Scavenging potential of hydrophytes for copper removal from textile dye wastewaters.
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Azo Compounds↗
Biomedical subjects
K Sharma
Publications and source records attributed to K Sharma.
Death the Fas way: regulation and pathophysiology of CD95 and its ligand.
Apoptotic cell death mediated by the members of the tumor necrosis factor receptor family is an essential process involved in the regulation of cellular homeostasis during development, differentiation, and pathophysiological conditions. Among the cell death receptors comprising the tumor necrosis factor receptor superfamily, CD95/APO-1 (Fas) is the best characterized. The specific interaction of Fas with its cognate ligand, Fas ligand (FasL), elicits the activation of a death-inducing caspase (cysteine aspartic acid proteases) cascade, occurring in a transcription-independent manner. Caspase activation executes the apoptosis process by cleaving various intracellular substrates, leading to genomic DNA fragmentation, cell membrane blebbing, and the exposure of phagocytosis signaling molecules on the cell surface. Recent studies have shown that the Fas/FasL pathway plays an important role in regulating the life and death of the immune system through activation-induced cell death. In addition, these molecules have been implicated in aging, human immunodeficiency virus infection, drug abuse, stress, and cancer development. In this review, we will focus on the mechanisms that regulate Fas and FasL expression, and how their deregulation leads to diseases.
Aging↗
Regulation of inositol 1,4,5-trisphosphate receptors by transforming growth factor-beta: implications for vascular dysfunction in diabetes.
Diabetes in its early stages is associated with enhanced glomerular blood flow and systemic vasodilation. Possible consequences of enhanced glomerular blood flow are glomerular hypertrophy, increased shear stress, and subsequent glomerulosclerosis. The prosclerotic cytokine, transforming growth factor-beta (TGF-beta), has been well established to play a key role in mesangial matrix accumulation in diabetes; however, its role in regulating vascular tone has not been studied in depth. Earlier studies have demonstrated that vascular smooth muscle cells and mesangial cells pretreated with TGF-beta have impaired calcium mobilization to inositol 1,4,5-trisphosphate (IP3) generating agonists, such as platelet-derived growth factor (PDGF) and Angiotensin I1 (Ang II). We postulated that this action of TGF-beta may be caused by regulation of the key intracellular calcium channel, the inositol 1,4,5-trisphosphate receptor (IP3R). Mesangial and smooth muscle cells primarily contain the types I IP3R and III IP3R isoforms. Short-term exposure of mesangial cells to TGF-beta (15-60 min) leads to phosphorylation of the type I IP3R at specific serine residues. Long-term exposure of mesangial cells to TGF-beta (24 hours) leads to down-regulation of protein levels of both types I and III IP3Rs as assessed by Western blot and confocal analysis. Permeabilization of cells and exposure to IP3 leads to impaired calcium mobilization if cells are pretreated with TGF-beta. As an in vivo correlation, we found that streptozotocin-induced diabetic rats and mice have reduced renal type I IP3R expression. By immunostaining, we found reduction of type I IP3R in glomerular cells and arteriolar smooth muscle cells of the diabetic rat kidney. Treatment of diabetic mice with a neutralizing anti-TGF-beta antibody completely prevents diabetic glomerular hypertrophy. We conclude that the vascular dysfunction of diabetes leading to glomerular hypertrophy is mediated, in part, by TGF-beta-induced regulation of IP3Rs.
Animals↗
Inhibition of type I and III IP(3)Rs by TGF-beta is associated with impaired calcium release in mesangial cells.
Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) mediate cytosolic free calcium concentration ([Ca(2+)](c)) signals in response to a variety of agonists that stimulate mesangial cell contraction and proliferation. In the present study, we demonstrate that mesangial cells express both type I and III IP(3)Rs and that these receptors occupy different cellular locations. Chronic treatment with transforming growth factor-beta1 (TGF-beta1; 10 ng/ml, 24 h) leads to downregulation of both type I and III IP(3)Rs as measured by immunoblot and confocal analysis. TGF-beta1 treatment does not affect IP(3) levels, and downregulation of type I IP(3)R is not due to enhanced degradation of the protein, as the half-life of type I IP(3)R is unchanged in the presence or absence of TGF-beta1. Functional effects of TGF-beta1-induced downregulation of the IP(3)Rs were evaluated by measuring [Ca(2+)](c) changes in response to epidermal growth factor (EGF) in intact cells and sensitivity of [Ca(2+)](c) release to IP(3) in permeabilized cells. TGF-beta1 pretreatment led to a significant decrease of [Ca(2+)](c) release induced by EGF in intact cells and by submaximal IP(3) (400 nm) in permeabilized cells. Total IP(3)-sensitive [Ca(2+)](c) stores were not changed, as assessed by stimulation with maximal doses of IP(3) (10.5 microm) and thapsigargin-mediated calcium release in permeabilized cells. We conclude that prolonged exposure to TGF-beta1 leads to downregulation of both type I and III IP(3)Rs in mesangial cells and this is associated with impaired sensitivity to IP(3).
Animals↗
Utility of serum and urinary transforming growth factor-beta levels as markers of diabetic nephropathy.
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Adult↗
Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice.
Macrophage scavenger receptors have been implicated as key players in the pathogenesis of atherosclerosis. To assess the role of the class B scavenger receptor CD36 in atherogenesis, we crossed a CD36-null strain with the atherogenic apo E-null strain and quantified lesion development. There was a 76.5% decrease in aortic tree lesion area (Western diet) and a 45% decrease in aortic sinus lesion area (normal chow) in the CD36-apo E double-null mice when compared with controls, despite alterations in lipoprotein profiles that often correlate with increased atherogenicity. Macrophages derived from CD36-apo E double-null mice bound and internalized more than 60% less copper-oxidized LDL and LDL modified by monocyte-generated reactive nitrogen species. A similar inhibition of in vitro lipid accumulation and foam cell formation after exposure to these ligands was seen. These results support a major role for CD36 in atherosclerotic lesion development in vivo and suggest that blockade of CD36 can be protective even in more extreme proatherogenic circumstances.
Animals↗
Critical care bug team: a multidisciplinary team approach to reducing ventilator-associated pneumonia.
BACKGROUND: Ventilator-associated pneumonia rates in the medical-surgical intensive care unit first exceeded the 90th percentile in September 1997 and were significantly (P <.05) higher than National Nosocomial Infections Surveillance System pooled mean data. In January 1998, a multidisciplinary "Critical Care Bug Team" was developed by the Infection Control Committee to review 1997 National Nosocomial Infections Surveillance System data for four adult intensive care units in a 583-bed tertiary care hospital. METHODS: Membership included clinical nurse specialists, a dietitian, a pharmacist, a respiratory therapist, an infection control professional, a research specialist, and a physician adviser. Having the team report directly to the hospital's Infection Control and Adult Critical Care Committees maximized support for recommendations and provided a direct link from patient care to hospital administration. By identifying issues, evaluating patient care processes, performing literature searches, and monitoring compliance, the team implemented numerous interventions, including policy and procedure changes, purchasing of equipment, and implementation of various education tools. RESULTS: Each member of the Critical Care Bug Team contributed to a synergized effort that may have produced the desired outcome of decreasing ventilator-associated pneumonia rates. Except for August 1998, ventilator-associated pneumonia rates have been below the 75th percentile since May 1998. CONCLUSION: This study illustrates the effectiveness of a multidisciplinary team approach devised to reduce and stabilize ventilator-associated pneumonia rates in a medical-surgical intensive care unit.
Adult↗
Cytodiagnosis of tuberculosis of the skull by fine needle aspiration cytology: a case report.
Close to one-third of the world's population is believed to be infected with tuberculosis, with the vast majority being in the developing world. However, even in the developed world, the incidence of this disease has been steadily increasing. Tuberculosis is very common in the Indian subcontinent, but at the same time tuberculous infection of the skull is rare and very few cases have been reported. We report a child who presented with a swelling of the frontal bone of the skull. Fine needle aspiration yielded the cytological diagnosis of tuberculosis on the basis of a necrotising granulomatous process with acid-fast bacilli detected on Ziehl Neelsen stain. This procedure obviated the need for an operative procedure and the patient responded to anti-tuberculous therapy. As the incidence of tuberculous infection is on the increase, both in the developed and in the developing world, the importance of diagnosis by newer non-invasive techniques like fine needle aspiration cytology cannot be overemphasized. To the best of our knowledge, this is the first report of its kind in the world literature.
