Biomedical subjects

D Pal

Publications and source records attributed to D Pal.

At least 37 records · Page 2Linked to original sources

PubMed2000

Noninvasive, transthoracic, low-frequency ultrasound augments thrombolysis in a canine model of acute myocardial infarction.

BACKGROUND: Limitations of coronary thrombolysis include the time to reperfusion, patency rate, and bleeding. We evaluated the use of noninvasive transcutaneous ultrasound to augment coronary thrombolysis. METHODS AND RESULTS: In 24 dogs, a thrombotic occlusion of the left anterior descending coronary artery was induced and documented by 12-lead ECG and coronary angiography. After >/=60 minutes of occlusion, tissue-type plasminogen activator (t-PA; 1.42 mg/kg) was given intravenously over 90 minutes. A total of 12 of the 24 dogs had concomitant transcutaneous application of low-frequency ultrasound (27 kHz) over the chest. At 90 minutes, the mean TIMI grade flow in the t-PA alone group was 0.92+/-1.4 compared with 2. 42+/-1.9 in the t-PA plus ultrasound group (P=0.006). TIMI 2 to 3 flow was present in 4 of 12 cases receiving t-PA alone compared with 10 of 12 cases receiving t-PA plus ultrasound (P=0.003). At 180 minutes, mean TIMI grade flow was 0.75+/-1.4 in the t-PA alone group versus 2.58+/-0.9 in the t-PA plus ultrasound group (P=0.001). Pathological examination confirmed the angiographic patency rate and did not reveal injury secondary to ultrasound in the skin, soft tissues, heart, or lungs. CONCLUSIONS: In vivo, the noninvasive transthoracic application of low-frequency ultrasound (1) greatly augments the efficacy of t-PA-mediated thrombolysis, (2) seems safe, and (3) has substantial potential as a noninvasive adjunct to improve coronary patency without increasing the risk of bleeding.

Animals↗

PubMed2000

Environment of tryptophan side chains in proteins.

Although relatively rare, the tryptophan residue (Trp), with its large hydrophobic surface, has a unique role in the folded structure and the binding site of many proteins, and its fluorescence properties make it very useful in studying the structures and dynamics of protein molecules in solution. An analysis has been made of its environment and the geometry of its interaction with neighbors using 719 Trp residues in 180 different protein structures. The distribution of the number of partners interacting with the Trp aromatic ring shows a peak at 6 (considering protein residues only) and 8 (including water and substrate molecules also). The means of the solvent-accessible surface areas of the ring show an exponential decrease with the increase in the number of partners; this relationship can be used to assess the efficiency of packing of residues around Trp. Various residues exhibit different propensities of binding the Trp side chain. The aromatic residues, Met and Pro have high values, whereas the smaller and polar-chain residues have weaker propensities. Most of the interactions are with residues far away in sequence, indicating the importance of Trp in stabilizing the tertiary structure. Of all the ring atoms NE1 shows the highest number of interactions, both along the edge (hydrogen bonding) as well as along the face. Various weak but specific interactions, engendering stability to the protein structure, have been identified.

Databases, Factual↗

PubMed2000

Terminal residues in protein chains: residue preference, conformation, and interaction.

The known protein structures have been analyzed to find out if there is any pattern in the type of residues used and their conformation at the two terminal positions of the polypeptide chains. While the N-terminal position is overwhelmingly occupied by Met (followed by Ala and Ser), the preference for the C-terminal is not as distinct, the residues with highest propensities being Lys, Arg, Gln, and Asn. Only one main-chain torsion angle, psi, can be defined for the N-terminal residue, which is found to be in the extended conformation due to a favorable electrostatic interaction between the charged amino group and the carbonyl oxygen atom. The distribution of the angle phi for the C-terminal residue, on the other hand, is not much different from that of the nonterminal residues. There are some differences in the distribution of the side-chain torsion angle chi1 of both the terminal residues from the general distribution. The terminal segments are generally flexible and there is a tendency for the more ordered residues to have lesser solvent exposure. About 40% of the terminal groups form a hydrogen bond with protein atoms--a slight preference is observed for the side-chain atoms (more than half of which belong to charged residues) over the main-chain ones. Although the terminal residues are not included in any regular secondary structure, the adjacent ones have a high preference to occur in the beta conformation. There is a higher chance of a beta-strand rather than an alpha-helix to start within the first 6 positions from the N-terminal end. It is suggested that the extended conformation observed for the N-terminal residue propagates along the chain leading to the formation of beta-strand. In the C-terminal end, on the other hand, as one moves upstream the alpha and beta structures are encountered in proportion similar to the average value for these structures in the database. The cleavage site of the zymogen structures has a conformation that can be retained by the N-terminal residue of the active enzyme.

