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Biomedical subjects

Sanjay Kumar

Publications and source records attributed to Sanjay Kumar.

At least 55 records · Page 3Linked to original sources
PubMed2005

Selective recognition of synthetic lysine and meso-diaminopimelic acid-type peptidoglycan fragments by human peptidoglycan recognition proteins I{alpha} and S.

The interactions of a range of synthetic peptidoglycan derivatives with PGRP-Ialpha and PGRP-S have been studied in real-time using surface plasmon resonance. A dissociation constant of K(D) = 62 mum was obtained for the interaction of peptidoglycan recognition protein (PGRP)-Ialpha with the lysine-containing muramyl pentapeptide (compound 6). The normalized data for the lysine-containing muramyl tetra- (compound 5) and pentapeptide (compound 6) showed that these compounds have similar affinities, whereas a much lower affinity for muramyl tripeptide (compound 3) was measured. Similar affinities were obtained when the lysine moiety of the muramyl peptides was replaced by meso-diaminopimelic acid (DAP). Furthermore, the compounds that contained only a stem peptide (pentapeptide, compound 1) and (DAP-PP, compound 2) as well as muramyldipeptide (compound 3) exhibited no binding indicating that the muramyltripeptide (compound 4) is the smallest peptidoglycan fragment that can be recognized by PGRP-Ialpha. Surprisingly, PGRP-S derived significantly higher affinities for the DAP-containing fragments to similar lysine-containing derivatives, and the following dissociation constants were measured: muramylpentapeptide-DAP, K(D) = 104 nm; muramyltetrapeptide-DAP, 92.4 nm; and muramyltripeptide-DAP, 326 nm. The binding profiles were rationalized by using a recently reported x-ray crystal structure of PGRP-Ialpha with the lysine-containing muramyltripeptide (4).

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2005

Force-induced triple point for interacting polymers.

We show the existence of a force induced triple point in an interacting polymer problem that allows two zero-force thermal phase transitions. The phase diagrams for two different models of mutually attracting but self-avoiding polymers are presented. One of these models has an intermediate phase and it shows a triple point. A general phase diagram with multicritical points in an extended parameter space is also discussed.

Journal Article↗
PubMed2005

NF-kappa B mediates the stimulation of cytokine and chemokine expression by human articular chondrocytes in response to fibronectin fragments.

Fibronectin fragments (FN-f) that bind to the alpha(5)beta(1) integrin stimulate chondrocyte-mediated cartilage destruction and could play an important role in the progression of arthritis. The objective of this study was to identify potential cytokine mediators of cartilage inflammation and destruction induced by FN-f and to investigate the mechanism of their stimulation. Human articular chondrocytes, isolated from normal ankle cartilage obtained from tissue donors, were treated with a 110-kDa FN-f in serum-free culture, and expression of various cytokine genes was analyzed by cDNA microarray and by a cytokine protein array. Compared with untreated control cultures, stimulation by FN-f resulted in a >2-fold increase in IL-6, IL-8, MCP-1, and growth-related oncogene beta (GRO-beta). Constitutive and FN-f-inducible expression of GRO-alpha and GRO-gamma were also noted by RT-PCR and confirmed by immunoblotting. Previous reports of IL-1beta expression induced by FN-f were also confirmed, while TNF expression was found to be very low. Inhibitor studies revealed that FN-f-induced stimulation of chondrocyte chemokine expression was dependent on NF-kappaB activity, but independent of IL-1 autocrine signaling. The ability of FN-f to stimulate chondrocyte expression of multiple proinflammatory cytokines and chemokines suggests that damage to the cartilage matrix is capable of inducing a proinflammatory state responsible for further progressive matrix destruction, which also includes the chemoattraction of inflammatory cells. Targeting the signaling pathways activated by FN-f may be an effective means of inhibiting production of multiple mediators of cartilage destruction.