Biopsy, Needle↗
SEMA3A regulates developing sensory projections in the chicken spinal cord.
The present study explores the role of SEMA3A (collapsin-1) in the temporal and spatial regulation of developing sensory projections in the chick spinal cord. During development, SEMA3A mRNA (SEMA3A) is first expressed throughout the spinal gray matter, but disappears from the dorsal region when small caliber (trkA(+)) sensory axon collaterals first grow into the dorsal horn. In explant cultures of spinal cord segments with attached sensory ganglia, the spatial extent of SEMA3A expression varied in different explants, but in each case the growth of trkA(+) sensory collaterals was largely excluded from areas of SEMA3A expression. To test if SEMA3A had a direct effect on sensory axon growth, we injected recombinant protein into the explants before placing them in culture. Increased levels of SEMA3A substantially reduced the ingrowth of trkA(+) axons, whereas trkC(+) axon collaterals were not affected. Consistent with the insensitivity of trkC(+) collaterals to SEMA3A, these collaterals did not express neuropilin-1, a receptor for SEMA3A. The inhibitory effects of SEMA3A on trkA(+) axons within the spinal cord suggests that the fall in SEMA3A expression in the dorsal horn may contribute to the initiation of growth of these axons into gray matter. In addition, the observation that trkA(+) axons frequently grew close to but rarely over areas of SEMA3A expression suggests that semaphorin may act principally as a short-range guidance cue within the spinal cord.
Afferent Pathways↗
Severe pulmonary hypertension associated with COPD.
Pulmonary hypertension can be associated with chronic obstructive pulmonary disease (COPD). Mild to moderate elevations in pulmonary artery pressures are commonly reported. Previous studies included patients initially diagnosed with COPD and subsequently evaluated for pulmonary hypertension. The occurrence of COPD in patients being evaluated for pulmonary hypertension has not been reported. We performed a retrospective chart review of approximately 600 patients evaluated in a large tertiary care pulmonary hypertension clinic. Subjects were included if they were older than 40 years, had no other secondary causes of pulmonary hypertension and had evidence of COPD by pulmonary function studies or thoracic computed tomography. Criteria was met by five subjects (3 males and 2 females, mean age = 65 years) all of whom were past smokers. The average mean pulmonary artery pressure (MPAP) was 59 +/- 7 mm Hg. The mean pulmonary vascular resistance (PVR) was 15.2 +/- 5 mmHg/liter/min. Only one patient had a fall in MPAP of more than 10% and a greater than 30% decline in PVR following infusion of adenosine to test vasodilator responsiveness. COPD is rare in a population referred primarily for evaluation of pulmonary hypertension. Although infrequent, severe pulmonary hypertension may be associated with COPD.
Adenosine↗
Stress induced neuron degeneration and protective effects of Semecarpus anacardium Linn. and Withania somnifera Dunn. in hippocampus of albino rats: an ultrastructural study.
Effects of herbal formulations were studied on hippocampal neuron cell bodies. Study was carried out in adult Swiss albino rats. Experimental rats (E) were divided into three groups. Group E1 rats were given immobilization stress for 14 hr/day for 30 days. Rats in E2 and E3 group were given daily single dose (40 mg/kg/body wt.) of alcoholic extract of S. anacardium and W. somnifera. After 1 hr giving the plant extract, the rats were subjected to stress. Treatment continued for 14 hr for 30 days. Control rats were kept in complete nonstress condition. Ultrastructural characteristics of neuron cell bodies in hippocampal sublayer (CA1-CA4 and Dg) was studied in rats of E1, E2 and E3 groups and compared with control. Results of the present study demonstrated, that both CA2 and Dg, 85% of neuron cell bodies exhibited degenerating characteristics, (which includes karyorrhexis, membrane blebbing, chromatin condensation, chromatin fragmentation and intracellular spacing). Interestingly, after the treatment with S. ancardium cells demonstrating degenerating characteristics was significantly reduced (80%) as compared to treatment with W. somnifera. Study suggests that probably both the herbal drugs have cytoprotective properties.
