Biomedical subjects
Publications and source records attributed to A Dar.
Hypotensive effects of aloeemodin, aloin A, elgonica dimer A and bisbenzopyran from Aloe barbadensis have been studied. Aloeemodin has emerged as a potent hypotensive agent in current pharmacological investigations and caused 26 %, 52 %, and 79 % falls in mean arterial blood pressure at the corresponding doses of 0.5, 1, and 3 mg/kg in rats. The paper also describes the absolute configuration of elgonica dimer A (1).
BACKGROUND: The myocardium is unable to regenerate because cardiomyocytes cannot replicate after injury. The heart is therefore an attractive target for tissue engineering to replace infarcted myocardium and enhance cardiac function. We tested the feasibility of bioengineering cardiac tissue within novel 3-dimensional (3D) scaffolds. METHODS AND RESULTS: We isolated and grew fetal cardiac cells within 3D porous alginate scaffolds. The cell constructs were cultured for 4 days to evaluate viability and morphology before implantation. Light microscopy revealed that within 2 to 3 days in culture, the dissociated cardiac cells form distinctive, multicellular contracting aggregates within the scaffold pores. Seven days after myocardial infarction, rats were randomized to biograft implantation (n=6) or sham-operation (n=6) into the myocardial scar. Echocardiography study was performed before and 65+/-5 days after implantation to assess left ventricular (LV) remodeling and function. Hearts were harvested 9 weeks after implantation. Visual examination of the biograft revealed intensive neovascularization from the neighboring coronary network. Histological examination revealed the presence of myofibers embedded in collagen fibers and a large number of blood vessels. The specimens showed almost complete disappearance of the scaffold and good integration into the host. Although control animals developed significant LV dilatation accompanied by progressive deterioration in LV contractility, in the biograft-treated rats, attenuation of LV dilatation and no change in LV contractility were observed. CONCLUSIONS: Alginate scaffolds provide a conducive environment to facilitate the 3D culturing of cardiac cells. After implantation into the infarcted myocardium, the biografts stimulated intense neovascularization and attenuated LV dilatation and failure in experimental rats compared with controls. This strategy can be used for regeneration and healing of the infarcted myocardium.
We present deep Hubble Space Telescope (HST) imaging, as well as ground-based imaging and spectroscopy, of the optical afterglow associated with the long-duration gamma-ray burst GRB 990712 and its host galaxy. The data were obtained 48-123 days after the burst occurred. The magnitudes of the host (R=21.9, V=22.5) and optical afterglow (R=25.4, V=25.8, 47.7 days after the burst) favor a scenario in which the optical light follows a pure power-law decay with an index of alpha approximately -1.0. We find no evidence for a contribution from a supernova like SN 1998bw. This suggests that either there are multiple classes of long-duration gamma-ray bursts or that the peak luminosity of the supernova was more than 1.5 mag fainter than SN 1998bw. The HST images and EFOSC2 spectra indicate that the gamma-ray burst was located in a bright, extended feature (possibly a star-forming region) 1.4 kpc from the nucleus of a 0.2L*B galaxy at z=0.434, possibly a Seyfert 2 galaxy. The late-time afterglow and host galaxy of GRB 990712 bear some resemblance to those of GRB 970508.
The dichloromethane fraction from Areca catechu was found to inhibit monoamine oxidase type A isolated from the rat brain with an IC50 of 665 +/- 65.1 microg/ml. Studies with pharmacological models of depression, i.e., forced swim and tail-suspension tests, indicated that it caused significant reduction in the immobility time similar to that of moclobemide (a selective inhibitor of MAO-A) without causing a significant change in motor performance. Alkaloids such as arecaidine, arecoline, and a few other constituents, reported to be present in Areca catechu were also tested, but none of them were found to inhibit MAO. Present study suggests that the dichloromethane fraction from A. catechu possesses antidepressant property via MAO-A inhibition.