Cartilage, Articular↗
PubMed2005

Purification and partial characterization of a low temperature responsive Mn-SOD from tea (Camellia sinensis (L.) O. Kuntze).

The manganese containing superoxide dismutase (Mn-SOD) was purified from a tea clone, TEENALI, which showed the lowest period of winter dormancy. Protein was purified using leaves of tea by ammonium sulfate precipitation, followed by column chromatography using DEAE-cellulose, and silica-based size exclusion chromatography on HPLC system. Upto 51-fold purification and a specific activity of 56.66 U/mg of protein was achieved, which yielded a single band upon denaturing PAGE. The enzyme had a native molecular weight of about 169 kDa, whereas a monomer with molecular weight of 43 kDa was found on SDS-PAGE suggesting it to be homotetramer. The purified enzyme had pH optima of 8.0. It exhibited a wide temperature range for its activity with optima at 0 degrees C suggesting its role in low temperature tolerance. The manuscript presents purification and characterization of high molecular weight Mn-SOD from tea and discusses its implication in tolerance of low temperature stress.

Camellia sinensis↗
PubMed2005

Tea (Camellia sinensis (L.) O. Kuntze) clone with lower period of winter dormancy exhibits lesser cellular damage in response to low temperature.

There is no literature available on the response of tea plant to low temperature. We studied the effect of low temperature on two clones of tea with contrasting periods of winter dormancy, a phenomenon in which the growth of apical shoots of tea is diminished during winter months. Clone 'Teenali 17/154' (TNL) showed shorter periods of winter dormancy than clone 'Kangra Jat' (KNJ). Low temperature (5 degrees C) resulted in increase of metabolic superoxide (O2*-) content and cellular damage (as measured by tetrazolium chloride reduction test) in both the clones, however, the increase was lesser in the case of TNL compared to KNJ. Activities of superoxide dismutase (SOD; EC 1.15.1.1), ascorbate peroxidase (APX; EC 1.11.1.11) and glutathione reductase (GR; EC 1.6.4.2) increased in both the clones in response to low temperature however, GR activity exhibited significant differences (P < 0.05) between the two clones. Low temperature caused increase in the intensity of various isozymes of SOD, APX and GR. A new isozyme of SOD (Cu/Zn type) was induced in both the clones at low temperature. Significantly higher GR activity in both the clones suggested a role of this enzyme in imparting better protection to tea at low temperature. Also, clonal variation for GR isozyme was observed between the clones. Based on these results it appears that TNL, a clone with relatively lesser period of winter dormancy experiences lesser oxidative stress in response to low temperature compared to KNJ, a clone with relatively higher period of winter dormancy.

Ascorbate Peroxidases↗
PubMed2005

Free heme toxicity and its detoxification systems in human.

Severe hemolysis or myolysis occurring during pathological states, such as sickle cell disease, ischemia reperfusion, and malaria results in high levels of free heme, causing undesirable toxicity leading to organ, tissue, and cellular injury. Free heme catalyzes the oxidation, covalent cross-linking and aggregate formation of protein and its degradation to small peptides. It also catalyzes the formation of cytotoxic lipid peroxide via lipid peroxidation and damages DNA through oxidative stress. Heme being a lipophilic molecule intercalates in the membrane and impairs lipid bilayers and organelles, such as mitochondria and nuclei, and destabilizes the cytoskeleton. Heme is a potent hemolytic agent and alters the conformation of cytoskeletal protein in red cells. Free heme causes endothelial cell injury, leading to vascular inflammatory disorders and stimulates the expression of intracellular adhesion molecules. Heme acts as a pro-inflammatory molecule and heme-induced inflammation is involved in the pathology of diverse conditions; such as renal failure, arteriosclerosis, and complications after artificial blood transfusion, peritoneal endometriosis, and heart transplant failure. Heme offers severe toxic effects to kidney, liver, central nervous system and cardiac tissue. Although heme oxygenase is primarily responsible to detoxify free heme but other extra heme oxygenase systems also play a significant role to detoxify heme. A brief account of free heme toxicity and its detoxification systems along with mechanistic details are presented.

