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Biomedical subjects

R Dhawan

Publications and source records attributed to R Dhawan.

29 records · Page 2Linked to original sources
PubMed1993

Depression of chemiluminescence during dengue virus infection of mice: role of cytokines.

The effect of dengue type 2 virus (DV) and the cytokines induced by it, on the chemiluminescence (CL) response of mouse spleen cells was studied by luminol-dependent CL. Following intracerebral (i.c.) inoculation of DV, an initial increase in CL response was observed which was followed by a sharp decline from the 4th day post-infection with lowest values on days 5 and 6. DV-induced depression of CL was inhibited by pretreatment of mice with antisera against the two DV-induced cytokines, the cytotoxic factor (CF) and the cytotoxin (CF2), but antisera against the other two helper (HF) or suppressor (SF) cytokines had minimal effect. Inoculation of CF or CF2 into mice depressed the CL in dose-dependent manner at 2 hours but increased it at the 3rd day. Inoculation of HF or SF had no significant effect. Treatment of mice with the cytokines in presence of the specific antisera had an enhancing effect on the CL response. The antisera alone had no effect on CL. Thus, these findings indicate that DV infection impaired the generation of respiratory burst, and the impairment appeared to be mediated by two DV-induced cytokines (CF/CF2). Targetting of the cytokines to M phi was significantly enhanced in the presence of specific anti-cytokine antibodies.

Animals↗
PubMed1991

Breakdown of the blood-brain barrier during dengue virus infection of mice.

A breakdown of the blood-brain barrier occurred in mice inoculated intracerebrally (i.c.) or intraperitoneally (i.p.) with dengue virus type 2 (DEN2). This resulted in leakage of protein-bound Evans blue dye and 51Cr-labelled erythrocytes into the brain tissue. The leakage increased with time after infection and coincided with an increase of a DEN2-induced cytokine, the cytotoxic factor (CF), in the spleens of such mice. The titres of virus in the brain increased exponentially in i.c. inoculated mice but the virus was not detected in brains of mice given DEN2 by the i.p. route. Similar breakdown of the blood-brain barrier also occurred in mice inoculated intravenously with CF; the damage was dose-dependent and the vascular integrity was restored during the 3 h period after inoculation. Treatment of mice with antihistamine drugs, blocking H1 or H2 receptors, decreased the DEN2-induced protein leakage by up to 50% in i.c. inoculated mice and up to 92% in those inoculated i.p. Indomethacin, a prostaglandin synthetase inhibitor, had no effect. In i.c. inoculated mice protein leakage was inhibited by about 60% by treatment with CF-specific (CFA) or DEN2-specific antisera (DEN2A) whereas protection was complete with the combined treatment with both antisera. On the other hand, in i.p. inoculated mice the inhibition of protein leakage was 80 to 89% with CFA. These findings show a breakdown of the blood-brain barrier leading to cerebral oedema during DEN2 infection which is mediated via the release of histamine by a virus-induced cytokine.

Animals↗
PubMed1991

Obligatory role of Ca2+ in the cytotoxic activity of dengue virus-induced cytotoxin.

The role of calcium ions (Ca2+) in the cytotoxic activity of the dengue type 2 virus (DV)-induced macrophage (M phi) cytotoxin (CF2) was investigated in the present study. The findings show that CF2 prepared in Ca(2+)-free medium had no cytotoxic activity on normal mouse spleen cells suspended in Ca(2+)-free medium but killed the cells suspended in the medium with Ca2+. Substitution with calcium chloride restored the cytotoxic activity of CF2 the optimal dose being 10(-4) M concentration. CF2 induced an influx of Ca2+, as assayed by uptake of radiolabelled calcium chloride (45Ca), in the susceptible target cells, viz. M phi and T lymphocytes. The cytotoxic activity of CF2 as well as the CF2-induced influx of 45Ca was inhibited by treatment of the target cell with the calcium channel blocking drugs verapamil and nifedipine. Thus, the presence of Ca2+ is obligatory for the cytotoxic activity of CF2 and cell death is associated with increased intracellular Ca2+.

Animals↗
PubMed1991

Presence of Ca2+ is obligatory for the cytotoxic activity of dengue virus-induced cytotoxic factor.

The present study was undertaken to investigate the role of calcium ions (Ca2+) in the cytotoxic activity of the cytotoxic factor (CF) produced by T lymphocytes of the dengue type 2 virus (DV)-infected mouse spleen. It was observed that CF prepared in Ca2(+)-free medium had no cytotoxic activity on normal mouse spleen cells suspended in Ca2(+)-free medium but had activity on cells suspended in medium having Ca2+. The cytotoxic activity of CF was restored by substitution with calcium chloride, the optimal dose being 10(-7) M. CF induced influx of Ca2+ as measured by uptake of radiolabelled calcium chloride (45Ca), in the susceptible target cells, macrophages (M phi) and T lymphocytes, but had no effect on CF-resistant B lymphocytes. Calcium channel blocking drugs, like verapamil, nifedipine and diltiazem, inhibited the cytotoxic activity of CF and also the CF-induced influx of 45Ca in M phi and T cells. Thus, presence of Ca2+ is obligatory for the cytotoxic activity of CF and the cell death is associated with increased intracellular Ca2+.

