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:3.4.22.56 (caspase-3)
35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thioredoxin system, composed of thioredoxin reductase (TrxR), thioredoxin (Trx), and NADPH (nicotinamide adenine dinucleotide phosphate), plays a central role in regulating cellular redox homeostasis and signaling pathways. TrxR, overexpressed in many tumor cells and contributing to drug resistance, has emerged as a new target for anticancer drugs. Gold complexes have been validated as potent TrxR inhibitors in vitro in the nanomolar range. In order to obtain potent and selective TrxR inhibitors, we have synthesized a series of linear, 'auranofin-like' gold(I) complexes all containing the [Au(PEt(3))](+) synthon and the ligands: Cl(-), Br(-), cyanate, thiocyanate, ethylxanthate, diethyldithiocarbamate and thiourea. Phosphine gold(I) complexes efficiently inhibited cytosolic and mitochondrial TrxR at concentrations that did not affect the two related oxidoreductases glutathione reductase (GR) and glutathione peroxidase (GPx). The inhibitory effect of the redox proteins was also observed intracellularly in cancer cells pretreated with gold(I) complexes. Gold(I) compounds were found to induce antiproliferative effects towards several human cancer cells some of which endowed with cisplatin or multidrug resistance. In addition, they were able to activate caspase-3 and induce apoptosis observed as nucleosome formation and sub-G1 cell accumulation. The complexes with thiocyanate and xanthate ligands were particularly effective in inhibiting thioredoxin reductase and inducing apoptosis. Pharmacodynamic studies in human ovarian cancer cells allowed for the correlation of intracellular drug accumulation with TrxR inhibition that leads to the induction of apoptosis via the mitochondrial pathway.
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PMID:Cancer cell death induced by phosphine gold(I) compounds targeting thioredoxin reductase. 1966 52

To investigate the antioxidative effects of ginsenosides [protopanaxadiol derivatives (PD):protopanaxatriol derivatives (PT) = 1:1] from the roots of Korean ginseng, cell viability, malondialdehyde (MDA) production, antioxidant enzyme activities, and expressions of apoptosis were analyzed after pretreatment of human hepatoma HepG2 cells with H(2)O(2). Cell death was increased through H(2)O(2) treatment dose dependently, and a dose of ginseng extract (PD:PT = 1:1) of 18.6 microg/mL was enough to derive it in reverse. MDA production was reduced through the administration of ginseng extracts even with more intensive H(2)O(2) treatments. Through the use of even low levels of ginseng extract (e.g., 1.86 microg/mL), catalase (CAT) activity was easily reduced from the plateau induced by H(2)O(2). The glutathione peroxidase activity was no better than that of CAT. We assume that ginseng extract acts as an antioxidant even when effective levels of ginseng differ. A ginseng extract dose of 18.6 microg/mL increased the apoptotic expression of oxidative stressed signals, such as c-Jun-N-terminal kinase and stress-activated protein kinase expressions, and mitochondrial cytochrome c released caspase-3 activation; however, these expressions changed with higher doses of ginseng.
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PMID:Antioxidant and apoptotic effects of korean white ginseng extracted with the same ratio of protopanaxadiol and protopanaxatriol saponins in human hepatoma HepG2 cells. 1972 59

Alzheimer's disease is the most common form of dementia. Amyloid-beta protein is considered as a key factor of pathogenesis of Alzheimer's disease. l-3-n-butylphthalide (L-NBP), an anti-cerebral ischemia drug, has been shown to have therapeutic effects in vascular dementia animal models. In the present study, we investigated the potential of L-NBP to protect against cognitive impairment, oxidative damage and neuropathological changes induced by intracerebroventricular infusion of amyloid-beta peptide in rats. Daily treatments of 10 and 30 mg/kg L-NBP significantly improved spatial learning deficits and attenuated working memory deficits in Morris water maze task. L-NBP partially reversed the reduction of glutathione peroxidase activities and decreased malondialdehyde levels in the cortex and hippocampus. Furthermore, L-NBP markedly inhibited amyloid-beta-induced neuronal apoptosis, possibly by blocking caspase-3 activation. In addition, L-NBP reduced activation of glycogen synthase kinase-3beta and tau protein phosphorylation. Our results demonstrate that L-NBP protects against amyloid-beta-induced neurodegeneration and cognitive decline in a rat model, suggesting that it may have potential as a therapy for Alzheimer's disease.
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PMID:L-3-n-butylphthalide improves cognitive impairment induced by intracerebroventricular infusion of amyloid-beta peptide in rats. 1973 53

