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Biomedical subjects

K Agarwal

Publications and source records attributed to K Agarwal.

At least 73 records · Page 4Linked to original sources
PubMed1993

In vivo cytogenetic studies on male mice exposed to Ponceau 4R and beta-carotene.

Chromosomal aberrations induced by Ponceau 4R (an azo food dye) and beta-carotene (a natural food colour) were studied on bone marrow cells of mice in vivo. The results indicated that Ponceau 4R was more clastogenic than beta-carotene. Ponceau 4R was found to have a minimum effective dose of 4 mg which induced a significant number of chromosome aberrations. This dose is also the recommended 'admissible daily intake'. Chromosome aberrations induced by beta-carotene were not significantly higher than those of the control (olive oil) in the dose range 0.27 to 27 mg/kg body weight. The genotoxicity of these dyes can be attributed to their chemical composition. In so far as genotoxicity is concerned the carotenoid beta-carotene can be safely used as a food colorant whereas Ponceau 4R should be delisted as a food dye.

Animals↗
PubMed1993

Treatment results obtained in metastatic soft-tissue sarcoma with a combination of doxorubicin and dacarbazine or doxorubicin and ifosfamide.

Between 1982 and 1986, 38 patients with soft-tissue sarcomas were treated with the combination doxorubicin/dacarbazine (group A); between 1986 and 1990, another 46 patients received doxorubicin/ifosfamide (group B); and between 1990 and 1991, 11 patients received an alternating regimen of doxorubicin and ifosfamide (group C). The patients' characteristics were comparable among the three groups. Overall remission rates were 34% in group A, 44% in group B, and 18% in group C. The duration of remission was 10 months and the median survival was 13 months in groups A and B. Toxicity, especially myelotoxicity, was severe, with no marked differences being noted between the groups. We conclude that both doxorubicin/dacarbazine and doxorubicin/ifosfamide are active regimens in metastatic soft-tissue sarcomas; nevertheless, the overall prognosis for these patients remains poor.

Adolescent↗
PubMed1992

Netropsin specifically enhances RNA polymerase II termination at terminator sites in vitro.

We describe an in vitro system that emulates the specific and efficient transcriptional termination associated with the human gastrin gene terminator in vivo. The system involves a dC-tailed DNA template containing the gastrin gene terminator sequence, purified RNA polymerase II, and purified elongation factor TFIIS. In this system, the basal level of termination by RNA polymerase II at the gastrin gene terminator is specifically enhanced by netropsin, an (A + T)-rich minor groove-binding peptide. This enhanced termination is maintained even with TFIIS, which normally suppresses termination at this site. In vitro termination is terminator sequence-specific. Mutant sequences that reduce or abolish termination in vivo show corresponding reductions in activity in the in vitro system. This in vitro emulation of in vivo activities of wild-type and mutant terminators strongly suggests that netropsin and a putative termination factor may share some aspects of their biochemical mechanisms. The general applicability of this system to the study of RNA polymerase II elongation and termination is suggested by the enhancement of termination seen at both the gastrin and human histone H3.3 gene terminators.

Base Sequence↗
PubMed1992

Clastogenic effect of fenfluramine in mice bone marrow cells in vivo.

Fenfluramine, an amphetamine derivative used in the treatment of obesity, has been evaluated in vivo in the bone marrow cells of Swiss albino mice using two cytogenetic endpoints for assessing its genotoxic and clastogenic potentials. Concentrations of 0.75, 1.5, 3.0, and 5.0 mg/kg b.w. were administered orally for the study of sister chromatid exchange frequencies and chromosome aberrations (CA). SCE frequencies showed a positive dose response; 1.5 mg/kg being the minimum effective concentration. Fen caused a prolongation of cell cycle at all concentrations. Except for the minimum therapeutic dose (0.75 mg), all other doses (1.5, 3.0, and 5.0 mg) showed a significant increase in the percentage of damaged cells over that of the vehicle control. The degree of clastogenicity was directly proportional to the dosage used and inversely related with the duration of treatment. A gradual reduction of the clastogenic potential was observed after 12 and 24 hr of exposure, indicating that the maximum effect occurs at the middle or late synthetic phase of the cell cycle. This study, probably the first detailed screening of the drug for its genotoxicity, shows that Fen is moderately clastogenic and a DNA damaging agent in vivo.

Administration, Oral↗
PubMed1992

Genotoxicity studies of the food additive ester gum.

Ester gum (EG) is used in citrus oil-based beverage flavourings as a weighting or colouring agent. In the present study, concentrations of 50, 100 and 150 mg/kg body weight were administered orally to male Swiss albino mice, and sister chromatid exchange and chromosomal aberration were used as the cytogenetic endpoints to determine the genotoxic and clastogenic potential of the food additive. Although EG was weakly clastogenic and could induce a marginal increase in sister chromatid exchange frequencies, it was not a potential health hazard at the doses tested.