Animals↗

PubMed2000

Transport of cosalane-a highly lipophilic novel anti-HIV agent-across caco-2 cell monolayers.

Cosalane is a potent inhibitor of HIV replication with activity against a broad range of viral targets. However, the oral bioavailability of this highly lipophilic compound is extremely poor (<1%). Also, cosalane accumulates in high concentration in the liver after intravenous administration, with clear resistance to hepatic metabolism. In the present study, the transcellular permeability of cosalane was examined using Transwell(R) filter as well as plastic-grown confluent Caco-2 cell monolayers. A cell-culture-based biophysical model was adopted to understand the interactions of protein binding, membrane partitioning, and aqueous solubility of cosalane in limiting transcellular flux of cosalane across Caco-2 cell monolayers. The transcellular permeability (P(app)) of cosalane was extremely low (4.494 x 10(-8) cm/s) and the effect of p-glycoprotein on the efflux of cosalane was negligible. A characteristic disparity exists between the kinetics of cosalane uptake from apical (AP) donor solution and efflux into basolateral (BL) receiver side. The AP uptake of cosalane was rapid, exhibiting exponential kinetics, and reached equilibrium within 60 min, whereas the concomitant appearance of the compound into the BL receiver side was slow but linear over time. Furthermore, the uptake of cosalane was significantly reduced in the presence of bovine serum albumin (BSA). In unidirectional efflux studies, AP efflux of cosalane was limited in the absence of BSA. Also, no detectable metabolites were found in Caco-2 cell incubations. In conclusion, the present study demonstrates that diffusion of cosalane across Caco-2 cell monolayers is extremely limited and kinetically regulated essentially by the equilibrium between protein-bound and free drug partitioning into cell membrane.

Anti-HIV Agents↗

PubMed2000

Synthesis of 11beta-(4-dimethylaminophenyl)-17beta-hydroxy-17alpha- (3-methyl-1-butynyl)-4, 9-estradien-3-one and 11beta-(4-acetophenyl)- 17beta-hydroxy-17alpha-(3-methyl-1-butynyl)-4, 9-estradien-3-one: two new analogs of mifepristone (RU-486).

From the structure activity relationship, two new analogs, 2 and 3, of the potent progesterone antagonist mifepristone 1 have been designed. The syntheses of these two analogs have been achieved in eleven steps through modified synthetic sequences and improved procedures starting from (+)-estrone. In comparison with mifepristone 1, the relative binding affinities of compound 2 for the progesterone receptor was found to be more, whereas that of compound 3 was less.

Animals↗

PubMed2000

Conformational similarity indices between different residues in proteins and alpha-helix propensities.

Various amino acid similarity matrices have been derived using data on physicochemical properties and molecular evolution. Conformational similarity indices, CS(XX'), between different residues are computed here using the distribution of the main-chain and side-chain torsion angles and the values have been used to cluster amino acids in proteins. A subset of these parameters, CS(AX') indicates the extent of similarity in the main-chain and side-chain conformations (phi,psi and chi1) of different residues (X) with Ala (A) and is found to have strong correlation with alpha-helix propensities. However, no subset of CS(XX') provides any linear relationship with beta-sheet propensities, suggesting that the conformational feature favouring the location of a residue in an alpha-helix is different from the one favouring the beta-sheet. Conformationally similar residues (close CS(AX) values) have similar steric framework of the side-chain (linear/branched, aliphatic/aromatic), irrespective of the polarity or hydrophobicity. Cooperative nucleation of helix may be facile for a contiguous stretch of residues with high overall CS(AX) values.

