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Biomedical subjects

S Navaratnam

Publications and source records attributed to S Navaratnam.

At least 19 recordsLinked to original sources
PubMed2006

Photophysics of an indigo derivative (keto and leuco structures) with singular properties.

Spectral and photophysical properties of the indigo derivative Cibalackrot in keto and reduced (leuco) forms were studied by absorption spectra, fluorescence and pulse radiolysis and compared with the structurally similar indigo. With the keto form of this dye, fluorescence (phiF = 0.76) and intersystem crossing (phiT = 0.11) are dominant, whereas with indigo, efficient internal conversion (phiIC = 0.99) is observed, probably involving proton transfer through intramolecular hydrogen bonds. With Cibalackrot, this pathway is blocked, supporting the above model for indigo. With the reduced form of Cibalackrot, more than 98% of the absorbed quanta are dissipated through S1 approximately --> S0 internal conversion, which contrasts with leuco-indigo, where fluorescence (phiF = 0.35), internal conversion (phiIC = 0.53) and intersystem crossing (phiT = 0.125) are found to be competitive. In addition, a synthetic precursor of Cibalackrot (preCiba) was also investigated. This has a rigid molecular structure (with a moiety identical to Cibalackrot and the other to indigo), but intra- or intermolecular proton transfer is allowed between adjacent carbonyl and N-H groups. With this precursor in its keto structure the photophysical parameters are generally very close to those of the keto form of indigo, and different from those of Cibalackrot. A more detailed investigation of the time-decay profiles of preCiba in dioxane (and with added water and D2O) has shown that these follow biexponential laws with a shorter component of 14-25 ps, which appears associated with a risetime at longer wavelength emissions (and to a positive preexponential at shorter emission wavelengths) and a longer lived (decay) component of 104-130 ps. In the steady-state spectra of preCiba, the variation with temperature reveals a blue shift of the emission maxima, which is interpreted as the presence (simultaneous emission) of two species (keto and enol) in the excited state. Indigo and deuterated indigo are also found to present a similar behavior. The overall data are interpreted as to be due to an excited-state process involving the proton transfer between keto and enol forms. Rate constants with values of 7 x 10(10) s-1 for preCiba and 1.6 x 10(11) s-1 for deuterated indigo were obtained. This inverse isotope effect is justified on the basis of the proposed model for proton-transfer excited-state deactivation.

Coloring Agents↗
PubMed2006

Triplet-state and singlet oxygen formation in fluorene-based alternating copolymers.

Data are reported on the triplet states of a series of fluorene-based A-alt-B type alternating copolymers based on pulse radiolysis-energy transfer and flash photolysis experiments. From the pulse radiolysis experiments, spectra are given for eight copolymers involving phenylene, thiophene, benzothiadiazole, and oligothienylenevinylene groups. Quantum yields for triplet-state formation (PhiT) have been obtained by flash photolysis following laser excitation and in one case by photoacoustic calorimetry. In addition, yields of sensitized formation of singlet oxygen have been determined by time-resolved phosphorescence and are, in general, in excellent agreement with the PhiT values. In all cases, the presence of thiophene units is seen to increase intersystem-crossing quantum yields, probably because of the presence of the heavy sulfur atom. However, with the poly[2,7-(9,9-bis(2'-ethylhexyl)fluorene)-alt-1,4-phenylene] (PFP), thiophene S,S-dioxide (PFTSO2) and benzothiadiazole (F8BT) copolymers, low yields of triplet formation are observed. With three of the copolymers, the energies of the triplet states have been determined. With PFP, the triplet energy is virtually identical to that of poly[2,7-(9,9-bis(2'-ethylhexyl)fluorene)]. In contrast, with fluorene-thiophene copolymers PFaT and PF3T, the triplet energies are closer to those of thiophene oligomers, indicating that there is significant conjugation between fluorene and thiophene units but also that there is a more localized triplet state than with the homopolymers.

Algorithms↗
PubMed2006

Chain scission of hyaluronan by carbonate and dichloride radical anions: potential reactive oxidative species in inflammation?