Administration, Oral↗
PubMed1991

Stimulation of transcript elongation requires both the zinc finger and RNA polymerase II binding domains of human TFIIS.

The eukaryotic transcriptional factor TFIIS enhances transcript elongation by RNA polymerase II. Here we describe two functional domains in the 280 amino acid human TFIIS protein: residues within positions 100-230 are required for binding to polymerase, and residues 230-280, which form a zinc finger, are required in conjunction with the polymerase binding region for transcriptional stimulation. Interestingly, a mutant TFIIS with only the polymerase binding domain actually inhibits transcription, whereas a mutant in which the polymerase binding and zinc finger domains are separated by an octapeptide is only weakly active. The zinc finger itself has no effect on transcription, but in contrast to the wild-type protein, it binds to oligonucleotides. These findings suggest that TFIIS may interact with RNA polymerase II such that the normally masked zinc finger can specifically contact nucleotides in the transcription elongation zone at a position juxtaposed to the polymerization site.

Amino Acid Sequence↗
PubMed1991

Modifying role of Phyllanthus emblica and ascorbic acid against nickel clastogenicity in mice.

Nickel, a major environmental pollutant is known for its clastogenic and carcinogenic potential. Dietary inhibitors of mutagenesis and carcinogenesis are of particular importance since they may have a role in cancer prevention. In the present investigation, aqueous extract of edible dried fruits of Phyllanthus emblica, a well known medicinal plant, was fed to Mus musculus for seven consecutive days prior to treatment with different doses of nickel chloride (10, 20 and 40 mg/kg body wt.); the fruit extract significantly reduced the frequency of CA/cell, the percentage of aberrant cells and the frequency of micronuclei induced by all doses of nickel in the bone marrow cells of mice. Ascorbic acid, a major constituent of the fruit, fed for 7 consecutive days in equivalent concentration as that present in the fruit, however, could only alleviate the cytotoxic effects induced by low doses of nickel; at the higher doses it was ineffective. The greater efficacy of the fruit extract could be due to the interaction of its various natural components rather than to any single constituent. The study assumes importance in view of the widespread human exposure to nickel compounds.

Animals↗
PubMed1991

Cloning, expression and characterization of the human transcription elongation factor, TFIIS.

The cDNA for the human elongation factor, TFIIS, has been cloned and expressed in E. coli with the T7 expression system. This 280-amino acid TFIIS protein is shorter by 21 residues than that of the mouse. The missing 21 residues are located in the amino-terminal region, which is not thought to be required for transcriptional stimulation. Apart from this gap, human and mouse proteins reveal 96% overall identity and 98.5% sequence similarity if conservative substitutions are taken into account. The bacterially expressed human protein and the purified calf thymus proteins are indistinguishable in their ability to stimulate transcript elongation by purified RNA polymerase II. Estimation of the native molecular size of the human protein in solution indicates that it exists as a dimer.

Amino Acid Sequence↗
PubMed1991

Anticlastogenic activity of beta-carotene against cyclophosphamide in mice in vivo.

beta-Carotene (BC), a natural food colourant and an antioxidant, acts as an antimutagen/anticarcinogen in several test systems. The anticlastogenic activity of BC against cyclophosphamide (CP) was studied in bone marrow cells of mice in vivo. Seven days' oral priming with BC (2.7 and 27 mg/kg b.w.) followed by an acute treatment with cyclophosphamide (25 mg/kg b.w.; i.p.) inhibited clastogenicity. The values of chromosomal aberrations and micronucleated polychromatic erythrocytes were consistently lower than the sum of the expected values of BC and CP given individually. This antagonistic response indicates anticlastogenic activity of BC against CP.

Animals↗
PubMed1991

Autoclaved partially decalcified bone as osteogenic substances--an experimental study.

A large osteoperiosteal gap was created in rabbit's ulna. A total of 18 allogenic decalbone grafts in left ulnar gap and 20 autoclaved allogenic decalbone grafts on right ulnar gaps were implanted. Five gaps were left unbridged to serve as controls. The results were assessed by clinical, radiological, macroscopic, histological and tetracycline fluorescent studies. It is observed that whereas the decalbone can successfully bridge a large gap in a vast majority of cases; the standard autoclaving of decalbone denatures its proteins which melt and cover the outer surface. The union, incorporation and remodelling of autoclaved decalbone grafts are slower as compared to that with unautoclaved decalbone.

Animals↗
PubMed1990

Molecular structure of deoxycytidyl-3'-methylphosphonate (RP) 5'-deoxyguanidine, d[Cp(CH3)G]. A neutral dinucleotide with Watson-Crick base pairing and a right handed helical twist.

