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At least 505 records · Page 28Linked to original sources
PubMed1996

The width of the minor groove affects the binding of the bisquaternary heterocycle SN-6999 to duplex DNA.

A complex between d(GGGAAAAACGG).d(CCGTTTTTCCC) and the minor groove binding drug SN-6999 has been studied by 1H nuclear magnetic resonance spectroscopy. The drug is found to bind in the d(A)5 tract, but with interactions extending one residue in the 3'-direction along each strand. Doubling of resonances in the complex indicates slow to intermediate exchange between two binding modes. An orientational preference (7:3) is found, the first such example in an SN-6999 complex. Furthermore, the upper limit of the lifetime for the major species is longer than was found for SN-6999 with other DNA duplexes. The preferred orientation of SN-6999 has the pyridinium ring near the 5'-end of the (+) strand; the minor binding mode has the reverse orientation. The orientational preference and slower exchange rate relative to other SN-6999 complexes is attributed to increased stabilization from van der Waals interactions due to better shape complementarity between the DNA duplex and ligand. The comparison of these results with studies of SN-6999 complexed to other DNA duplexes reveals the sensitivity of the binding properties to the delicate interplay between the molecular structure of the ligand and the specific characteristics of the DNA minor groove.

Antineoplastic Agents↗
PubMed1998

Direct laser trapping of single DNA molecules in the globular state.

A sharply focused laser is able to trap small particles at the laser focal point due to the difference in refractive index of the particles and that of the surrounding medium. This technique, called laser trapping, can be used to manipulate animal or bacterial cells without any contact and has been widely applied in biological research. However, it has been difficult to trap biological macromolecules such as DNA molecules, because these molecules give a low difference in refractive index and cannot overcome Brownian motion. DNA molecules can be transformed to a condensed globular state. This transformation results in a higher refractive index of DNA due to its increased density. We demonstrate in this paper that a single DNA molecule can be optically trapped using a Nd:YAG laser (1064 nm wavelength) upon transformation from the coiled state to the globular state.

Animals↗
PubMed2001

Real-time observation of a single DNA digestion by lambda exonuclease under a fluorescence microscope field.

A fluorescence microscopy technique has been developed to visualize the behavior of individual DNA and protein molecules. Real-time direct observation of a single DNA molecule can be used to investigate the dynamics of DNA-protein interactions, such as the DNA digestion reaction by lambda exonuclease. In conventional methods it is impossible to analyze the dynamics of an individual lambda exonuclease molecule on a DNA because they can only observe the average behavior of a number of exonuclease molecules. Observation of a single molecule, on the other hand, can reveal processivity and binding rate of an individual exonuclease molecule. To evaluate the dynamics of lambda exonuclease, a stained lambda DNA molecule with one biotinylated terminal was fixed on an avidin-coated coverslip and straightened using a d.c. electric field. Microscopic observation of digestion of a straightened DNA molecule by lambda exonuclease revealed that the DNA digestion rate was approximately 1000 bases/s and also demonstrated high processivity.

Avidin↗
PubMed2003

DNA condensation by the nucleocapsid protein of HIV-1: a mechanism ensuring DNA protection.

The nucleocapsid (NC) protein NCp7 of the immunodeficiency virus type 1 is a small basic protein with two zinc finger motifs. NCp7 has key roles in virus replication and structure, which rely on its interactions with nucleic acids. Although most interactions involve RNAs, binding to the viral DNA is thought to be of importance to achieve protection of the DNA against cellular nucleases and its integration into the host genome. We investigated the interaction of NCp7 with plasmid DNA as a model system. The fluorescence probe YOYO-1 was used as the reporter. Binding of NCp7 to DNA caused DNA condensation, as inferred from the dramatic decrease in YOYO-1 fluorescence. Efficient condensation of DNA required the full length NCp7 with the zinc fingers. The fingerless peptide was less efficient in condensing DNA. Binding of both these NC peptides led to freezing of the segmental dynamics of DNA as revealed by anisotropy decay kinetics of YOYO-1. The truncated peptide NC(12-55) which retains the zinc fingers did not lead to DNA condensation despite its ability to bind and partially freeze the segmental motion of DNA. We propose that the histone-like property of NCp7 leading to DNA condensation contributes to viral DNA stability, in vivo.

