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Biomedical subjects

K Sharma

Publications and source records attributed to K Sharma.

At least 73 records · Page 4Linked to original sources
PubMed1996

Suppression of experimental autoimmune uveitis in Lewis rats by oral administration of recombinant Escherichia coli expressing retinal S-antigen.

Experimental autoimmune uveitis (EAU) is an organ-specific T-lymphocyte-mediated autoimmune disease which serves as a model for several human ocular inflammations of an apparently autoimmune nature. S-antigen, a photoreceptor cell protein, is highly efficient in inducing EAU showing severe inflammation of the uveal tract and retina of the eye. We have demonstrated previously that recombinant Escherichia coli expressing retinal S-antigen induces EAU in Lewis rats. The oral administration of S-antigen prior to the uveitopathogenic challenge results in significant suppression of the disease and of the cellular responses. We examined the effect of oral administration of E. coli expressing retinal S-antigen on the development of EAU induced with native S-antigen in Lewis rats. Feeding rats with 1 mg of bacteria on Days 7, 5, 3, 2 and 1 prior to immunization with 50 micrograms of retinal S-antigen caused a significant suppression of the disease. Moderate suppression was found in animals fed 0.5 and 0.25 mg of recombinant bacteria. Oral feeding of 1 mg of JM105 transfected with plasmid alone had no significant effect on the subsequent induction of EAU by S-antigen. Feeding recombinant E. coli expressing retinal S-antigen before immunization significantly decreased the proliferative response of lymphocytes to native S-antigen in vitro. Our results indicate that recombinant microorganism-expressing autoantigen administered orally induces suppression of specific autoimmune disease as well as cellular response to particular autoantigen.

Administration, Oral↗
PubMed1996

Nuclear pore proteins are involved in the biogenesis of functional tRNA.

Los1p and Pus1p, which are involved in tRNA biogenesis, were found in a genetic screen for components interacting with the nuclear pore protein Nsp1p. LOS1, PUS1 and NSP1 interact functionally, since the combination of mutations in the three genes causes synthetic lethality. Pus1p is an intranuclear protein which exhibits a nucleotide-specific and intron-dependent tRNA pseudouridine synthase activity. Los1p was shown previously to be required for efficient pre-tRNA splicing; we report here that Los1p localizes to the nuclear pores and is linked functionally to several components of the tRNA biogenesis machinery including Pus1p and Tfc4p. When the formation of functional tRNA was analyzed by an in vivo assay, the los1(-) pus1(-) double mutant, as well as several thermosensitive nucleoporin mutants including nsp1, nup116, nup133 and nup85, exhibited loss of suppressor tRNA activity even at permissive temperatures. These data suggest that nuclear pore proteins are required for the biogenesis of functional tRNA.

Amino Acid Sequence↗
PubMed1996

Yeast nucleoporin mutants are defective in pre-tRNA splicing.

We have screened nucleoporin mutants for the inhibition of tRNA splicing, which has previously been proposed to be coupled to transport. Strains mutant for Nup49p or Nup116p, or genetically depleted of Nup145p, strongly accumulated unspliced pre-tRNAs. Splicing was inhibited for all 10 families of intron-containing pre-tRNA, but no effects on 5' or 3' end processing were detected. Strains mutant for Nup133p or Nsp1p accumulated lower levels of several unspliced pre-tRNAs. In contrast, no accumulation of any pre-tRNA was observed in strains mutant for Nup1p, Nup85p, or Nup100p. Other RNA processing reactions tested, pre-rRNA processing, pre-mRNA splicing, and small nucleolar and small nuclear RNA synthesis, were not clearly affected for any nucleoporin mutant. These data provide evidence for a coupling between pre-tRNA splicing and nuclear-cytoplasmic transport. Mutation of NUP49, NUP116, or NUP145 has previously been shown to lead to nuclear poly(A)+ RNA accumulation, indicating that these nucleoporins play roles in the transport of more than one class of RNA.

Base Sequence↗
PubMed1996

Morphine modulates migration of monocytes.

