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Biomedical subjects

K Agarwal

Publications and source records attributed to K Agarwal.

At least 19 recordsLinked to original sources
PubMed1998

Interplay of matrices in cartilage synovial fluid combine under moderate & high loadings.

Interplay of the constituents of the articular cartilage synovial fluid combine and its role was examined through the biochemical and rheological studies on bovine joints. The results showed an inverse relationship between the changes in the hyaluronic acid of synovial fluid and the proteoglycans content in articular cartilage together with alterations in the rheological properties of synovial fluid. The study indicated that the inter-movement of fluid solutes across the cartilage and synovial fluid may have an important role in the pathophysiology of osteoarthritis.

Animals↗
PubMed1996

Phenethyl isothiocyanate modulates clastogenicity of mitomycin C and cyclophosphamide in vivo.

Phenethyl isothiocyanate (PEITC), a constituent of many cruciferous vegetables, is an effective chemopreventive agent against N-nitrosamine-induced carcinogenesis. We have investigated the extent to which PEITC modulates the clastogenicity of standard genotoxicants, mitomycin C and cyclophosphamide, using bone marrow cells of Swiss albino mice. PEITC, 1 mumol/kg body weight in corn oil was administered by gavage for 7 consecutive days to prime the animals. 24 h later, mice received a single dose of cyclophosphamide (10 or 20 mg/kg body weight) or mitomycin C (1 or 2 mg/kg body weight) intraperitoneally. Clastogenicity of the chemicals was compared using PEITC-primed and non-primed animals 24 h after clastogen treatment. As a single agent, PEITC is not clastogenic even after 7 days of priming. Oral priming with PEITC decreased the aberrations per cell values by 22-67% in all cases. PEITC could only alleviate the clastogenicity of 1 mg/kg body weight mitomycin C to near-control values (p < or = 0.05). Although PEITC is reported to be effective against N-nitrosamine-induced tumorigenesis by preventing metabolic activation and by blocking the reactive species formed, it is virtually ineffective against the clastogenicity of cyclophosphamide. The results of inhibition by PEITC of the clastogenicity of mitomycin C suggest that the modulation of mitomycin C bio-activation contributes to, but may not be sufficient for, PEITC chemoprevention of clastogenicity by mitomycin C.

Animals↗
PubMed1996

Fidelity of RNA polymerase II transcription controlled by elongation factor TFIIS.

Fidelity of DNA and protein synthesis is regulated by a proofreading mechanism but function of a similar mechanism during RNA synthesis has not been demonstrated. Analysis of transcriptional fidelity and its control has been hampered by the necessity to employ complex DNA templates requiring either a promoter and initiation factors or 3'-extended templates. To circumvent this difficulty, we have created an RNA-DNA dumbbell template that can be recognized as a template-primer and extended by RNA polymerase II. By employing this system, we demonstrate that RNA polymerase II can misincorporate a nucleotide and carry out template-dependent elongation at the mispaired end. The transcripts containing misincorporated residues can be cleaved by the very slow 3'-->5' ribonuclease activity of the RNA polymerase II, but enhancement of this activity by the elongation factor TFIIS generates RNA with a high degree of fidelity. This enhanced preferential cleavage of misincorporated transcripts suggests an important role for TFIIS in maintaining transcriptional fidelity.

Animals↗
PubMed1995

Inhibition by capsaicin against cyclophosphamide-induced clastogenicity and DNA damage in mice.

We have demonstrated in an earlier paper that capsaicin, the pungent principle of red hot chili, has a potent anti-oxidant property that interferes with free-radical involved mechanisms. In the present paper we demonstrate that capsaicin significantly inhibits cyclophosphamide-induced (i.p.) chromosomal aberrations and DNA strand breakages. This protective action of capsaicin against CP-induced toxicity may possibly be linked with its already reported 'desensitisation' effect against chemical irritant-induced damages.

Animals↗
PubMed1995

Pregnancy induced hypertension: changes in coagulation profile of newborns.

Coagulation parameters and platelet count were studied in 30 neonates of mothers with pregnancy induced hypertension (PIH). 30 neonates born to normotensive mothers were taken as controls. The test group was further subdivided as neonates born to mothers with gestational hypertension, pre-eclamptic toxemia and eclampsia. The values of Prothrombin Time, Partial Thromboplastin Time with Kaolin, Thrombin Time, Fibrinogen Degradation Products were significantly raised and Fibrinogen and Platelet count were reduced significantly in both term and preterm test groups as compared to controls. The derangement in coagulation parameters was more marked with increasing severity of PIH.

Blood Coagulation Disorders↗
PubMed1994

The transcription factor TFIIS zinc ribbon dipeptide Asp-Glu is critical for stimulation of elongation and RNA cleavage by RNA polymerase II.