The protective effect of a diterpenoid acanthoic acid (AA) isolated from Acanthopanax koreanum Nakai was investigated in acetaminophen (APAP)-induced hepatic toxicity. Drug-induced hepatotoxicity induced by an intraperitoneal (i.p.) injection of 300mg/kg (sub-lethal dose) of APAP. Pretreatment with AA (50 and 100mg/kg) orally 2h before the APAP administration attenuated the APAP-induced acute increase in serum aspartate aminotransferase (AST), and alanine aminotransferase (ALT) activites, replenished the depleted hepatic glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activities, decreased malondialdehyde (MDA) level and considerably reduced the histopathological alterations in a manner similar to silymarin (Sily). Immunohistochemical analyses also demonstrated that AA could reduce the appearance of necrosis regions as well as caspase-3 and hypoxia inducible factor-1alpha (HIF-1alpha) expression in liver tissue. Our results indicated that AA protected liver tissue from the oxidative stress elicites by APAP-induced liver damage and suggestes that the hepatic protection mechanism of AA would relate to antioxidation and hypoxia factor on APAP-induced hepatotoxicity.
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PMID:Acanthoic acid, a diterpene in Acanthopanax koreanum, protects acetaminophen-induced hepatic toxicity in mice. 1983 21

Nerve growth factor differentiated PC12 cells were used to examine the antioxidative and anti-inflammatory effects of astaxanthin (AX) and canthaxanthin (CX). PC12 cells were pretreated with AX or CX at 10 or 20 muM, and followed by exposure of hydrogen peroxide (H(2)O(2)) or 1-methyl-4-phenylpyridinium ion (MPP(+)) to induce cell injury. H(2)O(2) or MPP(+) treatment significantly decreased cell viability, increased lactate dehydrogenase (LDH) release, enhanced DNA fragmentation, and lowered mitochondrial membrane potential (MMP) (P < 0.05). The pretreatments from AX or CX concentration-dependently alleviated H(2)O(2) or MPP(+)-induced cell death, LDH release, DNA fragmentation, and MMP reduction (P < 0.05). Either H(2)O(2) or MPP(+) treatment significantly increased malonyldialdehyde (MDA) and reactive oxygen species (ROS) formations, decreased glutathione content, and lowered glutathione peroxidase (GPX) and catalase activities (P < 0.05). The pretreatments from AX or CX significantly retained GPX and catalase activities, and decreased MDA and ROS formations (P < 0.05). H(2)O(2) or MPP(+) treatment significantly decreased Na(+)-K(+)-ATPase activity, elevated caspase-3 activity and levels of interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-alpha (P < 0.05); and the pretreatments from these agents significantly restored Na(+)-K(+)-ATPase activity, suppressed caspase-3 activity and release of IL-1, IL-6, and TNF-alpha (P < 0.05). Based on the observed antioxidative and anti-inflammatory protection from AX and CX, these 2 compounds were potent agents against neurodegenerative disorder.
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PMID:Antioxidative and anti-inflammatory neuroprotective effects of astaxanthin and canthaxanthin in nerve growth factor differentiated PC12 cells. 1989 74

Oxidative stress has been considered as the possible mechanism of renal ischemia/reperfusion injury. L-carnitine is an endogenous mitochondrial membrane compound and could effectively protect ischemia-reperfusion injury in the kidney. To elucidate the nephroprotective effects of L-carnitine, here we assessed the effect of L-carnitine on hydrogen peroxide (H(2)O(2))-mediated oxidative stress in the human proximal tubule epithelial cell line, HK-2 cells. The results showed that pretreatment with L-carnitine 12h inhibited H(2)O(2)-induced cell viability loss, intracellular reactive oxygen species generation and lipid peroxidation in a concentration-dependent manner. Also L-carnitine promoted endogenous antioxidant defense components including total antioxidative capacity, glutathione peroxidase, catalase and superoxide dismutase. In parallel, cell apoptosis triggered by H(2)O(2) characterized with the DNA fragment and caspase-3 activity were also inhibited by L-carnitine. Furthermore, mitochondrial dysfunction associated with cell apoptosis including membrane potential loss, down-regulation of Bcl-2 and up-regulation of Bax and the release of cytochrome c were abrogated in the presence of L-carnitine. These results suggested that L-carnitine could protect HK-2 cells from H(2)O(2)-induced injury through the inhibition of oxidative damage, mitochondria dysfunction and ultimately inhibition of cell apoptosis, which indicates that L-carnitine may be a promising approach for the treatment of oxidative stress in renal diseases.
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PMID:L-carnitine attenuates oxidant injury in HK-2 cells via ROS-mitochondria pathway. 2009 44

The role that antioxidants play in the process of carcinogenesis has recently gained considerable attention. alpha-Lipoic acid, a naturally occurring disulfide molecule, is a powerful antioxidant that reportedly exerts beneficial effects in patients with advanced cancer by reducing the level of reactive oxygen species and increasing glutathione peroxidase activity. In this study, we examined changes in the protein and mRNA expression associated with cell proliferation and apoptosis in MDA-MB-231 breast cancer cultured in the presence of various concentrations (0, 250, 500, and 1000 micromol/L) of alpha-lipoic acid. The results revealed that alpha-lipoic acid inhibited the growth of breast cancer cells in a dose-independent manner (P < 0.05). Additionally, ErbB(2) and ErbB(3) protein and mRNA expressions were significantly decreased in a dose-dependent manner in response to alpha-lipoic acid (P < 0.05). Furthermore, the protein expression of phosphorylated Akt (p-Akt) levels and total Akt, and the mRNA expression of Akt were decreased dose-dependently in cells that were treated with alpha-lipoic acid (P < 0.05). Bcl-2 protein and mRNA expressions were also decreased in cells that were treated with alpha-lipoic acid (P < 0.05). However, Bax protein and mRNA expressions were increased in cells treated with alpha-lipoic acid (P < 0.05). Finally, caspase-3 activity was significantly increased in a dose-dependent manner in cells treated with alpha-lipoic acid (P < 0.05). In conclusion, we demonstrated that alpha-lipoic acid inhibits cell proliferation and induces apoptosis in MDA-MB-231 breast cancer cell lines.
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PMID:Effects of alpha-lipoic acid on cell proliferation and apoptosis in MDA-MB-231 human breast cells. 2009 78