Anisotropy↗
PubMed2003

Groove-binding unsymmetrical cyanine dyes for staining of DNA: syntheses and characterization of the DNA-binding.

Two new crescent-shaped unsymmetrical cyanine dyes have been synthesised and their interactions with DNA have been investigated by different spectroscopic methods. These dyes are analogues to a minor groove binding unsymmetrical cyanine dye, BEBO, recently reported by us. In this dye, the structure of the known intercalating cyanine dye BO was extended with a benzothiazole substituent. To investigate how the identity of the extending heterocycle affects the binding to DNA, the new dyes BETO and BOXTO have a benzothiazole group and a benzoxazole moiety, respectively. Whereas BEBO showed a heterogeneous binding to calf thymus DNA, linear and circular dichroism studies of BOXTO indicate a high preference for minor groove binding. BETO also binds in the minor groove to mixed sequence DNA but has a contribution of non-ordered and non-emissive species present. A non-intercalative binding mode of the new dyes, as well as for BEBO, is further supported by electrophoresis unwinding assays. These dyes, having comparable spectral properties as the intercalating cyanine dyes, but bind in the minor groove instead, might be useful complements for staining of DNA. In particular, the benzoxazole substituted dye BOXTO has attractive fluorescence properties with a quantum yield of 0.52 when bound to mixed sequence DNA and a 300-fold increase in fluorescence intensity upon binding.

Animals↗
PubMed2004

Telomerase downregulation induced by the G-quadruplex ligand 12459 in A549 cells is mediated by hTERT RNA alternative splicing.

Ligand 12459, a potent G-quadruplex-interacting agent that belongs to the triazine series, was previously shown to downregulate telomerase activity in the human A549 lung carcinoma cell line. We show here that the downregulation of telomerase activity is caused by an alteration of the hTERT splicing pattern induced by 12459, i.e. an almost complete disappearance of the active (+alpha,+beta) transcript and an over-expression of the inactive -beta transcript. Spliced intron 6 forming the -beta hTERT transcript contained several tracks of G-rich sequences able to form G-quadruplexes. By using a specific PCR-stop assay, we show that 12459 is able to stabilize the formation of these G-quadruplex structures. A549 cell line clones selected for resistance to 12459 have been analyzed for their hTERT splicing pattern. Resistant clones are able to maintain the active hTERT transcript under 12459 treatment, suggesting the appearance of mechanisms able to bypass the 12459-induced splicing alterations. In contrast to 12459, telomestatin and BRACO19, two other G-quadruplex-interacting agents, have no effect on the hTERT splicing pattern in A549 cells, are cytotoxic against the A549-resistant clones and display a lower efficiency to stabilize hTERT G-quadruplexes. These results lead us to propose that 12459 impairs the splicing machinery of hTERT through stabilization of quadruplexes located in the hTERT intron 6. Differences of selectivity between 12459, BRACO19 and telomestatin for these hTERT quadruplexes may be important to explain their respective activity and inactivity against hTERT splicing.

Acridines↗
PubMed2005

Overexpression of Bcl-2 is associated with apoptotic resistance to the G-quadruplex ligand 12459 but is not sufficient to confer resistance to long-term senescence.

The triazine derivative 12459 is a potent G-quadruplex interacting agent that inhibits telomerase activity. This agent induces time- and dose-dependent telomere shortening, senescence-like growth arrest and apoptosis in the human A549 tumour cell line. We show here that 12459 induces a delayed apoptosis that activates the mitochondrial pathway. A549 cell lines selected for resistance to 12459 and previously characterized for an altered hTERT expression also showed Bcl-2 overexpression. Transfection of Bcl-2 into A549 cells induced a resistance to the short-term apoptotic effect triggered by 12459, suggesting that Bcl-2 is an important determinant for the activity of 12459. In sharp contrast, the Bcl-2 overexpression was not sufficient to confer resistance to the senescence-like growth arrest induced by prolonged treatment with 12459. We also show that 12459 provokes a rapid degradation of the telomeric G-overhang in conditions that paralleled the apoptosis induction. In contrast, the G-overhang degradation was not observed when apoptosis was induced by camptothecin. Bcl-2 overexpression did not modify the G-overhang degradation, suggesting that this event is an early process uncoupled from the final apoptotic pathway.