Macrophages seem to play an important role in the development of glomerulosclerosis. In the present study we evaluated the effect of morphine, an active metabolite of heroin, on the migration of monocytes across a filter in a modified Boyden chamber. Morphine-mesangial cell interaction enhanced (p < 0.004) the migration of monocytes across the filter (control 14.2 +/- 0.6 vs. morphine 22.1 +/- 1.7 monocytes/HPF). Dimethylthiourea (DMTU), a free radical scavenger, attenuated this effect of morphine. Morphine-monocyte secretory products (MMSP) did not modulate the migration of monocytes. However, the products of interaction between mesangial cells and MMSP enhanced (p < 0.001) the passage of monocytes across the filter. Mesangial cells treated with MMSP showed mRNA expression for monocyte chemoat-tractant peptide-1 (MCP-1). Superoxide also induced mRNA expression for MCP-1 on MC. DMTU attenuated this effect of superoxide. Since morphine activates MC to produce superoxide and DMTU attenuated the effect of superoxide on MC, the effect of morphine on the migration of macrophages may be mediated through superoxide-induced generation of MCP-1. We conclude that morphine enhances the migration of monocytes. This effect of morphine may be contributing to the development of glomerulosclerosis in patients with heroin addiction.

Animals↗
PubMed1996

Stroke--a rare presentation of Eales' disease. A case report.

Eales' disease is common in India and the Middle East, but its neurologic manifestations are rare. The authors report a young man with recurrent vitreous hemorrhage and acute amnestic confusional state who subsequently developed myelopathy. Eales' disease should be considered in the differential diagnosis of stroke in a young patient.

Adult↗
PubMed1996

Poly (D,L-lactide) glycolide polymer microsphere entrapped tetanus toxoid: safety evaluation in Wistar rats.

A vaccine preparation consisting of tetanus toxoid (TT) encapsulated in biodegradable poly (D,L-Lactide) glycolide polymer has been developed. The toxicity of the preparation was evaluated in adult male and female Wistar rats injected IM with 20, 100 and 200 Lf tetanus toxoid, in polymer in 0.5 ml vehicle. No adverse effect of the vaccine could be seen, except for a granulomatous reaction at the site of injection. The vaccine was considered safe based on the findings in rats of both sexes.

Animals↗
PubMed1996

Subtype-selective induction of wild-type p53 and apoptosis, but not cell cycle arrest, by human somatostatin receptor 3.

Somatostatin (SST) exerts direct antiproliferative effects in tumor cells, triggering either growth arrest or apoptosis. The cellular actions of SST are transduced through a family of five distinct somatostatin receptor subtypes (SSTR1-5). Whereas growth inhibition has been reported to follow stimulation of protein tyrosine phosphatase via SSTR2 or inhibition of Ca2+ channels via SSTR5 in heterologous expression systems, the subtype selectivity for signaling apoptosis has not been investigated. The tumor suppressor protein p53 and the protooncogene product c-Myc regulate cell cycle progression (growth factors present) or apoptosis (growth factors absent). The p53-induced G1 arrest requires induction of p21, an inhibitor of cyclin-dependent kinases, whereas apoptosis requires induction of Bax. c-Myc is capable of abrogating p53-induced G1 arrest by interfering with the inhibitory action of p21 on cyclin-dependent kinases. We have, therefore, investigated the regulation of p53, p21, c-Myc, and Bax and cellular apoptosis in relation to cell cycle progression in CHO-K1 cells stably expressing individual human SSTR1-5. We demonstrate that apoptosis is signaled uniquely through human SSTR3 and is associated with dephosphorylation-dependent conformational change in wild-type (wt) p53 as well as induction of Bax. The induction of wt p53 occurs rapidly and precedes the onset of apoptosis. We show that the increase in wt p53 is not associated with the induction of p21 or c-Myc when octreotide-induced apoptosis becomes evident, suggesting that such apoptosis does not require G1 arrest and is not c-Myc dependent. These findings provide the first evidence for hormonal induction of wt p53-associated apoptosis via G protein-coupled receptor in a subtype-selective manner.

Animals↗
PubMed1996

Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice.

Diabetic nephropathy is characterized by renal hypertrophy, thickening of basement membranes, and accumulation of extracellular matrix in the glomerular mesangium and the interstitium. Our previous investigations have shown that high glucose concentration increases transforming growth factor (TGF)-beta1 mRNA in mesangial and proximal tubule cells and that treatment with anti-TGF-beta antibody results in prevention of the effects of high glucose on cell growth (e.g., induction of cellular hypertrophy) and the stimulation of collagen biosynthesis. We evaluated in vivo the functional role of the renal TGF-beta system in diabetic kidney disease by treatment of streptozotocin-induced diabetic mice with either a neutralizing monoclonal antibody against TGF-beta1, -beta2, and -beta3 (alphaT) or nonimmune murine IgG for 9 days. Diabetic mice given IgG demonstrated total kidney and glomerular hypertrophy, significantly elevated urinary TGF-beta1 protein, and increased mRNAs encoding TGF-beta1, type II TGF-beta receptor, alpha1(IV) collagen, and fibronectin. Treatment of diabetic mice with alphaT prevented glomerular hypertrophy, reduced the increment in kidney weight by approximately 50%, and significantly attenuated the increase in mRNA levels without having any effect on blood glucose. The antibody was without significant effect on mRNA levels in nondiabetic mice. This is the first demonstration that the early characteristic features of diabetic renal involvement, which include hypertrophy and increased matrix mRNAs, are largely mediated by increased endogenous TGF-beta activity in the kidney and that they can be significantly attenuated by treatment with neutralizing anti-TGF-beta antibodies.