Animals↗
Induction by adozelesin and hydroxyurea of origin recognition complex-dependent DNA damage and DNA replication checkpoints in Saccharomyces cerevisiae.
DNA damaging agents induce a conserved intra-S-phase checkpoint that inhibits DNA replication in eukaryotic cells. To better understand this checkpoint and its role in determining the efficacy of antitumor drugs that damage DNA, we examined the effects of adozelesin, a DNA-alkylating antitumor agent that has a profound inhibitory effect on initiation of DNA replication in mammals, on the replication of Saccharomyces cerevisiae chromosomes. Adozelesin inhibited initiation of S. cerevisiae DNA replication by inducing an intra-S-phase DNA damage checkpoint. This inhibitory effect was abrogated in orc2-1 cells containing a temperature-sensitive mutation in a component of the origin recognition complex (ORC) that also causes a defect in initiation. The orc2-1 mutation also caused a defect in a checkpoint that regulates the activation of origins in late S phase in cells treated with hydroxyurea. Defects in both initiation and checkpoint regulation in the orc2-1 strain were suppressed by deletion of a gene encoding a putative acetyltransferase, SAS2. Adozelesin also induced a cellular response that requires a function of ORC in G(1). A similar G(1)-specific response in mammals may contribute to the cytotoxic and antitumor properties of this and other DNA-damaging drugs.
Antineoplastic Agents, Alkylating↗
Amantadine-induced peripheral neuropathy.
We report a 48-year-old woman with a 17-year history of PD who developed a peripheral sensory-motor neuropathy secondary to chronic administration (8 years) of amantadine. Discontinuation of amantadine resulted in resolution of trophic skin ulcers, paresthesias, and distal weakness. Amantadine may be hazardous to patients with severe and chronic livedo reticularis.
Amantadine↗
Regulation of acidification and apoptosis by SHP-1 and Bcl-2.
Recruitment of the SH2 domain containing cytoplasmic protein-tyrosine phosphatase SHP-1 to the membrane by somatostatin (SST) is an early event in its antiproliferative signaling that induces intracellular acidification-dependent apoptosis in breast cancer cells. Fas ligation also induces acidification-dependent apoptosis in a manner requiring the presence of SHP-1 at the membrane. Moreover, we have recently reported that SHP-1 is required not only for acidification, but also for apoptotic events that follow acidification (Thangaraju, M., Sharma, K., Liu, D., Shen, S. H., and Srikant, C. B. (1999) Cancer Res. 59, 1649-1654). Here we show that ectopically expressed SHP-1 was predominantly membrane-associated and amplified the cytotoxic signaling initiated upon SST receptor activation and Fas ligation. The catalytically inactive mutant of SHP-1 (SHP-1C455S) abolished the ability of the SST agonists to signal apoptosis by preventing the recruitment of wild type SHP-1 to the membrane. Overexpression of the anti-apoptotic protein Bcl-2 in MCF-7 cells inhibited SST-induced apoptosis upstream of acidification by inhibiting p53-dependent induction of Bax as well as by raising the resting pH(i) and attenuating SST-induced decrease in pH(i). By contrast, Bcl-2 failed to prevent apoptosis triggered by direct acidification. These data demonstrate that (i) membrane-associated SHP-1 is required for receptor-mediated cytotoxic signaling that causes intracellular acidification and apoptosis, and (ii) Bcl-2 acts distal to SHP-1 and p53 to prevent SST-induced acidification but cannot inhibit the apoptotic events that ensue intracellular acidification.
Amiloride↗
Activation of dormant origins of DNA replication in budding yeast.
Eukaryotic genomes often contain more potential replication origins than are actually used during S phase. The molecular mechanisms that prevent some origins from firing are unknown. Here we show that dormant replication origins on the left arm of budding yeast chromosome III become activated when both passive replication through them is prevented and the Mec1/Rad53 checkpoint that blocks late-origin firing is inactivated. Under these conditions, dormant origins fire very late relative to other active origins. These experiments show that some dormant replication origins are competent to fire during S phase and that passage of a replication fork through such origins can inactivate them.