Antineoplastic Agents↗
PubMed2003

Sequence-specific fluorescent labeling of double-stranded DNA observed at the single molecule level.

Fluorescent labeling of a short sequence of double-stranded DNA (dsDNA) was achieved by ligating a labeled dsDNA fragment to a stem-loop triplex forming oligonucleotide (TFO). After the TFO has wound around the target sequence by ligand-induced triple helix formation, its extremities hybridize to each other, leaving a dangling single-stranded sequence, which is then ligated to a fluorescent dsDNA fragment using T4 DNA ligase. A non-repeated 15 bp sequence present on lambda DNA was labeled and visualized by fluorescence microscopy after DNA combing. The label was found to be attached at a specific position located at 4.2 +/- 0.5 kb from one end of the molecule, in agreement with the location of the target sequence for triple helix formation (4.4 kb from one end). In addition, an alternative combing process was noticed in which a DNA molecule becomes attached to the combing slide from the label rather than from one of its ends. The method described herein provides a new tool for the detection of very short sequences of dsDNA and offers various perspectives in the micromanipulation of single DNA molecules.

Bacteriophage lambda↗
PubMed2000

Single long DNA molecule analysis using fluorescence microscopy.

Single long DNA molecule (T4 DNA) in agarose gel was visualized with a fluorescence microscope. We confirmed alternating current electric fields is effective for stretching of single DNA molecule in agarose gel. This stretching phenomenon was observed with wide range of agarose gel concentration from 0.5%(W/V) to 1.5%. From this observation, the presence of agarose gel fiber is essential for this stretching phenomenon. The stretching process of several DNA molecules in gel shows discontinuity, which is never observed in polymer systems. It would be based on topological restriction from gel fibers.

Bacteriophage T4↗
PubMed1989

The effects of PAF antagonists on arrhythmias and platelets during acute myocardial ischaemia and reperfusion.

The aim of the study was to examine a possible role for platelet activating factor (PAF) in experimental myocardial ischaemia and reperfusion. Anaesthetized open-chest greyhounds were subjected to 40 min of coronary artery (LAD) occlusion followed by reperfusion. Blood samples for platelet counting were obtained from a local coronary vein draining the ischaemic region. Pretreatment with PAF antagonists BN52021 (5 mg kg-1 i.v.) or SRI63441 (10 mg kg-1 i.v.), 15 min prior to occlusion reduced the ventricular ectopic count during the ischaemic period from 614 +/- 82 (controls) to 296 +/- 145 (BN52021) and 474 +/- 200 (SRI63441). Both drugs also reduced the incidence of ventricular fibrillation (VF) (during ischaemia and reperfusion) from 90% (controls), to 50% (BN52021) and 43% (SRI63441). Ischaemia was accompanied by a 32 +/- 7% reduction in coronary venous platelets; this was attenuated by both BN52021 (-2 +/- 6%) and SRI63441) (-1 +/- 5%). These results suggest that PAF may contribute to ischaemia and reperfusion-induced arrhythmias by activating platelets.

Acute Disease↗
PubMed1993

Role of chloride transport in the development of the rat blastocyst.