Alanine↗

PubMed2000

beta-sheet propensity and its correlation with parameters based on conformation.

The dispersion of the main-chain and side-chain conformations in the phi, psi, chi(1) space for all residues have been estimated in terms of three parameters corresponding to the entropy (S) of the distribution, the volume (D(V)) and the area (D(A)) the points are enclosed in. These parameters are inversely correlated with Chou and Fasman beta-sheet propensities, P(beta) (Gly and Pro excluded), suggesting that residues with greater dispersion in the conformational space are weak beta-sheet formers. It was also found that different residues have different relative populations in the bridging region (intervening between the helical and beta-sheet regions) which may lie on the pathway for interconversion between alpha and beta conformations. The energy barrier for this transformation, as obtained from the population of residues in the bridging region relative to the beta region, is directly correlated to P(beta). Residues with high P(beta) have branched side chains, which have greater steric interactions with the main-chain atoms resulting in a shrinking of the available conformational space (first correlation) and a steeper energy gradient beyond the allowed space (second correlation) compared with linear residues. It is proposed that if residues exist in an extended conformation when the polypeptide chain is synthesized, a stretch of residues with high P(beta), because of the high energy barrier for their conversion into the alpha conformation, will continue to remain in the extended conformation and will ultimately constitute a beta-strand in the folded structure.

Amino Acids↗

PubMed2000

Involvement of estrogen receptors alpha and beta in the regulation of cervical permeability.

Estrogen increases the permeability of cultured human cervical epithelia (Gorodeski, GI. Am J Physiol Cell Physiol 275: C888-C899, 1998), and the effect is blocked by the estrogen receptor modulators ICI-182780 and tamoxifen. The objective of the study was to determine involvement of estrogen receptor(s) in mediating the effects on permeability. In cultured human cervical epithelial cells estradiol binds to high-affinity, low-capacity sites, in a specific and saturable manner. Scatchard analysis revealed a single class of binding sites with a dissociation constant of 1.3 nM and binding activity of approximately 0.5 pmol/mg DNA. Estradiol increased the density of estrogen-binding sites in a time- and dose-related manner (half time approximately 4 h, and EC(50) approximately 1 nM). RT-PCR assays revealed the expression of mRNA for the estrogen receptor alpha (alphaER) and estrogen receptor beta (betaER). Removal of estrogen from the culture medium decreased and treatment with estrogen increased the expression of alphaER and betaER mRNA. In cells not treated with estrogen, ICI-182780 and tamoxifen increased betaER mRNA. In cells treated with estrogen, neither ICI-182780 nor tamoxifen had modulated significantly the increase in alphaER or betaER mRNA. The transcription inhibitor actinomycin D blocked the estrogen-induced increase in permeability, and it abrogated the estradiol-induced increase in estrogen binding sites. These results suggest that the estrogen-dependent increase in cervical permeability is mediated by an alphaER-dependent increase in transcription.

Adult↗

PubMed2000

Recent trends in leprosy in a large district of West Bengal, India, revealed by a modified leprosy elimination campaign (MLEC), 1998.

A Modified Leprosy Elimination Campaign (MLEC) in September 1998 in the District of Midnapore, West Bengal, covered a population of 8.1 million people and detected 8181 new cases. Available data from 7328 cases were studied to observe the trend for leprosy in this area. Data are presented on sex and age distribution, classification and the proportions of multibacillary (MB), paucibacillary (PB) and single skin lesion (SSL) cases discovered in a period of only 8 days. The large numbers of people examined in this district and the high total of new cases revealed are in keeping with experience in other parts of the State and in other parts of India. However, many cases were found in endemic areas and these will receive special attention in a second MLEC, planned for January 2000.