The reactions of the carbonate and dichloride radical anions, CO3- and Cl2-, with the extracellular matrix glycosaminoglycan hyaluronan (HA) have been studied using the kinetic technique of pulse radiolysis and also by steady-state irradiation combined with gel permeation chromatography/multiangle laser light scattering(gpc/MALLS) to measure the rates of reaction with HA and the yield of HA chain scission, respectively. For comparison, the same measurements were made for the reactions of the free radicals *OH, Br2*-, and N3*. The carbonate and dichloride radical anions were found to react relatively quickly with HA (7.0 x 10(5) and 6.9 x 10(6) dm3 mol(-1) s(-1), respectively) although they are much less reactive than the hydroxyl radical, *OH. Significant yields (20 and 38%, respectively) of chain scission of HA by these radical anions were also determined from the gpc/MALLS experiments, providing some support for their potential participation in the depolymerization of HA in vivo. These results are compared with data obtained for the other free radicals (hydroxyl, azide radicals, and dibromide radical anions) investigated in this study in order to gain an insight into their mechanism of reaction with HA. Earlier chain scission yields of HA by hydroxyl radicals determined by the authors have also been revised using the gpc/MALLS technique employed in the current study. The yields of 52% (absence of air) and 44% (in air) are much lower than the previous values. In the current study, the effect of oxygen on the yields of HA chain breaks is discussed in terms of the reactivity of HA peroxyl radicals in the presence of superoxide radical anions. The relevance of the results of this study to mechanisms of inflammation is discussed.

Carbonates↗
PubMed2006

Dopaquinone redox exchange with dihydroxyindole and dihydroxyindole carboxylic acid.

A pulse radiolytic investigation has been conducted to establish whether a redox reaction takes place between dopaquinone and 5,6-dihydroxyindole (DHI) and its 2-carboxylic acid (DHICA) and to measure the rate constants of the interactions. To obviate possible confounding reactions, such as nucleophilic addition, the method employed to generate dopaquinone used the dibromide radical anion acting on dopa to form the semiquinone which rapidly disproportionates to dopaquinone. In the presence of DHI the corresponding indole-5,6-quinone (and/or tautomers) was also formed directly but, by judicious selection of suitable relative concentrations of initial reactants, we were able to detect the formation of additional indolequinone from the redox exchange reaction of DHI with dopaquinone which exhibited a linear dependency on the concentration of DHI. Computer simulation of the experimental time profiles of the absorption changes showed that, under the conditions chosen, redox exchange does proceed but not quite to completion, a forward rate constant of 1.4 x 10(6)/M/s being obtained. This is in the same range as the rate constants previously established for reactions of dopaquinone with cyclodopa and cysteinyldopa. In similar experiments carried out with DHICA, the reaction more obviously does not go to completion and is much slower, k (forward) =1.6 x 10(5)/M/s. We conclude that, in the eumelanogenic pathway, DHI oxidation may take place by redox exchange with dopaquinone, although such a reaction is likely to be less efficient for DHICA.

Computer Simulation↗
PubMed2003

Chain scission of hyaluronan by peroxynitrite.

The reaction of peroxynitrite with the biopolymer hyaluronan has been studied using stopped-flow techniques combined with detection of molecular weight changes using the combination of gel permeation chromatography and multiangle laser light scattering. From the effect of peroxynitrite on the yield of hyaluronan chain breaks, it was concluded that the chain breaks were caused by hydroxyl radicals which escape a cage containing the *OH NO*(2) radical pair. The yield of free hydroxyl radicals was determined as 5+/-1% (as a proportion of the total peroxynitrite concentration). At high peroxynitrite concentrations, it was observed that the yield of chain breaks leveled out, an effect largely attributable to the scavenging of hydroxyl radicals by nitrite ions present in the peroxynitrite preparation. These experiments also provided some support for a previous proposal that the adduct formed between ONOOH and ONOO(-) might itself produce hydroxyl radicals. The rate of this reaction would have to be of the order of 0.05 s(-1) to produce hydroxyl radical yields that would account quantitatively for chain break yields at high peroxynitrite concentrations. By carrying out experiments at higher hyaluronan concentrations, it was also concluded that an additional yield of chain breaks was produced by the bimolecular reaction of the polymer with ONOOH at a rate constant of about 10 dm(3)mol(-1)s(-1). At 5.3 x 10(-3)mol dm(-3) hyaluronan, this amounted to 3.5% chain breaks (per peroxynitrite concentration). These conclusions support the proposal that the yield of hydroxyl radicals arising from the isomerization of ONOOH to nitrate ions is relatively low.