Preimplantation mammalian development culminates in the generation of a fluid-filled cavity, the blastocoel, which requires the vectorial transport of ions across the trophectoderm, followed by the movement of water. Experiments were carried out to establish the role of Cl- transport in blastocoel formation in the rat. These included investigations of the effect of Cl- substitution and the Cl- transport inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid, furosemide, and anthracene-9-carboxylic acid, on the development of morulae into blastocysts in culture, and on the rate at which blastocoel fluid is accumulated. In addition, a novel technique was developed in which the Cl(-)-sensitive fluorescent dye 6-methoxy-N-(3-sulfopropyl) quinolium (SPQ) was loaded into the blastocoel cavity, in order to characterize the pathways of transtrophectodermal Cl- transport. We established that 1) blastocoel formation in the rat requires the external presence of Cl- ions; 2) transport across the trophectoderm appears to be via a transcellular pathway, since rates of blastocyst development, fluid accumulation, and SPQ-monitored Cl- efflux are all reduced in the presence of Cl- transport inhibitors; and 3) Cl- transport occurs via Cl-/HCO3- exchange.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1987

Prolongation of pig-to-dog renal xenograft survival by modification of the inflammatory mediator response.

The pathogenesis of hyperacute renal rejection consists of a nonspecific effector cascade that invokes most of the components of a typical acute inflammatory response. Platelet-activating factor (PAF) represents the most recent and perhaps the most significant mediator and promoting agent of this phenomenon. These studies evaluated SRI 63-441, a novel, synthetic, and the most potent PAF receptor antagonist available, alone and in combination with other prostanoids, for their ability to influence this response and to prolong renal xenograft survival and function in a model of pig-to-dog heterotransplantation. Inhibition of PAF by SRI 63-441 alone, at the dosage and schedule used in these experiments, did not significantly prolong xenograft survival or function. However, the combination of SRI 63-441 with either prostacyclin (PGI2) or prostaglandin E1 (PGE1) infusion demonstrated significant synergism, and resulted in a 6-9-fold increase in kidney survival and a 3-20-fold increase in urine output. Neither PGI2 nor PGE1 infusions alone significantly influenced this xenograft model. Electromagnetic flow studies demonstrated significantly delayed diminution in renal artery blood flow in the combination-treated animals. Serial and end-stage histologic examination of kidneys receiving combination therapy demonstrated a delayed onset of the pathologic deterioration and an overall amelioration of the entire process. These studies demonstrate that significant abrogation of a rapid and violent form of hyperacute rejection can be achieved solely by the pharmacologic manipulation of the inflammatory mediator response.

Alprostadil↗
PubMed1989

Pharmacologic modulation of experimental postischemic hepatic function.

The present study evaluated and compared the effects of SRI 63-441, a potent platelet activating factor antagonist, superoxide dismutase (SOD), an oxygen free radical scavenger, and ibuprofen, a cyclooxygenase inhibitor on hepatic function after 90 minutes of warm ischemia. After warm ischemia, livers were harvested and underwent 90 minutes of warm, oxygenated, sanguinous perfusion on an isolated liver perfusion apparatus. Pretreatment of donor animals with 20 mg/kg intravenous (I.V.) SRI 63-441 5 minutes before induction of total hepatic ischemia resulted in significantly increased bile production, a significant decrease in transaminase release, and a higher tissue adenosine triphosphate (ATP) content when compared with ischemic nontreated controls. SOD resulted in improved bile production and decreased transaminase liberation only when present in the perfusate at the time of in vitro reperfusion. Ibuprofen did not improve postischemic hepatic function in this model. Electron microscopy revealed patchy hepatocellular vacuolization with an intact sinusoidal endothelium in all ischemic livers. However, the degree of damage was less severe in the livers from those rats pretreated with 20 mg/kg SRI 63-441. This study demonstrates that SRI 63-441 pretreatment significantly reduces hepatic warm ischemic injury, and in the present model, appears superior to two other agents that have been advanced in the treatment of ischemic injury. The use of such agents singly or in combinations have important implications as regards gaining a better understanding of the basic mechanisms in organ ischemia, and moreover, for therapeutic applications in organ ischemia and preservation.

Animals↗
PubMed2004

Effects of KCNQ1 channel blocker, 293B, on the acetylcholine-induced Cl- secretion of rat pancreatic acini.