The present study examined the inhibitory effect of licorice compounds glycyrrhizin and a metabolite 18beta-glycyrrhetinic acid on the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the mouse and on the 1-methyl-4-phenylpyridinium (MPP(+))-induced cell death in differentiated PC12 cells. MPTP treatment increased the activities of total superoxide dismutase, catalase and glutathione peroxidase and the levels of malondialdehyde and carbonyls in the brain compared to control mouse brain. Co-administration of glycyrrhizin (16.8 mg/kg) attenuated the MPTP effect on the enzyme activities and formation of tissue peroxidation products. In vitro assay, licorice compounds attenuated the MPP(+)-induced cell death and caspase-3 activation in PC12 cells. Glycyrrhizin up to 100microM significantly attenuated the toxicity of MPP(+). Meanwhile, 18beta-glycyrrhetinic acid showed a maximum inhibitory effect at 10microM; beyond this concentration the inhibitory effect declined. Glycyrrhizin and 18beta-glycyrrhetinic acid attenuated the hydrogen peroxide- or nitrogen species-induced cell death. Results from this study indicate that glycyrrhizin may attenuate brain tissue damage in mice treated with MPTP through inhibitory effect on oxidative tissue damage. Glycyrrhizin and 18beta-glycyrrhetinic acid may reduce the MPP(+) toxicity in PC12 cells by suppressing caspase-3 activation. The effect seems to be ascribed to the antioxidant effect.
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PMID:Glycyrrhizin Attenuates MPTP Neurotoxicity in Mouse and MPP-Induced Cell Death in PC12 Cells. 2015 96

Thiamine is an important cofactor of metabolic enzymes, and its deficiency leads to cardiovascular dysfunction. First, we characterized the metabolic status measuring resting oxygen consumption rate and lactate blood concentration after 35 days of thiamine deficiency (TD). The results pointed to a decrease in resting oxygen consumption and a twofold increase in blood lactate. Confocal microscopy showed that intracellular superoxide (approximately 40%) and H(2)O(2) (2.5 times) contents had been increased. In addition, biochemical activities and protein expression of SOD, glutathione peroxidase, and catalase were evaluated in hearts isolated from rats submitted to thiamine deprivation. No difference in SOD activity was detected, but protein levels were found to be increased. Catalase activity increased 2.1 times in TD hearts. The observed gain in activity was attended by an increased catalase protein level. However, a marked decrease in glutathione peroxidase activity (control 435.3 + or - 28.6 vs. TD 199.4 + or - 30.2 nmol NADPH x min(-1) x ml(-1)) was paralleled by a diminution in the protein levels. Compared with control hearts, we did observe a greater proportion of apoptotic myocytes by TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 reactivity techniques. These results indicate that during TD, reactive oxygen species (ROS) production may be enhanced as a consequence of the installed acidosis. The perturbation in the cardiac myocytes redox balance was responsible for the increase in apoptosis.
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PMID:Cardiac oxidative stress is involved in heart failure induced by thiamine deprivation in rats. 2030 17

This study explored the effects of indole-3-carbinol on the proliferation of human nasopharyngeal carcinoma, both in vitro and in vivo, and the underlying mechanisms in inducing apoptosis of CNE1 cells. Proliferation, apoptosis, malondialdehyde, superoxide dismutase, glutathione peroxidase, expressions of caspase-9, and caspase-3 in human nasopharyngeal carcinoma cells CNE1 were examined. Indole-3-carbinol suppressed proliferation, induced apoptosis, decreased malondialdehyde level, increased the activity of superoxide dismutase and glutathione peroxidase, and up-regulated the expression of active fragments of caspase-9 and caspase-3 both in vitro and in vivo. It was concluded that indole-3-carbinol could inhibit proliferation and induce apoptosis of CNE1 cells and inhibit tumor growth in mice. Increased activity of superoxide dismutase and glutathione peroxidase and activated expression of caspase-9 and caspase-3 were also observed in indole-3-carbinol-treated tumors or tumor cells, suggesting that stress- and apoptosis-related molecules are involved in the indole-3-carbinol-induced apoptosis and inhibition of tumor growth.
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PMID:Indole-3-carbinol inhibits nasopharyngeal carcinoma. 2033 13


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