Chromatography, Gel↗
PubMed2001

Triplet energies of pi-conjugated polymers.

Using pulse radiolysis and triplet energy transfer has enabled us to measure the triplet energies in a broad range of different pi-conjugated polymers. In all cases we find that the 1 (3)B(u) is of order 0.6 to 1 eV below the 1 (1)B(u), indicative of localized triplet states with strong electron-electron correlation. We also observe that the 1 (1)A(g)-1 (3)B(u) gap decreases linearly as the 1 (1)A(g)-1 (1)B(u) gap decreases even though polymers with very different structure have been studied. This surprising result suggests that polymers with singlet gap <1.3 eV will have a triplet ground state.

Journal Article↗
PubMed2000

Primary photophysical properties of ofloxacin.

Steady-state fluorescence has been used to study the excited singlet state of ofloxacin (OFLX) in aqueous solutions. Fluorescence emission was found to be pH dependent, with a maximum quantum yield of 0.17 at pH 7. Two pKa*s of around 2 and 8.5 were obtained for the excited singlet state. Laser flash photolysis and pulse radiolysis have been used to study the excited states and free radicals of OFLX in aqueous solutions. OFLX undergoes monophotonic photoionization from the excited singlet state with a quantum yield of 0.2. The cation radical so produced absorbs maximally at 770 nm with an extinction coefficient of 5000 +/- 500 dm3 mol-1 cm-1. This is confirmed by one-electron oxidation in the pulse radiolysis experiments. The hydrated electron produced in the photoionization process reacts with ground state OFLX with a rate constant of 2.0 +/- 0.2 x 10(10) dm3 mol-1 s-1, and the anion thus produced has two absorption bands at 410 nm (extinction coefficient = 3000 +/- 300 dm3 mol-1 cm-1) and at 530 nm. Triplet-triplet absorption has a maximum at 610 nm with an extinction coefficient of 11,000 +/- 1500 dm3 mol-1 cm-1. The quantum yield of triplet formation has been determined to be 0.33 +/- 0.05. In the presence of oxygen, the triplet reacts to form both excited singlet oxygen and superoxide anion with quantum yields of 0.13 and < or = 0.2, respectively. Moreover, superoxide anion is also formed by the reaction of oxygen with the hydrated electron from photoionization. Hence the photosensitivity due to OFLX could be initiated by the oxygen radicals and/or by OFLX radicals acting as haptens.

Anti-Infective Agents↗
PubMed1999

Singlet oxygen quenching and the redox properties of hydroxycinnamic acids.

The singlet oxygen quenching rate constants (kq) for a range of hydroxycinnamic acids in acetonitrile and D2O solutions were measured using time resolved near infrared phosphorescence in order to establish their antioxidant activity. The magnitude of kq observed depends on both the nature of the substituent groups and solvent polarity. The variations in kq depend on the energy of the hydroxycinnamic acid/molecular oxygen charge transfer states, (O2delta- ...HCAdelta+). In D2O the values of kq range from 4x10(7) M(-1) s(-1) to 4x10(6) M(-1) s(-1) for caffeic acid and o-coumaric acid respectively. In acetonitrile, the charge transfer energy levels are raised and this is reflected in lower singlet oxygen quenching rate constants with a kq value of 5x10(6) M(-1) s(-1) for caffeic acid. The phenoxyl radical spectra derived from the hydroxycinnamic acids were determined using pulse radiolysis of aqueous solutions and the reduction potentials were found to range from 534 to 596 mV. A linear correlation is observed between reduction potential, and hence free energy for electron transfer, and log kq. These correlations suggest a charge transfer mechanism for the quenching of singlet oxygen by the hydroxycinnamic acids.

Antioxidants↗
PubMed1998

Intramolecular electron transfer in the dipeptide, histidyltyrosine: a pulse radiolysis study.