The eukaryotic transcription factor TFIIS enhances elongation and nascent transcript cleavage activities of RNA polymerase II in a stalled elongation complex. By site-directed mutagenesis, we have demonstrated that invariant residues Asp-261 and Glu-262 of the nucleic acid-binding TFIIS Zn ribbon are critical for stimulation of both elongation and RNA cleavage activities of RNA polymerase II. Substitution of either of these residues inactivates both TFIIS functions, suggesting a related role in both activities. These acidic residues may participate in phosphoryl transfer reactions by a two-metal-ion mechanism in a manner analogous to Klenow fragment. The RNA polymerase II itself may contain a Zn ribbon, in as much as the polymerase's 15-kDa subunit contains a sequence that aligns well with the TFIIS Zn ribbon sequence, including a similarly placed pair of acidic residues.

Amino Acid Sequence↗
PubMed1994

Characterization of the gene encoding the human transcriptional elongation factor TFIIS.

The transcriptional elongation factor TFIIS causes stimulation of RNA polymerase II elongation and readthrough of some of the elongation blocks. We present cloning and sequence characterization of the human TFIIS gene and a pseudogene. The intron-less organization of both of these genes indicates that previously identified cDNAs which suggested the presence of an intron were the products of cloning artifacts. The gene is organized in an uninterrupted ORF which codes for 301 amino acids, whereas the pseudogene lacks an ORF able to code for a full-length protein. The potential promoter for the gene has two putative GC-box-type consensus sequences, two CCAAT-box consensus sequences, and is bounded by a human Alu sequence. Two potential transcriptional termination signal sequences downstream from the consensus polyadenylation signal are proposed.

Base Sequence↗
PubMed1994

Etoposide (VP-16): cytogenetic studies in mice.

Etoposide (VP 16-213), the epipodophyllotoxin derivative that is widely used in the treatment of cancer, forms complexes with DNA-topoisomerase type II alpha to exert its cytotoxicity. The drug was evaluated in vivo in Swiss albino mouse bone marrow cells for its ability to induce clastogenicity and sister chromatid exchanges (SCEs). Doses of 5, 10, 15, and 20 mg/kg body weight etoposide given intraperitoneally induced a dose-dependent significant increase of clastogenicity (Trend test, alpha < or = 0.05). The aberrations induced were predominantly chromatid types. The drug shows specificity for S-phase cells: cells harvested 6 and 12 hr posttreatment showed a significantly increased number of damaged cells and aberrations per cell. Doses of 0.5, 1.0, 2.5, 5.0, and 10.0 mg etoposide/kg body weight induced a dose-dependent significant induction of SCEs (Trend test, alpha < or = 0.05). The minimal effective concentration was 0.5 mg/kg body weight. Etoposide significantly prolonged the cell cycle time at all concentrations tested: 12-13 hr in treated animals vs. 11 hr in control. The results confirm in vivo cell cycle phase specificity of the drug and further designate etoposide as a potent clastogen and a genotoxic agent in mice.

Analysis of Variance↗
PubMed1994

In vivo cytogenetic studies on mice exposed to natural food colourings.

Safflower Yellow and Kokum Red, two food colourings developed from natural plant products, were assessed in vivo for their clastogenic potential. Swiss albino male mice were exposed to the compounds through ip injections. Bone marrow cells isolated from femora were analysed for chromosome aberrations. The results show that the two food colourings were weakly clastogenic.

Animals↗
PubMed1994

Potentiation by caffeine of the frequencies of chromosomal aberrations induced by chronic exposure to fenfluramine in mice.

Fenfluramine (Fen), an amphetamine-derivative widely used in the treatment of obesity, has been evaluated in vivo in the bone marrow cells of Swiss albino mice for assessing its clastogenic potentials. Concentrations of 0.75, 1.50 and 5.0 mg Fen/kg body weight (b.w.) were administered orally for the study. Long-term treatment for 21 days showed dose-dependent significant increase in chromosomal aberrations on the 8th day. A significant decrease in aberration levels was seen in the late treatment period. Caffeine alone produced dose- and duration-dependent clastogenicity at doses of 2.0, 4.0 and 6.0 mg/kg b.w. when given by gavage. Using caffeine post-treatment (4.0 and 6.0 mg/kg b.w.) 2 h after Fen application, a strong synergism could be seen in the late treatment period as shown by the dose-response curves and by statistical analysis using the principle of least squares. The results support the hypothesis that prolonged Fen application induces dose-dependent increase in post-replication repair and caffeine enhanced toxicity by inhibiting repair process(es). The study suggests that Fen is a clastogen and since caffeine may have a synergistic effect, it should be avoided during treatment.

Administration, Oral↗
PubMed1994

Increased interleukin-4 production in response to mast cell mediators and human type I collagen in patients with rheumatoid arthritis.

