Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Addition of a 5' cap to RNA polymerase II transcripts, the first step of pre-mRNA processing in eukaryotes from yeasts to mammals, is catalyzed by the sequential action of RNA triphosphatase, guanylyltransferase, and (guanine-N-7)methyltransferase. The effects of knockdown of these capping enzymes in mammalian cells were investigated using T7 RNA polymerase-synthesized small interfering RNA and also a lentivirus-based inducible, short hairpin RNA system. Decreasing either guanylyltransferase or methyltransferase resulted in caspase-3 activation and elevated terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) staining characteristic of apoptosis. Induction of apoptosis was independent of p53 tumor suppressor but dependent on BAK or BAX. In addition, levels of the BH3 family member Bim increased, while Mcl-1 and Bik levels remained unchanged during apoptosis. In contrast to capping enzyme knockdown, apoptosis induced by cycloheximide inhibition of protein synthesis required BAK but not BAX. Both Bim and Mcl-1 levels decreased in cycloheximide-induced apoptosis while Bik levels were unchanged, suggesting that apoptosis in siRNA-treated cells is not a direct consequence of loss of mRNA translation. siRNA-treated BAK(-/-) BAX(-/-) double-knockout mouse embryonic fibroblasts failed to activate capase-3 or increase TUNEL staining but instead exhibited autophagy, as demonstrated by proteolytic processing of microtubule-associated protein 1 light chain 3 (LC3) and translocation of transfected green fluorescent protein-LC3 from the nucleus to punctate cytoplasmic structures.
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PMID:Apoptosis and autophagy induction in mammalian cells by small interfering RNA knockdown of mRNA capping enzymes. 1867 51

Several research teams have proposed that shrinkage and swelling in cells undergoing apoptosis and oncosis are not only the earliest morphological markers of the two modes of cell death but are also obligatory steps in the development of the death machinery. We examined this hypothesis as well as the role of monovalent cations as major intracellular osmolytes using vascular smooth muscle cells (VSMC) from the rat aorta and C7-MDCK cells derived from the Madin-Darby canine kidney. 48-hr inhibition of the Na(+)-K+ pump with ouabain did not affect VSMC survival and delayed serum deprivation-induced apoptosis at a step upstream of caspase-3 via elevation of the [Na+]i/[K+]i ratio and the expression of Na+ i-sensitive antiapoptotic genes including mortalin. Transient and modest (15-20%) shrinkage observed in serum-deprived VSMC did not contribute to triggering of the apoptotic machinery. In contrast to VSMC, ouabain led to oncosis of C7-MDCK cells, indicated by swelling and resistance to the pan-caspase inhibitor z-VAD.fmk. In these cells, the death signal was mediated by interaction of ouabain with the Na(+)-K(+)-ATPase alpha-subunit but was independent of the inhibition of Na(+)-K+ pump-mediated ion fluxes and elevation of the [Na+]i/[K+]i ratio.
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PMID:Apoptosis vs. oncosis: role of cell volume and intracellular monovalent cations. 1872 43

Diets high in soy are neuroprotective in experimental stroke. This protective effect is hypothesized to be mediated by phytoestrogens contained in soy, because some of these compounds have neuroprotective effects in in vitro models of cell death. We tested the ability of the soy phytoestrogens genistein, daidzein, and the daidzein metabolite equol to protect embryonic rat primary cortical neurons from ischemic-like injury in vitro at doses typical of circulating concentrations in human populations (0.1-1 microM). All three phytoestrogens inhibited lactate dehydrogenase (LDH) release from cells exposed to glutamate toxicity or the calcium-ATPase inhibitor, thapsigargin. In cells exposed to hypoxia or oxygen-glucose deprivation (OGD), pretreatment with the phytoestrogens inhibited cell death in an estrogen receptor (ER) dependent manner. Although OGD results in multiple modes of cell death, examination of alpha-spectrin cleavage and caspase-3 activation revealed that the phytoestrogens were able to inhibit apoptotic cell death in this model. In addition, blockade of phosphoinositide 3-kinase prevented the protective effects of genistein and daidzein, and blockade of mitogen-activated protein kinase prevented genistein-dependent neuroprotection. These results suggest that pretreatment with dietary levels of soy phytoestrogens can mimic neuroprotective effects observed with estrogen and appear to use the same ER-kinase pathways to inhibit apoptotic cell death.
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PMID:Soy phytoestrogens are neuroprotective against stroke-like injury in vitro. 1897 94