Animals↗
PubMed2005

The Wolbachia genome of Brugia malayi: endosymbiont evolution within a human pathogenic nematode.

Complete genome DNA sequence and analysis is presented for Wolbachia, the obligate alpha-proteobacterial endosymbiont required for fertility and survival of the human filarial parasitic nematode Brugia malayi. Although, quantitatively, the genome is even more degraded than those of closely related Rickettsia species, Wolbachia has retained more intact metabolic pathways. The ability to provide riboflavin, flavin adenine dinucleotide, heme, and nucleotides is likely to be Wolbachia's principal contribution to the mutualistic relationship, whereas the host nematode likely supplies amino acids required for Wolbachia growth. Genome comparison of the Wolbachia endosymbiont of B. malayi (wBm) with the Wolbachia endosymbiont of Drosophila melanogaster (wMel) shows that they share similar metabolic trends, although their genomes show a high degree of genome shuffling. In contrast to wMel, wBm contains no prophage and has a reduced level of repeated DNA. Both Wolbachia have lost a considerable number of membrane biogenesis genes that apparently make them unable to synthesize lipid A, the usual component of proteobacterial membranes. However, differences in their peptidoglycan structures may reflect the mutualistic lifestyle of wBm in contrast to the parasitic lifestyle of wMel. The smaller genome size of wBm, relative to wMel, may reflect the loss of genes required for infecting host cells and avoiding host defense systems. Analysis of this first sequenced endosymbiont genome from a filarial nematode provides insight into endosymbiont evolution and additionally provides new potential targets for elimination of cutaneous and lymphatic human filarial disease.

Animals↗
PubMed2005

Differential display-mediated identification of three drought-responsive expressed sequence tags in tea [Camellia sinensis (L.) O. Kuntze].

There is no information on drought-modulated gene(s) in tea [Camellia sinensis (L.) O. Kuntze], a woody and perennial plant of commercial importance. Using differential display of mRNA, three drought-modulated expressed sequence tags (ESTs) were identified. Northern and BLAST analysis revealed that clone dr1 (drought-responsive), induced only by drought but not by ABA, showed significant scores with PR-5 (pathogenesis related) family of PR-protein gene. Another clone dr2, repressed by drought but not by ABA, had nucleotide repeats for polyasparate that are also present in chicken calsequestrin-like mRNA. Clone dr3, responded similarly to clone dr2 but did not show significant homology with the reported genes, hence appears to be novel. Identification of these ESTs is an initial step to clone the full length genes and their promoters.

Adaptation, Physiological↗
PubMed2005

Pulmonary and paradoxical embolism in protein C and S deficient patient.

We document the case of a 67-year-old woman who presented with a history of right upper quadrant anopia, dyspnea, hypoxemia, and a systolic murmur. An intracardiac embolus wedged at a patent foramen ovale was successfully removed by resecting the atrial septum along with a pulmonary embolectomy on cardiopulmonary bypass. We review the literature with specific focus on the pathogenesis and acute treatment options of this life-threatening occurrence.

Aged↗
PubMed2005

Mining nematode genome data for novel drug targets.

Expressed sequence tag projects have currently produced over 400 000 partial gene sequences from more than 30 nematode species and the full genomic sequences of selected nematodes are being determined. In addition, functional analyses in the model nematode Caenorhabditis elegans have addressed the role of almost all genes predicted by the genome sequence. This recent explosion in the amount of available nematode DNA sequences, coupled with new gene function data, provides an unprecedented opportunity to identify pre-validated drug targets through efficient mining of nematode genomic databases. This article describes the various information sources available and strategies that can expedite this process.

Animals↗
PubMed2005

A rare association of major aorto-pulmonary collaterals with right isomerism and totally anomalous pulmonary venous drainage.