Carcinogenesis involves inactivation or subversion of the normal controls of proliferation, differentiation, and apoptosis. However, these controls are robust, redundant, and interlinked at the gene expression levels, regulation of mRNA lifetimes, transcription, and recycling of proteins. One of the central systems of control of proliferation, differentiation and apoptosis is retinoid signaling. The hRAR alpha nuclear receptor occupies a central position with respect to induction of gene transcription in that when bound to appropriate retinoid ligands, its homodimers and heterodimers with hRXR alpha regulate the transcription of a number of retinoid-responsive genes. These include genes in other signaling pathways, so that the whole forms a complex network. In this study we showed that simple, cause-effect interpretations in terms of hRAR alpha gene transcription being the central regulatory event would not describe the retinoid-responsive gene network. A set of cultured bladder-derived cells representing different stages of bladder tumorigenesis formed a model system. It consisted of 2 immortalized bladder cell lines (HUC-BC and HUC-PC), one squamous cell carcinoma cell line (SCaBER), one papilloma line (RT4), and 4 transitional cell carcinomas (TCC-Sup, 5637, T24, J82) of varying stages and grades. This set of cells were used to model the range of behaviors of bladder cancers. Relative gene expression before (constitutive) and after treatment with 10 microM all-trans-retinoic acid (aTRA) was measured for androgen and estrogen receptor; a set of genes involved with retinoid metabolism and action, hRAR alpha nd beta, hRXR alpha and beta CRBP, CRABP I and II; and for signaling genes that are known to be sensitive to retinoic acid, EGFR, cytokine MK, ICAM I and transglutaminase. The phenotype for inhibition of proliferation and for apoptotic response to both aTRA and the synthetic retinoid 4-HPR was determined. Transfection with a CAT-containing plasmid containing an aTRA-sensitive promoter was used to determine if the common retinoic acid responsive element (RARE)-dependent pathway for retinoid regulation of gene expression was active. Each of the genes selected is known from previous studies to react to aTRA in a certain way, either by up- or down-regulation of the message and protein. A complex data set not readily interpretable by simple cause and effect was observed. While all cell lines expressed high levels of the mRNAs for hRXR alpha and beta that were not altered by treatment with exogenous aTRA, constitutive and stimulated responses of the other genes varied widely among the cell lines. For example, CRABP I was not expressed by J82, T24, 5637 and RT4, but was expressed at low levels that did not change in SCaBER and at moderate levels that decreased, increased, or decreased sharply in HUC-BC, TCC-Sup and HUC-PC, respectively. The expression of hRAR alpha, which governs the expression of many retinoid-sensitive genes, was expressed at moderate to high levels in all cell lines, but in some it was sharply upregulated (TCC-Sup, HUC-PC and J82), remained constant (5637 and HUC-BC), or was down-regulated (SCaBER, T24 and RT4). The phenotypes for inhibition of proliferation showed no obvious relationship to the expression of any single gene, but cell lines that were inhibited by aTRA (HUC-BC and TCC-Sup) were not sensitive to 4-HPR, and vice versa. One line (RT4) was insensitive to either retinoid. Transfection showed very little retinoid-stimulated transfection of the CAT reporter gene with RT4 or HUC-PC. About 2-fold enhancement transactivation was observed with SCaBER, HUC-BC, J82 and T24 cells and 3-8 fold with 5637, TCC-Sup cells. In HUC-BC, a G to T point mutation was found at position 606 of the hRAR alpha gene. This mutation would substitute tyrosine for asparagine in a highly conserved domain. These data indicate that retinoid signaling is probably a frequent target of inactivation in bladder carcinogenesis. (ABSTRAC
The present study demonstrates the calcium antagonistic activity in ethanol extract of Bacopa monniera. The plant extract inhibited the spontaneous movements of both guinea-pig ileum (IC50 = 24+/-4 microg/ml) and rabbit jejunum (IC50 = 136+/-9 microg/ml). A marked reduction in acetylcholine- and histamine-induced responses (0.0001-10 microM) in the ileum was evident in the presence of extract (260 microg/ml). The acetylcholine (1 microM)-induced contraction in the ileum was also inhibited by the extract (100-700 microg/ml) in a concentration dependent way (IC50 = 285+/-56 microg/ml). All these results indicate a direct action of the extract on smooth muscles. Calcium chloride-induced responses in the rabbit blood vessels and jejunum were attenuated in the presence of plant extract (10-700 microg/ml) implying a direct interference of plant extract with influx of calcium ions in the cells. However, the lack of modification of either noradrenaline- or caffeine-induced contractions in the presence of extract suggests that extract has no detectable effect on mobilization of intracellular calcium. These results indicate that spasmolytic effect of the B. monniera extract in smooth muscles is predominantly due to inhibition of calcium influx via both voltage and receptor operated calcium channels of the cell membrane.
The methanolic extract of Mimusops elengi caused hypotensive activity in anaesthetized rats. On intravenous administration (i.v.) at a dose range of 2-16 mg/kg, it produced about a 7-38% fall in mean arterial blood pressure, in a dose-dependent manner. The effect was independent of adrenergic, muscarinic and histaminergic receptors. The hypotension was also unchanged after autonomic ganglion or angiotensin-converting-enzyme blockade. Administration of calcium channel blockers, however, including nifedipine (0.9 mg/kg) and verapamil (3.9 mg/kg), caused corresponding reductions of 81 and 64% in extract-induced hypotension. These data imply M. elengi might possess calcium-blocking activity which would explain its hypotensive effect.
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Preliminary screening of herbal extracts employs the determination of their biological activity and the estimation of their therapeutic potential. This eliminates the unnecessary effort of fractionation and purification of constituents unimportant from the practice pharmacological point of view. It also gives a scientific basis to the herbs traditionally used in folk medicine. Thus, during the present investigation the spasmolytic effect of Anemone pulsatilla extract on isolated tissues of rabbit jejunum was evaluated. In addition the pharmacological screening of Anemone pulsatilla extract was also earned out.
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The sequence specificity of bleomycin A5 and of its light-activated cobalt complex were compared by examining the relative cleavage of each strand of two DNA fragments by either species. Significant differences between the two metallobleomycins were observed. The iron-bleomycin (Fe-BLM) complex cleaved the DNA molecules preferentially at dinucleotides GpT and GpC, whereas the light-activated cobalt-bleomycin complex (Co-BLM) showed a preference for cutting at the dinucleotide GpA in addition to cleavage at every GpT dinucleotide. Further, new sites of preferential cleavage were noted for Co-BLM in regions of the DNA where enhanced reaction with DNAaseI can be observed in the presence of the antibiotic. No differences in the cutting behaviour of the Fe-BLM were evident upon irradiation of the reaction mixture. A reduction in the relative efficiency of cutting at GpC sequences by Co-BLM is responsible for the previously observed diminution of double-strand breaks under conditions of photoactivated cleavage. The results are discussed in terms of the likely production of highly reactive, diffusible cutting elements in the light activated reaction which cause cleavage of the DNA in regions where the antibiotic is not bound.
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