The green sturgeon is a long-lived, highly migratory species with populations that are currently listed as threatened. Their anadromous life history requires that they make osmo- and ionoregulatory adjustments in order to maintain a consistent internal milieu as they move between fresh-, brackish-, and seawater. We acclimated juvenile green sturgeon (121 +/- 10.0 g) to 0 (freshwater; FW), 15 (estuarine; EST), and 24 g/l (SF Bay water; BAY) at 18 degrees C for 2 weeks and measured the physiological and biochemical responses with respect to osmo- and ionoregulatory mechanisms. Plasma osmolality in EST- and BAY-acclimated sturgeon was elevated relative to FW-acclimated sturgeon (P < 0.01), but there was no difference in muscle water content or abundance of stress proteins. Branchial Na(+), K(+)-ATPase (NKA) activity was also unchanged, but abundance within mitochondrion-rich cells (MRC) was greater in BAY-acclimated sturgeon (P < 0.01). FW-acclimated sturgeon had the greatest NKA abundance when assessed at the level of the entire tissue (P < 0.01), but there were no differences in v-type H(+)ATPase (VHA) activity or abundance between salinities. The Na(+), K(+), 2Cl(-) co-transporter (NKCC) was present in FW-acclimated sturgeon gills, but the overall abundance was lower relative to sturgeon in EST or BAY water (P < 0.01) where this enzyme is crucial to hypoosmoregulation. Branchial caspase 3/7 activity was significantly affected by acclimation salinity (P < 0.05) where the overall trend was for activity to increase with salinity as has been commonly observed in teleosts. Sturgeon of this age/size class were able to survive and acclimate following a salinity transfer with minimal signs of osmotic stress. The presence of the NKCC in FW-acclimated sturgeon may indicate the development of SW-readiness at this age/size.
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PMID:Osmo- and ionoregulatory responses of green sturgeon (Acipenser medirostris) to salinity acclimation. 1906 9

Accumulating evidence suggests that endoplasmic reticulum (ER) stress by mechanisms that include ER Ca(2+) depletion via NO-dependent down-regulation of sarcoendoplasmic reticulum Ca(2+) ATPase 2b (SERCA2b) contributes to beta-cell death in type 1 diabetes. To clarify whether the molecular pathways elicited by NO and ER Ca(2+) depletion differ, we here compare the direct effects of NO, in the form of the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), with the effects of SERCA2 inhibitor thapsigargin (TG) on MAPK, nuclear factor kappaB (NFkappaB), Bcl-2 proteins, ER stress, and apoptosis. Exposure of INS-1E cells to TG or SNAP caused caspase-3 cleavage and apoptosis. Both TG and SNAP induced activation of the proapoptotic transcription factor CCAAT/enhancer-binding protein homologous protein (CHOP). However, other classical ER stress-induced markers such as up-regulation of ER chaperone Bip and alternative splicing of the transcription factor Xbp-1 were exclusively activated by TG. TG exposure caused NFkappaB activation, as assessed by IkappaB degradation and NFkappaB DNA binding. Inhibition of NFkappaB or the Bcl-2 family member Bax pathways protected beta-cells against TG- but not SNAP-induced beta-cell death. These data suggest that NO generation and direct SERCA2 inhibition cause two quantitative and qualitative different forms of ER stress. In contrast to NO, direct ER stress induced by SERCA inhibition causes activation of ER stress signaling pathways and elicit proapoptotic signaling via NFkappaB and Bax.
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PMID:Inhibition of nuclear factor-kappaB or Bax prevents endoplasmic reticulum stress- but not nitric oxide-mediated apoptosis in INS-1E cells. 1955 21