The technique of pulse radiolysis has been used to investigate the possibility of intramolecular charge transfer in the dipeptide histidyltyrosine, following one-electron oxidation of one of its amino acid residues. The radical anion, Br2.- was found to react with the dipeptide at pH 6.0 with a bimolecular rate constant of 2.3+/-0.2 x 10(7) dm3 mol(-1)s(-1) suggesting that it reacts very selectively with the histidine moiety. Spectral observations at, or close to the end of this reaction show only the presence of a tyrosinyl free radical (TyrO.), however, indicating that fast (>10(6) s(-1) intramolecular charge transfer has taken place between histidine radicals (His+.) and tyrosine (TyrOH). This finding was supported by the direct observation of the rate of formation of TyrO. in experiments with the free amino acids, histidine and tyrosine, under conditions where Br2.- reacted selectively with histidine. The bimolecular rate constant for the reaction between His+. and TyrOH was found to be 2.4+/-0.5 x 10(6) dm3 mol(-1)s(-1). Taken together, the results of the study indicate that His+. is a relatively strong oxidising agent where (E (His+./His) > 770 mV at pH 6.0.

Bromides↗
PubMed1998

Expression of p53 predicts treatment failure in aggressive non-Hodgkin's lymphomas.

Approximately 50% of patients with aggressive non-Hodgkin's lymphomas (NHL) achieve a complete remission (CR) and cure with combination chemotherapy. The International Index is a useful clinical measure that predicts the patients' tolerance of therapy and likelihood of achieving CR, but it is not a direct measure of chemosensitivity. In this study we have investigated the predictive value of the tumor suppressor gene, p53, as a biological marker for response to treatment in the aggressive NHL. A retrospective study was carried out on 50 patients with aggressive NHL who were treated with CHOP chemotherapy. Treatment outcome was correlated with the expression of p53 in the lymphoma, as measured by routine immunohistochemistry using the monoclonal antibody Do-7. Forty percent of the lymphomas had >5% of the cells staining positively for p53 and this finding correlated significantly with response to treatment. Fifty percent of patients with p53 positive tumors achieved a CR versus 77% of patients with p53 negative tumors. In addition, the relapse rate and time to relapse were significantly different in the two groups. In the p53 positive group, 60% of patients relapsed in a median time of 6 months, whereas 26% of the p53 negative group relapsed with the time to relapse being >22 months. The overall survival of the p53 positive group (17 months) was significantly shorter than that of p53 negative group (>24 months). These results suggest that the immunohistochemical assessment of p53 is a simple and important prognostic measure for patients with aggressive NHL who are treated with CHOP chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Pharmacological characterization of the activity of endogenous inotropic factor from porcine left ventricle.

We report some of the unique pharmacological properties of a semipurified endogenous inotropic factor (EIF) present in the extract of the porcine left ventricle. EIF produced the following effects: (a) increase in isometric contractile force developed by electrically driven canine right ventricular trabecula, reaching a maximum with 60-100 microliters/ml concentration; (b) inhibition of Na-pump activity in canine portal vein; (c) no digitalis-like cardiac toxicity, e.g., increased diastolic tension or spontaneous diastolic mechanical oscillatory activity, despite inhibition of the sodium pump; (d) a small increase in sarcoplasmic reticular Ca release from the heart but a large increase in transsarcolemmal Ca influx as seen in biphasic contractions, an action similar to that produced by digitalis-like substances; and (e) prolongation of the action potential duration and refractory period of the canine isolated trabeculae. This latter action may confer a unique antiarrhythmic property to EIF.

Action Potentials↗
PubMed1992

X-ray absorption spectroscopy of soybean lipoxygenase-1. Influence of lipid hydroperoxide activation and lyophilization on the structure of the non-heme iron active site.

X-ray absorption spectra at the Fe K-edge of the non-heme iron site in Fe(II) as well as Fe(III) soybean lipoxygenase-1, in frozen solution or lyophilized, are presented; the latter spectra were obtained by incubation of the Fe(II) enzyme with its product hydroperoxide. An edge shift of about 2-3 eV to higher energy occurs upon oxidation of the Fe(II) enzyme to the Fe(III) species, corresponding to the valence change. The extended X-ray absorption fine structure shows clear differences in active-site structure as a result of this conversion. Curve-fitting on the new data of the Fe(II) enzyme, using the EXCURV88 program, leads to a coordination sphere that is in agreement with the active-site structure proposed earlier (6 +/- 1 N/O ligands at 0.205-0.209 nm with a maximum variance of 0.009 nm, including 4 +/- 1 imidazole ligands) [Navaratnam, S., Feiters, M. C., Al-Hakim, M., Allen, J. C., Veldink, G. A. and Vliegenthart, J. F. G. (1988) Biochim. Biophys. Acta 956, 70-76], while for the Fe(III) enzyme a shortening in ligand distances occurs (6 +/- 1 N/O ligands at 0.200-0.203 nm with maximum variance of 0.008 nm) and one imidazole is replaced by an oxygen ligand of unknown origin. Lyophilization does not lead to any apparent differences in the iron coordination of either species and gives a much better signal/noise ratio, allowing analysis of a larger range of data.