Adolescent↗

PubMed2000

Evolution of drug resistance and interpretation of drug sensitivity test.

Though with the advent of more and more numbers of antibiotics, infection control has become easier but it has been established more resistant strains of microbes are appearing. These resistant strains are becoming major public health problem. Drug misuse is one of the factors for resistant strains. While discussing mechanisms of drug resistance, gene transfer plays an important part. Drug resistance can be prevented by taking several strategies. There are several methods for performing antibiotic sensitivity test e.g., diffusion methods and dilution methods which are discussed elaborately.

Anti-Bacterial Agents↗

PubMed1999

Cis peptide bonds in proteins: residues involved, their conformations, interactions and locations.

An analysis of a non-redundant set of protein structures from the Brookhaven Protein Data Bank has been carried out to find out the residue preference, local conformation, hydrogen bonding and other stabilizing interactions involving cis peptide bonds. This has led to a reclassification of turns mediated by cis peptides, and their average geometrical parameters have been evaluated. The interdependence of the side and main-chain torsion angles of proline rings provided an explanation why such rings in cis peptides are found to have the DOWN puckering. A comparison of cis peptides containing proline and non-proline residues show differences in conformation, location in the secondary structure and in relation to the centre of the molecule, and relative accessibilities of residues. Relevance of the results in mutation studies and the cis-trans isomerization during protein folding is discussed.

Amino Acids↗

PubMed1999

Estimates of the loss of main-chain conformational entropy of different residues on protein folding.

The average contribution of conformational entropy for individual amino acid residues towards the free energy of protein folding is not well understood. We have developed empirical scales for the loss of the main-chain (torsion angles, phi and psi) conformational entropy by taking its side-chain into account. The analysis shows that the main-chain component of the total conformational entropy loss for a residue is significant and reflects intrinsic characteristics associated with individual residues. The values have direct correlation with the hydrophobicity values and this has important bearing on the folding process. Proteins 1999;36:332-339.

Amino Acid Substitution↗

PubMed1999

Protein folding in Escherichia coli: role of 23S ribosomal RNA.

Post-translational control of Escherichia coli ribosome on newly synthesised polypeptide leading to its active conformation (protein folding) has been shown in the case of the enzyme beta-galactosidase. As expected, antibiotics chloramphenicol and lincomycin, which bind to 23S rRNA/50S subunit and kasugamycin and streptomycin which interact with the 30S subunit instantaneously inhibited protein synthesis when they were added to the growing cells. The increase in beta-galactosidase activity, though stopped immediately after the addition of chloramphenicol and lincomycin, went on considerably in the presence of streptomycin and kasugamycin even after the stoppage of protein synthesis.

Aminoglycosides↗

PubMed1999

Graphical representation of the salient conformational features of protein residues.

A composite plot for depicting in two dimensions the conformation and the secondary structural features of protein residues has been developed. Instead of presenting the exact values of the main- and side-chain torsion angles (φ, psi and chi(1)), it indicates the region in the three-dimensional conformational space to which a residue belongs. Other structural aspects, like the presence of a cis peptide bond and disulfide linkages, are also displayed. The plot may be used to recognize patterns in the backbone and side-chain conformation along a polypeptide chain and to compare protein structures derived from X-ray crystallography, NMR spectroscopy or molecular modelling studies and also to highlight the effect of mutation on structure.

Amino Acid Sequence↗

PubMed1999

Packing of aromatic rings against tryptophan residues in proteins.

The geometry of the interaction of the aromatic side chains of phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp) and histidine (His) with the indole ring of Trp has been analyzed using the structures in the Protein Data Bank in order to understand the dependence of the packing behaviour on the size and chemical nature of the aromatic rings. The Phe ring prefers to interact either perpendicularly, with its edge pointing towards the Trp face, or in an offset-stacked arrangement. The edge-to-face motif is typical of a Trp-Trp pair. While parallel stacking is the dominant feature of Trp-His interaction, Tyr packs in a more uniform manner around Trp with a higher than expected occurrence at the edge and a few cases of possible OH-pi interaction.