A female neonate, born at term, presented with complex cardiac anatomy dominated by right isomerism and infra-diaphragmatic totally anomalous pulmonary venous connection. Surgical repair was performed using circulatory arrest under deep hypothermia. In the postoperative period, the patient could not be weaned off mechanical ventilation, and underwent cardiac catheterization. This revealed major aortopulmonary collateral arteries, which were occluded with coils. We review the literature with specific focus on the occurrence of this unusual combination and its implication in the management during the postoperative period.

Aorta, Thoracic↗
PubMed2005

Antiangiogenic cancer gene therapy by adeno-associated virus 2-mediated stable expression of the soluble FMS-like tyrosine kinase-1 receptor.

Antiangiogenic gene transfer has the potential to be more efficacious than protein-based therapies or pharmacotherapies for the control of solid tumor growth, invasion and metastasis. For a sustained antiangiogenic effect, a vector capable of long-term expression without vector-associated immunity or toxicity is advantageous. The present study evaluated the potential of a recombinant adeno-associated virus-2 (rAAV) encoding the human soluble FMS-like tyrosine kinase receptor 1 (sFlt-1), which functions by both sequestering vascular endothelial growth factor (VEGF) and forming inactive heterodimers with other membrane-spanning VEGF receptors, in vitro and in vivo. Results indicated significant growth inhibitory activity of the transgenic factor in a human umbilical vein endothelial cell proliferation assay in vitro and protection against the growth of an angiogenesis-dependent human ovarian cancer cell line, SKOV3.ip1, xenograft in vivo with increased disease-free survival. Stable expression of the secretory factor and transgene persistence were confirmed by immunohistochemistry and in situ hybridization analyses, respectively. Increased therapeutic effects on both the growth index of the implanted tumor cells and tumor-free survival also correlated with an increasing dose of the vector used. These studies indicate that rAAV-mediated sFlt-1 gene therapy may be a feasible approach for inhibiting tumor angiogenesis, particularly as an adjuvant/therapy.

Angiogenesis Inhibitors↗
PubMed2005

Genomic stability of self-complementary adeno-associated virus 2 during early stages of transduction in mouse muscle in vivo.

Studies have demonstrated that packaging of recombinant adeno-associated virus 2 (rAAV) as self-complementary duplex strand (sc) results in early transgene expression, possibly eliminating rate-limiting second-strand synthesis. In the present study, we evaluated the molecular organization, stability of the sc AAV genome, and transgene expression in the quadriceps muscle of C57BL/6J mice in vivo as compared with single-stranded (ss) AAV. Studies were carried out with rAAV encoding green fluorescent protein (GFP) or human carcinoembryonic antigen (CEA) either as single-stranded or self-complementary duplex strand structures, encapsidated in AAV-2 capsids. Mice were injected with 10(11) particles of the respective viruses and the vector-injected muscles were harvested 1 week, 2 weeks, 3 weeks, or 2 months later. Tissues were processed for total DNA isolation for the analyses of vector genomic configuration and copy number, and for immunostaining of transgene expression. ELISA was done on serum samples to quantitate CEA-specific humoral immune response as a correlate of transgene expression. Results of Southern blot and PCR analyses indicated more disintegration of the monomeric ss AAV DNA in vivo compared with linear sc AAV DNA. The results also indicated efficient conversion of the self-complementary duplex-stranded vector genome to dimer during early time points. As expected, transgene expression was detected at early time points with self-complementary duplex-stranded vector and persisted stably. However, the advantage of higher transgene expression from sc AAV was balanced over time by the single-stranded vector. These data demonstrate that sc AAV provides better stability for transgene structure during the initial stages of transduction and may have better utility in AAV gene therapy in situations, which mandate early transgene expression.

Animals↗
PubMed2005

Sensory gating impairment in development of post-concussive symptoms in mild head injury.