Animals↗
PubMed1990

Effect of dengue virus-induced cytotoxin on capillary permeability.

Capillary permeability is increased in cases of dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) but its genesis is not known. Dengue type 2 virus (DV) induces production of a cytokine (CF2) by mouse macrophages. The present study was undertaken to investigate the effect of CF2 on capillary permeability. It was observed that intraperitoneal inoculation of CF2 in mice increased the capillary permeability in a dose-dependent manner, as shown by leakage of intravenously injected radioactive iodine (125I) or Evan's blue dye in the peritoneal cavity. Peak leakage occurred at 30 min and the vascular integrity was restored by 1-2 h. The increase in capillary permeability was abrogated by pretreatment of mice with avil (H1 receptor blocker) but not by ranitidine (H2 receptor blocker). The findings thus show that DV-induced CF2 increases the capillary permeability via release of histamine.

Animals↗
PubMed1987

Folate analogues. 30. Synthesis and biological evaluation of N10-propargyl-5,8-dideaza-5,6,7,8-tetrahydrofolic acid and related compounds.

The 5,6,7,8-tetrahydro derivative (1) of the powerful thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (PDDF) has been synthesized and evaluated for its antifolate activity. A convenient method for the preparation of the key intermediate 2-amino-6-(bromomethyl)-4-hydroxy-5,6,7,8-tetrahydroquinazoline (18) is described. Two closely related analogues of 1 were also synthesized and evaluated for their antifolate activity and thymidylate synthase inhibition. N10-Propargyl-5,8-dideaza-5,6,7,8-tetrahydrofolate (1) and N10-methyl and N10-hydrogen analogues 2 and 3 were weaker inhibitors of Lactobacillus casei thymidylate synthase compared to PDDF. N10-Methyl-5,8-dideaza-5,6,7,8-tetrahydrofolate (2) exhibited the most potent antifolate activity against L. casei (IC50 = 2.8 nM) and Streptococcus faecium (IC50 = 0.57 nM). In intact and permeabilized murine leukemia L1210 cells, the replacement of the quinazoline moiety with its tetrahydro derivative resulted in a marked decrease in potency and a loss of the contribution of the propargyl substituent to enzyme inhibition, indicating an altered binding mode to thymidylate synthase.

Folic Acid↗
PubMedDate not supplied

Plasma cortisol following injection of 1-39 or 1-18 ACTH.

Forty units of 1-39 ACTH of animal origin or 0.4 mg of synthetic 1-18 ACTH administered at 8 A.M. via either the intramuscular route to 10 subjects with intact adrenocortical function produced comparable increases in plasma cortisol at 1, 2, and 6 hours. The increase in plasma cortisol lasted at least 6 hours but less than 12 hours after intravenous crystalline 1-39 ACTH and at least 16 hours but less than 24 hours after the same dose of 1-39 ACTH administered as a depot gel via the intramuscular route. However, neither intravenous nor the intramuscular injection of 1-39 ACTH produced increases that were still evident at 24 hours. Following either the intramuscular or intravenous injection of 0.4 mg of the synthetic 1-18 ACTH, the plasma cortisol increase was still evident at the 24th hour. Our findings indicate that the plasma cortisol responses to either 40 units of exogenous 1-39 ACTH of animal origin or to 0.4 mg of a synthetic 1-18 ACTH are most consistent in the first 6 hours following either intravenous or intramuscular injection.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

Synthesis of polyamide oligomers based on 14-amino-3,6,9, 12-tetraoxatetradecanoic acid.

A series of oligomers of polyamides based on 14-amino-3,6,9, 12-tetraoxatetradecanoic acid monomers (ATTAn) was synthesized. These materials were designed as monodisperse analogues of poly(ethylene glycol) for use in biomedical applications where reproducible behavior is important. Synthesis of the monomer was evaluated using two routes. For small-scale preparations, tetraethylene glycol (TEG) was monoprotected with dihydropyran, converted to an alkoxide, and alkylated with ethyl bromoacetate. On larger scales, TEG was alkylated directly by treatment with sodium, followed by ethyl bromoacetate. The amine function was introduced by mesylation followed by treatment with sodium azide. Reduction of the azide to amino groups was performed over Pd/C using either hydrogen or formic acid as proton sources. Assembly of the oligomers was accomplished using standard DCC/NHS chemistry and an iterative dimerization sequence after appropriate deprotection of a pair of monomers. The amino group was protected by retaining the azido group as a latent amine. A series of ATTAn oligomers was prepared (n = 1-8). A lipid conjugate of the octamer, ATTA8-DSPE, was synthesized.

Biocompatible Materials↗