Apoptotic effects of protocatechuic acid (PCA) at 1, 2, 4, 8 micromol/L on human breast cancer MCF7 cell, lung cancer A549 cell, HepG2 cell, cervix HeLa cell, and prostate cancer LNCaP cell were examined. Results showed that PCA concentration-dependently decreased cell viability, increased lactate dehydrogenase leakage, enhanced DNA fragmentation, reduced mitochondrial membrane potential, and lowered Na(+)-K(+)-ATPase activity for these cancer cells (P < 0.05). PCA also concentration-dependently elevated caspase-3 activity in five cancer cells (P < 0.05), but this agent at 2-8 micromol/L significantly increased caspase-8 activity (P < 0.05). PCA concentration-dependently decreased intercellular adhesion molecule level in test cancer cells (P < 0.05) but significantly inhibited cell adhesion at 2-8 micromol/L (P < 0.05). PCA also concentration-dependently lowered the levels of interleukin (IL)-6 and IL-8 in five cancer cells (P < 0.05), but this agent at 2-8 micromol/L significantly suppressed vascular endothelial growth factor production (P < 0.05). These findings suggest that PCA is a potent anticancer agent to cause apoptosis or retard invasion and metastasis in these five cancer cells.
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PMID:Apoptotic effects of protocatechuic acid in human breast, lung, liver, cervix, and prostate cancer cells: potential mechanisms of action. 1960 77

Diabetic nephropathy is a common cause for end-stage renal disease. Present study investigated the beneficial role of arjunolic acid (AA) against streptozotocin (STZ) induced diabetic nephropathy in rats. Diabetic renal injury was associated with increased kidney weight to body weight ratio, glomerular area and volume, blood glucose (hyperglycemia), urea nitrogen and serum creatinine. This nephro pathophysiology increased the productions of reactive oxygen species (ROS) and reactive nitrogen species (RNS), enhanced lipid peroxidation, protein carbonylation and decreased intracellular antioxidant defense in the kidney tissue. In addition, hyperglycemia activates polyol pathway by increasing aldose reductase (AR) with a concomitant reduction in Na+-K+-ATPase activity. Investigating the oxidative stress responsive signaling cascades, we found the activation of PKCdelta, PKCvarepsilon, MAPKs and NF-kappaB (p65) in the renal tissue of the diabetic animals. Furthermore, hyperglycemia disturbed the equilibrium between the pro and anti-apoptotic members of Bcl-2 family of proteins as well as reduced mitochondrial membrane potential, elevated the concentration of cytosolic cytochrome C and caspase-3 activity. Treatment of AA effectively ameliorated diabetic renal dysfunctions by reducing oxidative as well as nitrosative stress and deactivating the polyol pathways. Histological studies also support the experimental findings. Results suggest that AA might act as a beneficial agent against the renal dysfunctions developed in STZ-induced diabetes.
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PMID:Prophylactic role of arjunolic acid in response to streptozotocin mediated diabetic renal injury: activation of polyol pathway and oxidative stress responsive signaling cascades. 1968 44

Glucocorticoid (GC) are stress hormones, whose cytotoxicity has been shown in various cells. The imbalance of calcium homeostasis is believed to be associated with the dexamethasone (DEX, a synthetic GC)-induced apoptosis. Here we show that in C2C12 myoblasts, DEX markedly up-regulated the expression of inositol 1,4,5-triphosphate receptor 1 (IP3R1) and down-regulated the expression of SERCA1 (sarcoendoplasmic reticulum Ca(2+)-ATPase 1), leading to calcium overload. Furthermore, the imbalance of calcium homeostasis increased the level of BAX, decreased the level of Bcl-2, induced cytochrome c release and activated caspase-3, leading to intranucleosomal DNA fragmentation and plasma membrane damage, eventually resulting in cell apoptosis. Taken together, by using C2C12 myoblasts as a model system, we demonstrated a novel mechanism for stress hormone-induced apoptosis: it is dependent on the induction of intracellular calcium overload via the alterations of IP3R1 and SERCA1 expressions.
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PMID:Induction of Ca2+ signal mediated apoptosis and alteration of IP3R1 and SERCA1 expression levels by stress hormone in differentiating C2C12 myoblasts. 1972 25

