 5a–d and 6d, showed excellent efficacy with a αmax close to 1. Selected compounds (2d, 3a, 3b, 5a–d) were further studied to evaluate their doxorubicin cytotoxicity potentiation (RF) on doxorubicin-resistant erythroleukemia K562 cells and were found able to enhance significantly doxorubicin cytotoxicity on K562/DOX cells.The results of both pirarubicin uptake and the cytotoxicity assay, indicate that the new compounds of the series are potent P-gp-mediated MDR reversers. They present a structure with a mix of flexible and rigid moieties, a property that seems critical to allow the molecules to choose the most productive of the several binding modes possible in the transporter recognition site.In particular, compounds 5c and 5d, similar to the already reported analogous isomers 1c and 1d,29 are potent and efficacious modulators of P-gp-dependent MDR and may be promising leads for the development of MDR-reversal drugs. 相似文献
6.
Phosphorylation can have profound effects on the properties of nuclear lamins. For instance, phosphorylation of specific sites on mammalian lamins drastically alters their propensity to polymerize. Relatively little is known about the effects of phosphorylation during interphase and about phosphorylation of invertebrate nuclear lamins. Here, using electrospray ionization tandem mass spectrometry, we determined the phosphorylation sites of both interphase and M-phase isoforms of nuclear lamin Dm from Drosophila melanogaster. Interphase lamins are phosphorylated at three sites: two of these sites (Ser25 and a site located between residues 430 and 438) flank the alpha-helical rod domain, whereas the third site (Ser595) is located close to the C-terminus. The M-phase lamin isoform is phosphorylated predominantly at Ser45, a residue contained within a sequence matching the consensus site for phosphorylation by cdc2 kinase. Our study confirms the important role in vivo for cdc2 kinase in M-phase disassembly of nuclear lamins and provides the basis for understanding Drosophila lamin phosphorylation during interphase. 相似文献
7.
Sajan MP Standaert ML Miura A Kahn CR Farese RV 《Molecular endocrinology (Baltimore, Md.)》2004,18(10):2513-2521
Insulin receptor substrates (IRSs) 1 and 2 are postulated to control the activation of phosphatidylinositol 3-kinase (PI3K)-dependent signaling factors, namely, atypical protein kinase C (aPKC) and protein kinase B (PKB)/Akt, which mediate metabolic effects of insulin. However, it is uncertain whether aPKC and PKB are activated together or differentially in response to IRS-1 and IRS-2 activation in insulin-sensitive tissues. Presently, we examined insulin activation of aPKC and PKB in vastus lateralis muscle, adipocytes, and liver in wild-type and IRS-1 knockout mice, and observed striking tissue-specific differences. In muscle of IRS-1 knockout mice, the activation of both aPKC and PKB was markedly diminished. In marked contrast, only aPKC activation was diminished in adipocytes, and only PKB activation was diminished in liver. These results suggest that IRS-1 is required for: 1) activation of both aPKC and PKB in muscle; 2) aPKC, but not PKB, activation in adipocytes; and 3) PKB, but not aPKC, activation in liver. Presumably, IRS-2 or other PI3K activators account for the normal activation of aPKC in liver and PKB in adipocytes of IRS-1 knockout mice. These complexities in aPKC and PKB activation may be relevant to metabolic abnormalities seen in tissues in which IRS-1 or IRS-2 is specifically or predominantly down-regulated. 相似文献
8.
Protein kinase C-lambda knockout in embryonic stem cells and adipocytes impairs insulin-stimulated glucose transport 总被引:3,自引:0,他引:3
Bandyopadhyay G Standaert ML Sajan MP Kanoh Y Miura A Braun U Kruse F Leitges M Farese RV 《Molecular endocrinology (Baltimore, Md.)》2004,18(2):373-383
Atypical protein kinase C (aPKC) isoforms have been suggested to mediate insulin effects on glucose transport in adipocytes and other cells. To more rigorously test this hypothesis, we generated mouse embryonic stem (ES) cells and ES-derived adipocytes in which both aPKC-lambda alleles were knocked out by recombinant methods. Insulin activated PKC-lambda and stimulated glucose transport in wild-type (WT) PKC-lambda(+/+), but not in knockout PKC-lambda(-/-), ES cells. However, insulin-stimulated glucose transport was rescued by expression of WT PKC-lambda in PKC-lambda(-/-) ES cells. Surprisingly, insulin-induced increases in both PKC-lambda activity and glucose transport were dependent on activation of proline-rich tyrosine protein kinase 2, the ERK pathway, and phospholipase D (PLD) but were independent of phosphatidylinositol 3-kinase (PI3K) in PKC-lambda(+/+) ES cells. Interestingly, this dependency was completely reversed after differentiation of ES cells to adipocytes, i.e. insulin effects on PKC-lambda and glucose transport were dependent on PI3K, rather than proline-rich tyrosine protein kinase 2/ERK/PLD. As in ES cells, insulin effects on glucose transport were absent in PKC-lambda(-/-) adipocytes but were rescued by expression of WT PKC-lambda in these adipocytes. Our findings suggest that insulin activates aPKCs and glucose transport in ES cells by a newly recognized PI3K-independent ERK/PLD-dependent pathway and provide a compelling line of evidence suggesting that aPKCs are required for insulin-stimulated glucose transport, regardless of whether aPKCs are activated by PI3K-dependent or PI3K-independent mechanisms. 相似文献
9.
10.
Messori L Marcon G Cinellu MA Coronnello M Mini E Gabbiani C Orioli P 《Bioorganic & medicinal chemistry》2004,12(23):6039-6043
The solution behaviour of some novel organogold(III) compounds was investigated, and their cytotoxic properties evaluated against a few human tumour cell lines (A2780/S, A2780/R, MCF7, HT29 and A549). Specifically, the following compounds were considered: [Au(bipy(dmb)-H)(2,6-xylidine-H)][PF(6)] (AuXyl) and [Au(bipy(dmb)-H)(p-toluidine-H)][PF(6)] (AuTol) (in which bipy(dmb)=6-(1,1-dimethylbenzyl)-2,2'-bipyridine), [Au(py(dmb)-H)(AcO)(2)] (AuPyAcO) (in which py(dmb)=2-(1,1-dimethylbenzyl)-pyridine) and [Au(pz(Ph)-H)Cl(3)]K (AuPzCl) (in which pz(Ph)=1-phenylpyrazole). The solution chemistry of these compounds, under physiological-like conditions, was investigated through UV-vis absorption and (1)H NMR spectroscopies. Significant cytotoxic effects in vitro were observed in selected cases. 相似文献