Post-concussive symptoms reported by mild head injury (MHI) patients have been inadequately understood. Post-concussive symptoms reported by patients with MHI have so far been explained in terms of impairment in neurocognitive functions or deficits in modulation of flow of information. There are no studies that have looked into sensory gating impairment in MHI and its relation to post-concussive symptoms. The purpose of the present paper was to investigate the role of sensory gating impairment in post-concussive symptoms in mild head injury patients. Thirty MHI patients were evaluated for their neuropsychological functions, sensory gating deficits, and post-concussive symptoms. Neuropsychological functions were in the domain of attention, executive functions, and learning and memory. Sensory gating was assessed by Structured Interview for Assessing Perceptual Anomalies and post-concussive symptoms were assessed using the Neurobehavioral Rating Scale. Multiple regression method was used to identify predictors for post-concussive symptoms. Post-concussive symptoms were predicted by sensory gating deficits when sensory gating deficit was one of the predictors along with neuropsychological functions. Post-concussive symptoms were predicted by scores of Digit Vigilance and Digit Symbol Substitution Test, when predictors were restricted to neuropsychological functions. Sensory gating deficits were correlated with performance on Digit Symbol Substitution test. Post-concussive symptoms reported by MHI patients are the result of poor modulation of incoming sensory information.

Adolescent↗
PubMed2005

Schizosaccharomyces pombe Swi1, Swi3, and Hsk1 are components of a novel S-phase response pathway to alkylation damage.

The Swi1 and Swi3 proteins are required for mat1 imprinting and mating-type switching in Schizosaccharomyces pombe, where they mediate a pause of leading-strand replication in response to a lagging-strand signal. In addition, Swi1 has been demonstrated to be involved in the checkpoint response to stalled replication forks, as was described for the Saccharomyces cerevisiae homologue Tof1. This study addresses the roles of Swi1 and Swi3 during a replication process perturbed by the presence of template bases alkylated by methyl methanesulfonate (MMS). Both the swi1 and swi3 mutations have additive effects on MMS sensitivity and on the MMS-induced damage checkpoint response when combined with chk1 and cds1, but they are nonadditive with hsk1. Cells with swi1, swi3, or hsk1 mutations are also defective in slowing progression through S phase in response to MMS damage. Moreover, swi1 and swi3 strains show increased levels of genomic instability even in the absence of exogenously induced DNA damage. Chromosome fragmentation, increased levels of single-stranded DNA, increased recombination, and instability of replication forks stalled in the presence of hydroxyurea are observed, consistent with the possibility that the replication process is affected in these mutants. In conclusion, Swi1, Swi3, and Hsk1 act in a novel S-phase checkpoint pathway that contributes to replication fork maintenance and to survival of alkylation damage.

Alkylation↗
PubMed2005

Crystal structure of a peptidoglycan recognition protein (PGRP) in complex with a muramyl tripeptide from Gram-positive bacteria.

Peptidoglycan recognition proteins (PGRPs) are pattern recognition receptors of the innate immune system that bind, and in some cases hydrolyse, bacterial peptidoglycans (PGNs). We determined the crystal structure of the C-terminal PGN-binding domain of human PGRP-Ialpha in complex with a muramyl tripeptide representing the conserved core of lysine-type PGNs. The peptide stem of the ligand is buried at the deep end of a long binding groove, with N-acetylmuramic acid situated in the middle of the groove, whose shallow end could accommodate N-acetylglucosamine. Both peptide and glycan moieties are essential for binding by PGRPs. Conservation of key PGN-contacting residues indicates that all PGRPs employ this basic PGN-binding mode. The structure identifies variable residues that likely mediate discrimination between lysine- and diaminopimelic acid-type PGNs. In addition, we propose a mechanism for PGN hydrolysis by Zn2+-containing catalytic PGRPs.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2005

Chylopericardium following atrial septal defect repair: case report.

Chylopericardium after intrapericardial cardiac operations is extremely rare. We present an unusual case of postoperative chylopericardium with cardiac tamponade following atrial septal defect repair, and we comment on the clinical course and treatment.

Cardiac Surgical Procedures↗