The crystal structure of d[Cp(CH3)G] has been determined as part of a project to study the mechanism of the B----Z transition in DNA. The asymmetric unit contains two dinucleotides and the equivalent of 7.5 water molecules, partially disordered over 12 definable positions. The two symmetry-independent dinucleotides form a duplex with Watson-Crick base-pairing and a right-handed helical sense. Comparison with previously determined structures of the B and A conformation showed that this duplex is closer to B than to A but significantly different from B. It corresponds to a stretched out helix with a 4 A rise per base pair and a helical twist of 32 degrees. This structure may serve as a model for the bending of DNA in certain situations. The configuration at the methyl phosphonate is RP, and a mechanism, based on this assignment, is presented for the B----Z transition in DNA.

Base Composition↗
PubMed1990

Clastogenic effects of copper sulphate on the bone marrow chromosomes of mice in vivo.

Copper sulphate administered intraperitoneally to Swiss albino mice in vivo induced a significant increase in the frequency of chromosomal aberrations in bone marrow cells as all concentrations used (1.1-6.6 mg/kg b.w.), when compared to the negative control. Statistical analysis indicates that the degree of clastogenicity was directly related to the concentrations used and indirectly to the period of exposure. The effect was maximal at 6 h after treatment as compared with 12 and 24 h.

Animals↗
PubMed1989

Synthesis and properties of a nonhydrolyzable adenosine phosphosulfate analog.

Initial activation of inorganic sulfate for subsequent synthesis of sulfated biomolecules requires the action of ATP-sulfurylase to generate adenosine 5'-phosphosulfate (APS). This activated sulfate intermediate is both chemically labile and susceptible to enzymatic degradation. Consequently, it has not proven useful as a ligand for either purification or characterization of the various APS-utilizing enzymes. For these purposes, a stable analog of APS was required. This paper describes the simple and efficient synthesis and structural confirmation of a nonhydrolyzable APS analog, beta-methylene APS, with an overall molar yield of 40-50%. The method involves nucleophilic substitution of the chlorine moiety of a 5'-chloromethylphosphonate ester of 2',3'-O-isopropylidene adenosine by a sulfite ion. We also report the initial utilization of this compound as an inhibitor in kinetic trials of both ATP-sulfurylase and APS kinase and as an affinity ligand for the purification of these two APS-utilizing enzymes from cartilaginous tissue.

Adenosine Monophosphate↗
PubMed1989

Effects of copper on mammalian cell components.

Both deficiency and excess of copper induce toxic effects on mammalian cell systems in vivo and in vitro. The effects can be related to the affinities of Cu(II) ions for specific cell components. The nucleus is a potential site for temporary Cu storage while primary targets for free Cu(II) ions are the thiol groups which reduce the ions to Cu(I). Cu(II) ions show a high affinity for nucleic acids, binding with DNA both at intrastrand and interstrand levels, possibly through intercalation between GC pairs. The ability to chelate Cu(II) ions is seen to be of the order: purine greater than purine ribonucleotides greater than purine ribonucleoside greater than pyrimidine ribonucleotides. Copper is an integral part of enzyme activation and enters into the molecular structure of several proteins, like ceruloplasmin. Cu(II) ion is a potential mutagenic agent as seen by its property of inducing infidelity in DNA synthesis in vitro. Teratogenic activities of copper have been reported but carcinogenicity is not yet confirmed. Copper is an essential component of chromatin and is known to accumulate preferentially in the heterochromatic regions. External application of higher doses, however, induces both clastogenic effects and spindle disturbances. In certain forms, inorganic copper enhances the clastogenic activity of other agents. The most widely studied human genetic maladies linked with copper metabolism are Menkes' and Wilson's diseases. Several mutations are known which influence Cu homeostasis in mammals. Such mutations in mice have been used extensively for biochemical studies.

Animals↗
PubMed1988

Effect of 24 mm levonorgestrel IUD on uterine endometrium of female rhesus monkeys, Macaca mulatta.

Hysterectomy specimens were obtained from ten adult female rhesus monkeys treated with levonorgestrel-releasing intrauterine devices (IUDs) for a period of three, six and twelve months. The effect of levonorgestrel on the endometria, ovaries and fallopian tubes of removed uteri was examined in luteal phase of cycle. A uniform suppression of endometrium with glandular atrophy and pseudodecidualization of stromal cells was observed in endometrial biopsies, whereas ovaries and tubal epithelium exhibited normal physiological changes as evidenced by presence of ovulatory stigma along with well formed corpus luteum and secretory activity of tubal epithelium.

Animals↗
PubMed1988

Mechanism of transcription termination in eukaryotic cell.

We developed an in vivo screening system for the DNA region involved in transcription termination. This system is based on the idea that the CAT gene bearing transcription terminator upstream of poly(A) signal should produce a low CAT activity in the transfected cell. Using this system, we located termination elements in the human gastrin gene and adenovirus E1 gene. Furthermore, the terminator of gastrin gene was identified by S1 nuclease mapping and in vitro transcription.

Adenovirus Early Proteins↗