Animals↗
PubMed1996

Cellular immune response to retinal S-antigen & interphotoreceptor retinoid binding protein fragments in idiopathic human uveitis.

The role of retinal antigens in idiopathic human uveitis has been studied in 38 patients of uveitis, and 30 patients of systemic connective tissue disease (CTD) and 30 healthy volunteers. Lymphocyte proliferative responses were tested in vitro against native S-antigen, its uveitopathogenic peptides (peptide M, peptide G), yeast histone H3 peptide and uveitopathogenic fragment of interphotoreceptor retinoid binding protein (IRBP: R16) to establish their role in pathogenesis of human uveitis. Seven patients with uveitis, and none among CTD patients and healthy volunteers, responded (stimulation index > 3) to at least one retinal antigen used. One uveitis patient showed response to native S-antigen, peptide M and yeast histone H3. One responded to both S-antigen and peptide M and another responded to both peptide G and R16 peptide. Two responded to S-antigen only, one to peptide M and one to peptide G. In addition, one uveitis patient responded to yeast histone H3 only. These results suggest that retinal antigens may play a role in the etiopathogenesis of a subset of idiopathic human uveitis.

Adolescent↗
PubMed1996

An epidemiological study of obesity in Shimla Town.

A cross sectional study of 888 randomly selected subjects in Shimla town was done to determine prevalence of obesity, its relation to age and physical activity. The prevalence of obesity was 21.5% using cut off levels of BMI 25. The prevalence of obesity rose significantly with age. Obesity was less in those having moderate physical activity as compared to those with low and high activity. Primary prevention is required to tackle this disease risk factor through health education focussing on promotion of moderate regular physical activity.

Adult↗
PubMed1995

Growth arrest of a murine mesangial cell line by transforming growth factor beta 1 is associated with inhibition of mitogen-induced Ca2+ mobilization.

Transforming growth factor-beta (TGF beta) is a multifunctional cytokine showing growth effects on many cell types. In the present study effects of TGF beta 1 on mitogen-induced Ca2+ responses were investigated in an immortalized murine mesangial cell line where TGF beta 1 effects on growth are inhibitory. TGF beta 1 was found to inhibit intracellular Ca2+ mobilization induced by platelet-derived growth factor (PDGF). This effect was completely reversed by previous addition of the non-specific serine/threonine kinase inhibitor H-7, but was unaffected by GF 109203X, a specific inhibitor of protein kinase C (PKC). These findings suggest that inhibition of mitogen-induced Ca2+ mobilization by TGF beta 1 appears not to involve prior activation of PKC, but may participate in the mechanisms whereby mesangial cell growth is inhibited by TGF beta 1.

Animals↗
PubMed1995

Enhanced expression of inducible nitric oxide synthase in murine macrophages and glomerular mesangial cells by elevated glucose levels: possible mediation via protein kinase C.

Increased blood flow and vascular permeability of early diabetes have been associated with increased nitric oxide formation in diabetic rats, but the specific nitric oxide synthase responsible is unknown. We examined the modulation of the induction and activity of the inducible NOS isoform by high glucose concentration in a murine macrophage cell line, RAW 264.7, and murine glomerular mesangial cells. Culturing both cell types in high glucose concentration led to significant increases in nitrite production and the mRNA encoding iNOS upon stimulation with LPS plus interferon-gamma, as compared with normal glucose concentration. High glucose also modestly enhanced LPS/IFN-gamma-induced stimulation of the iNOS promoter in transient transfection experiments in mesangial cells. Protein kinase C activation led to enhanced mRNA expression of iNOS, and inhibitors of protein kinase C blocked nitrite accumulation in mesangial cells. These findings suggest that high glucose in combination with stimulation by LPS plus IFN-gamma enhances iNOS expression, and protein kinase C activation may be playing a role in this enhancement.

Amino Acid Oxidoreductases↗