Binding Sites↗

PubMed1999

Estrogen modulates paracellular permeability of human endothelial cells by eNOS- and iNOS-related mechanisms.

Estradiol had a biphasic effect on permeability across cultures of human umbilical vein endothelial cells (HUVEC): at nanomolar concentrations it decreased the HUVEC culture permeability, but at micromolar concentrations it increased the permeability. The objective of the present study was to test the hypothesis that the changes in permeability were mediated by nitric oxide (NO)-related mechanisms. The results revealed dual modulation of endothelial paracellular permeability by estrogen. 1) An endothelial NO synthase (eNOS)-, NO-, and cGMP-related, Ca2+-dependent decrease in permeability was activated by nanomolar concentrations of estradiol, resulting in enhanced Cl- influx, increased cell size, and increases in the resistance of the lateral intercellular space (RLIS) and in the resistance of the tight junctions (RTJ); these effects appeared to be limited by the ability of cells to generate cGMP in response to NO. 2) An inducible NO synthase (iNOS)- and NO-related, Ca2+-independent increase in permeability was activated by micromolar concentrations of estradiol, resulting in enhanced Cl- efflux, decreased cell size, and decreased RLIS and RTJ. We conclude that the net effect on transendothelial permeability across HUVEC depends on the relative contributions of each of these two systems to the total paracellular resistance.

Arylsulfonates↗

PubMed1999

Evaluation of hematological and hepatorenal functions of methanolic extract of Moringa oleifera Lam. root treated mice.

Methanolic extract of M. oleifera root was found to contain some alkaloids (total alkaloid 0.2%). Effects of multiple weekly (35, 46, 70 mg/kg) and daily therapeutic (3.5, 4.6, 7.0 mg/kg) i.p. doses of the crude extract (CE) on liver and kidney functions and hematological parameters in mice were studied. No alteration in hematological and biochemical parameters at low and moderate dose level of daily and low dose level of weekly treatment of the extract was observed. However, the extract at moderate dose level in weekly treatment changed serum aminotransferase and plasma cholesterol levels significantly. High dose in addition to the above parameters changed total bilirubin, non protein nitrogen, blood urea and plasma protein. High dose of daily treatment and moderate and high dose of weekly treatment of CE increased WBC count and decreased clotting time significantly. The results indicate that the weekly moderate and high dose (> 46 mg/kg body wt.) and daily/therapeutic high dose (7 mg/kg) of CE affects liver and kidney functions and hematological parameters whereas the weekly dose (3.5 mg/kg) and low and moderate daily/therapeutic dose (3.5 and 4.6 mg/kg) did not produce adverse effects on liver and kidney functions.

Animals↗

PubMed1998

Different types of interactions involving cysteine sulfhydryl group in proteins.

Various types of interactions involving the sulfhydryl group of free cysteine residues have been analyzed using known protein structures. In a hydrogen bond the -SH group is more amenable to donating its proton to a carbonyl group, rather than acting as a proton acceptor. It rarely interacts with a carboxylate group, and is a poor ligand to bind an anionic substrate. It is quite prone to make contacts that are definitely non-hydrogen bond type. In the S...C=O interaction the S atom is placed on the face of an amide group (mostly from the main-chain, but there are cases from the side-chain also) close to the C atom. Cases of S...N interaction, where the S atom is on top of the N atom of another residue (both main-, as well as side-chains, including the guanidinium group) are also observed. A considerable number of Cys residues have aromatic residues as neighbors, and here too, the preferred mode of interaction is along the face. The intra-residue S...C=O interaction constrains the main-chain and side-chain torsion angles (psi and chi1), whereas the inter-residue interactions are non-local and stabilize the tertiary structure. The S...C=O interaction may have a role in lowering the pKa values of the Cys residues in enzyme active sites.

Carbon↗