Mast cell synovial hyperplasia can occur in patients with rheumatoid arthritis. Histamine can accelerate synovitis and heparin can inhibit lymphocyte function. Since interleukin-4 (IL-4) can stimulate murine mast cell and IgE synthesis, we determined whether mast cell mediators and anti-IL-4 might effect lymphocyte proliferation from patients with rheumatoid arthritis. Twenty-four patients with rheumatoid arthritis and nine normal controls were evaluated by history, physical examination, physician and patient-assessed joint and allergic symptoms, and diary scores. An IL-2-driven-T cell (3H) Tdr proliferation assay with monoclonal anti-IL-4 and a sensitive ELISA were performed with isolated peripheral blood mononuclear cells (PBMC) with 10 micrograms/mL of either concanavalin A (Con A), type I human collagen, or heparin and 10(-6) M histamine. Increased lymphocyte proliferation indices with Con A (mean 21.69 +/- 4.9; 6.54 +/- 3.2 normal controls), type I human collagen (mean 2.17 +/- 0.52; 1.1 +/- .17, normal controls), histamine (mean 1.66 +/- .36; 0.62 +/- 0.08, normal controls), heparin (mean 1.61 +/- .38; 0.69 +/- .11, normal controls) occurred in peripheral blood mononuclear cells from all patients with rheumatoid arthritis compared with normal controls (P < .0236 to .0015) which was inhibited in 32% of peripheral blood mononuclear cells by anti-IL-4. Increased IL-4 ELISA levels in cultured supernatants were noted with heparin (P < .25) and collagen (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Novel zinc finger motif in the basal transcriptional machinery: three-dimensional NMR studies of the nucleic acid binding domain of transcriptional elongation factor TFIIS.

Transcriptional elongation provides a key control point in the regulation of eukaryotic gene expression. Here we describe homonuclear and 15N-heteronuclear 3D NMR studies of the nucleic acid binding domain of human transcriptional elongation factor TFIIS. This domain contains a Cys4 Zn(2+)-binding site with no homology to previously characterized Cys4, Cys6, or Cys2-His2 Zn fingers. Complete 1H and 15N NMR resonance assignment of a 50-residue TFIIS peptide-Zn2+ complex is obtained. Its solution structure, as determined by distance geometry/simulated annealing (DG/SA) calculations, exhibits a novel three-stranded antiparallel beta-sheet (designated the Zn ribbon). Analogous sequence motifs occur in a wide class of proteins involved in RNA or DNA transactions, including human basal transcriptional initiation factor TFIIE. A three-dimensional model of the TFIIE Cys4 domain is obtained by DG-based homology modeling. The role of the TFIIS Zn ribbon in the control of eukaryotic transcriptional elongation is discussed.

Amino Acid Sequence↗
PubMed1993

Structure of a new nucleic-acid-binding motif in eukaryotic transcriptional elongation factor TFIIS.

Transcriptional elongation involves dynamic interactions among RNA polymerase and single-stranded and double-stranded nucleic acids in the ternary complex. In prokaryotes its regulation provides an important mechanism of genetic control. Analogous eukaryotic mechanisms are not well understood, but may control expression of proto-oncogenes and viruses, including the human immunodeficiency virus HIV-1 (ref. 8). The highly conserved eukaryotic transcriptional elongation factor TFIIS enables RNA polymerase II (RNAPII) to read though pause or termination sites, nucleosomes and sequence-specific DNA-binding proteins. Two distinct domains of human TFIIS, which bind RNAPII and nucleic acids, regulate read-through and possibly nascent transcript cleavage. Here we describe the three-dimensional NMR structure of a Cys4 nucleic-acid-binding domain from human TFIIS. Unlike previously characterized zinc modules, which contain an alpha-helix, this structure consists of a three-stranded beta-sheet. Analogous Cys4 structural motifs may occur in other proteins involved in DNA or RNA transactions, including RNAPII itself. This new structure, designated the Zn ribbon, extends the repertoire of Zn-mediated peptide architectures and highlights the growing recognition of the beta-sheet as a motif of nucleic-acid recognition.

Amino Acid Sequence↗
PubMed1993

Tumors in hepatobiliary tract and pancreatic islet tissues of transgenic mice harboring gastrin simian virus 40 large tumor antigen fusion gene.

Gastrin is expressed in the gastric antrum and in fetal pancreatic islets but not in adult islets. We have now identified the hepatobiliary tract as another, previously unknown, potential site of gastrin gene expression. Two human gastrin simian virus 40 large tumor antigen (SV40 T antigen) fusion genes containing 1.5 kb of 5' flanking sequence and 10.5 kb that included 5.5 kb upstream, 1.5 kb downstream, and the entire transcribed region were used to generate transgenic mice. Analysis of several transgenic lines, derived from both fusion genes, revealed development of transmissible hepatobiliary tract tumors and pancreatic islet cell tumors. Analysis of each of the tumor cells demonstrates expression of SV40 T antigen but no expression of gastrin. Of the two fusion genes, only the 10.5-kb sequence induces hyperplasia of gastrin-producing cells in the antrum. Analysis of these cells demonstrates expression of SV40 T antigen and gastrin, suggesting that the 10.5-kb sequence is sufficient for gastrin cell hyperplasia in the antrum. These data raise the possibility that gastrin is transiently expressed in the hepatobiliary tract.

Adenoma, Islet Cell↗