Binding Sites↗
PubMed1992

Enhancement in myocardial inotropic response to BAY K 8644 with advancing age.

In the present study, age-related alterations in cardiovascular response to Ca2+ agonist BAY K 8644 were investigated in rats. Dose response of BAY K 8644 (1-30 micrograms/kg) was studied in open chest rats by intravenous bolus administration. Maximum elevation of mean arterial pressure and (+)dp/dt of left ventricular pressure were significantly higher and the dose of BAY K 8644 required to produce half maximal response was substantially lower in 12 months old (4 micrograms/kg) than in 2 months old (10 micrograms/kg) rats. Larger doses of BAY K 8644 produced arrhythmias only in 12 months old rats, which was not totally abolished by nitroglycerine pretreatment. Perfusion of isolated rat hearts with 10(-6) M BAY K 8644 produced positive inotropic response, which was on the average 50% greater and developed much faster in 12 months old than in 2 months old rats. It is therefore concluded that the myocardial sensitivity to BAY K 8644 increases during adult maturation.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Increased [3H]nitrendipine binding sites in rat heart during adult maturation and aging.

To study the effects of maturation and aging on calcium channels, we investigated the characteristics of binding of a radioligand, [3H]nitrendipine, to relatively pure sarcolemmal membranes from 2-, 12- and 24-month-old Sprague-Dawley rat hearts. Specific binding of [3H]nitrendipine was saturable, and the Scatchard analysis of the binding revealed a single class of binding sites. Binding of [3H]nitrendipine to the membrane of 12-month-old-rats was 50-75% greater than to the membrane of 2-month-old young adult rats with no further changes in binding during aging from 12 to 24 months. The maximum number of dihydropyridine binding sites (Bmax) was 70% higher in 12- and 24-month-old rat hearts (0.45 and 0.43 pmol/mg protein) than in 2-month-old rats (0.27 pmol/mg protein). The affinity for [3H]nitrendipine binding, on the other hand, was similar in all three age groups (KD values of 0.27, 0.31 and 0.29 nM in 2-, 12- and 24-month-old rats, respectively, at 25 degrees). Membranes of all three age groups showed a similar degree of enrichment in sarcolemmal marker enzymes, indicating that the difference in membrane purity was not a contributing factor to the observed increase in density. Furthermore, increased binding of [3H]nitrendipine to the membranes of older rat hearts was observed throughout the purification scheme. Since [3H]nitrendipine binding sites are considered to be specific sites for voltage-gated Ca2+ channels of the sarcolemma, it is concluded that the density of these channels in the myocardium increases during adult maturation and is maintained through senescence.

Age Factors↗
PubMed1991

Endogenous inotropic substance from heart tissue has digitalis-like properties.

In the past few years, we developed an extraction procedure which we successfully used to isolate a crude fraction containing digitalis-like substance (DLS) from porcine left ventricular tissue. In this study, the crude fraction was found to cross-react with digoxin antibodies and showed immunoreactivity of 4.25 +/- 0.6 ng digoxin equivalent/ml. On further purification of the crude fraction using silica gel G column chromatography, a fraction C was obtained, which was highly positive inotropic on canine trabeculae and it dose-dependently inhibited ouabain sensitive 86Rb+ uptake in rat heart slices. A 50% inhibition of uptake was obtained by 25 microliters of fraction C. Fraction C also inhibited canine kidney Na+, K(+)-ATPase (Sigma, U.S.A.) dose-dependently and a 50% inhibition of this enzyme required 17 microliters of fraction C. Ashing of the fraction C at 500 degrees C resulted in loss of inotropic and enzyme inhibitory activities, indicating an organic nature of the unknown digitalis-like substance.

Animals↗