In rat pancreatic acini (RPAs), acetylcholine (ACh) typically induces a tonic depolarization of membrane potential (Vm) via increasing cytoplasmic Ca2+ concentration and subsequent activation of Cl- channels. In this study, to investigate the role of K+ channels during the ACh-induced Cl- secretion, the intracellular Cl- concentration ([Cl-]i) of RPAs was monitored using SPQ, a fluorescent dye quenchable by Cl-, and the effects of K+ channel blockers were examined. Also, the secretion of fluid and enzyme from the whole pancreas of rat was measured. The fluorescence of RPAs loaded with SPQ (FSPQ) was slightly increased by the application of ACh (ACh-Delta FSPQ), indicating net secretion of Cl-. However, the relative change of FSPQ normalized to the control fluorescence (F/F0) of RPAs was only about 20% of the effect observed in rat submandibular gland acinus. The ACh-Delta FSPQ of RPAs was not influenced by the pretreatment with 293B (20 micromol/L), a blocker of KCNQ-type K+ channels. Even the cocktail of K+ channel blockers (10 mmol/L TEA, 3 mmol/L Ba2+, 20 micromol/L 293B) exerted only minute inhibitory effects on ACh-Delta FSPQ in RPAs. In the vascularly perfused rat pancreas, the fluid and enzyme secretion induced by ACh was directly measured. 293B and HMR-1556, both specific blockers of KCNQ1 channel, did not block but even enhanced the secretion of fluid and amylase. These results suggest that the role of KCNQ1 channels may not be essential in the Ca2+-mediated Cl- secretion in rat pancreatic acini.

Acetylcholine↗
PubMed2005

Measurement of apoptosis of intact human islets by confocal optical sectioning and stereologic analysis of YO-PRO-1-stained islets.

Apoptosis is an established pathway for islet cell demise. Current protocols for assessment of islet cell apoptosis are time-consuming (as with terminal deoxynucleotide transferase-mediated dUTP nick-end labeling reaction) and involve disruption of the islet architecture (as with flow cytometry) or destruction of cell integrity (as with enzyme-linked immunosorbent assay). The membranes of apoptotic cells, but not those of live cells, are permeant to the DNA-intercalant dye YO-PRO-1. We report a novel methodology for the rapid quantification of apoptosis of human islets: confocal laser optical sectioning and stereologic analysis of intact human islets stained with YO-PRO-1 and Hoechst 33342. The advantages include (1) rapid quantification of apoptosis without disrupting islet architecture and (2) identification of significant heterogeneity in the extent of apoptosis among islets from the same isolate. Confocal laser scanning microscopy microscopic imaging of YO-PRO-1-stained islets may advance investigation of islet cell apoptosis and help develop islet parameters predictive of posttransplant function.

Apoptosis↗
PubMed1999

Hydrogen bonding and C-H...X interactions in two triclinic phases of 4-carboxyquinolinium chloride monohydrate.

The title substance, C10H8NO2+.Cl-.H2O, crystallized in the centrosymmetric space group P1 in two phases, alpha and beta, each with one organic cation, one Cl- ion and one water molecule in the asymmetric unit. The principle structural difference in the two asymmetric units lies in the relative orientation of the water molecule. Three hydrogen bonds in the alpha phase have donor-acceptor distances (N...Cl or O...Cl) ranging from 3.052 (1) to 3.189 (2) A, while one has an O...O distance of 2.603 (3) A. Three hydrogen bonds in the beta phase have donor-acceptor distances (N...Cl or O...Cl) ranging from 3.044 (2) to 3.206 (2) A, while two have O...O distances of 2.586 (2) and 3.147 (3) A. The H atoms in all these hydrogen bonds are ordered. Each of these phases has five leading C-H...X interactions, for which the H...X distances are less than, or at most slightly greater than, the corresponding van der Waals radius sums. Taken together, these hydrogen bonds and C-H...X interactions form a three-dimensional network of interactions in each phase. The dihedral angle between the best-fit quinoline core plane and the carboxyl group plane is 25.9 (1) degree for the alpha phase and 20.0 (1) degree for the beta phase.

Crystallography, X-Ray↗