Hexachlorocyclohexane (HCH) is a highly recalcitrant organochlorine insecticide known for its chronic toxicity. In spite of many isolated studies a clear mechanism of cytotoxic action of HCH and the structure-toxicity relationship of its isomers is not well understood. We have investigated the toxicity of HCH isomers and its mechanism in Ehrlich Ascites tumor (EAT) cells. Our studies show differential cytotoxicity of HCH isomers (alpha, beta, gamma, and delta), delta isomer being most toxic and beta the least. HCH-induced cell death was associated with induction of reactive oxygen species (ROS) formation, lipid peroxidation (LPO), and depletion of glutathione (GSH). The increase in oxidative stress was linked with increased NAD(P)H oxidase activity. HCH inhibited Na(+),K(+)-ATPase, which could be involved in raising the intracellular calcium and increased Ca(2+),Mg(2+)-ATPase activity. HCH lead to apoptotic as well as necrotic cell death as it was marked by increased caspase-3 activity and lactate dehydrogenase (LDH) leakage, respectively. Based on the results it is concluded that the HCH isomers inflict differential cytotoxicity which was highest by delta and lowest by beta. Further, this study demonstrates for the first time a clear link between Na(+),K(+)-ATPase, i[Ca(2+)] level, and oxidative stress in HCH-induced cytotoxicity.
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PMID:Stereospecificity in the cytotoxic action of hexachlorocyclohexane isomers. 1981 41

Several studies have indicated the involvement of oxidative stress in the development of diabetic neuropathy. In the present study, we have targeted oxidative stress mediated nerve damage in diabetic neuropathy using N-acetyl-l-cysteine (NAC), a potent antioxidant. After 8 weeks, streptozotocin-induced diabetic rats developed neuropathy which was evident from decreased tail-flick latency (thermal hyperalgesia). This was accompanied by decreased motor coordination as assessed by performance on rota-rod treadmill. Na(+) K(+) ATPase, a biochemical marker of development of diabetic neuropathy, was significantly inhibited in sciatic nerve of diabetic animals. NAC treatment at a daily dose between 1.4 and 1.5 g/kg body weight to diabetic animals for 7 weeks in drinking water ameliorated hyperalgesia, improved motor coordination and reversed reduction in Na(+) K(+) ATPase activity. There was an increase in lipid peroxidation in sciatic nerve of diabetic animals along with decrease in phospholipid levels, while NAC treatment attenuated lipid peroxidation and restored phospholipids to control levels. This was associated with decrease in glutathione and protein thiols. The activities of antioxidant enzymes; superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and glutathione-S-transferase were reduced in sciatic nerve of diabetic animals. Cytochrome c release and active caspase 3 were markedly increased in nerve from diabetic animals suggesting activation of apoptotic pathway. NAC treatment significantly ameliorated decrease in antioxidant defense and prevented cytochrome c release and caspase 3 activation. Electron microscopy revealed demyelination, Wallerian degeneration and onion-bulb formation in sciatic nerve of diabetic rats. NAC on the other hand was able to reverse structural deficits observed in sciatic nerve of diabetic rats. Our results clearly demonstrate protective effect of NAC is mediated through attenuation of oxidative stress and apoptosis, and suggest therapeutic potential of NAC in attenuation of diabetic neuropathy.
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PMID:N-acetylcysteine inhibits hyperglycemia-induced oxidative stress and apoptosis markers in diabetic neuropathy. 1984 Feb 21


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