Cell Cycle↗
A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism.
A null mutation in the scavenger receptor gene CD36 was created in mice by targeted homologous recombination. These mice produced no detectable CD36 protein, were viable, and bred normally. A significant decrease in binding and uptake of oxidized low density lipoprotein was observed in peritoneal macrophages of null mice as compared with those from control mice. CD36 null animals had a significant increase in fasting levels of cholesterol, nonesterified free fatty acids, and triacylglycerol. The increase in cholesterol was mainly within the high density lipoprotein fraction, while the increase in triacylglycerol was within the very low density lipoprotein fraction. Null animals had lower fasting serum glucose levels when compared with wild type controls. Uptake of 3H-labeled oleate was significantly reduced in adipocytes from null mice. However, the decrease was limited to the low ratios of fatty acid:bovine serum albumin, suggesting that CD36 was necessary for the high affinity component of the uptake process. The data provide evidence for a functional role for CD36 in lipoprotein/fatty acid metabolism that was previously underappreciated.
Adipocytes↗
Interdependent regulation of intracellular acidification and SHP-1 in apoptosis.
The G protein-coupled receptor agonist somatostatin (SST)-induces apoptosis in MCF-7 human breast cancer cells. This is associated with induction of wild-type p53, Bax, and an acidic endonuclease. We have shown recently that its cytotoxic signaling is mediated via membrane-associated SHP-1 and is dependent on decrease in intracellular pH (pHi) to 6.5. Here we investigated the relationship between intracellular acidification and SHP-1 in cytotoxic signaling. Clamping of pHi at 7.25 by the proton-ionophore nigericin abolished SST-signaled apoptosis without affecting its ability to regulate SHP-1, p53, and Bax. Apoptosis could be induced by nigericin clamping of pHi to 6.5. Such acidification-induced apoptosis was not observed at pHi <6.0 or >6.7. pHi-dependent apoptosis was associated with the translocation of SHP-1 to the membrane, enhanced in cells overexpressing SHP-1, and was abolished by its inactive mutant SHP-1C455S. Acidification caused by inhibition of Na+/H+ exchanger and H+ ATPase (pHi = 6.55 and 6.65, respectively) also triggered apoptosis. The effect of concurrent inhibition of Na+/H+ exchanger and H(+)-ATPase on pHi and apoptosis was comparable with that of SST. Acidification-induced, SHP-1-dependent apoptosis occurred in breast cancer cell lines in which SST was cytotoxic (MCF-7 and T47D) or not (MDA-MB-231). We conclude that: (a) SST-induced SHP-1-dependent acidification occurs subsequent to or independent of the induction of p53 and Bax; (b) SST-induced intracellular acidification may arise due to inhibition of Na+/H+ exchanger and H(+)-ATPase; and (c) SHP-1 is necessary not only for agonist-induced acidification but also for the execution of acidification-dependent apoptosis. We suggest that combined targeting of SHP-1 and intracellular acidification may lead to a novel strategy of anticancer therapy bypassing the need for receptor-mediated signaling.
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
Comparison of motor conduction abnormalities in lumbosacral radiculopathy and axonal polyneuropathy.
We compared the frequencies and types of motor conduction abnormalities found in peroneal and tibial nerves of patients with either L5/S1 radiculopathies (n = 47) or axonal polyneuropathies (n = 49). In axonal neuropathies, compound muscle action potentials (CMAPs) were more likely to be either unobtainable or, if present, of low amplitude, prolonged in distal latency or both. F responses were more often absent, impersistent, or prolonged in minimal latency. In contrast, CMAPs in lumbosacral radiculopathies were more likely to be normal in both amplitude and distal latency. The most frequent F-response abnormality in radiculopathies was a prolonged maximum-minimum latency range rather than abnormalities of minimal latency or persistence. Logistic regression analysis demonstrated that different patterns of motor conduction abnormalities result from lumbosacral radiculopathy and distal axonopathies. The model was able to correctly classify disease state in 76% of subjects with a sensitivity of 74% and specificity of 80%.
Adult↗