Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Huperzine A, a novel Lycopodium alkaloid originally discovered in the Chinese herb Qian Ceng Ta (Huperzia serrata), is a reversible, potent, and selective acetylcholinesterase (AChE) inhibitor and has been extensively used for the treatment of Alzheimer's disease (AD) in China. The present studies were designed to investigate effects of huperzine A on amyloid beta-peptide fragment 25-35 (Abeta25-35)-induced neuronal apoptosis and potential mechanisms in primary cultured rat cortical neurons. After exposure of the cells to Abeta25-35 (20 microM), apoptotic cell death was observed as evidenced by a significant decrease in cell viability, alteration of neuronal morphology, and DNA fragmentation. Pretreatment of the cells with huperzine A (0.01-10 microM) prior to Abeta25-35 exposure significantly elevated the cell survival and reduced Abeta25-35-induced nuclei fragmentation. Reactive oxygen species (ROS)-based fluorescence, caspase-3-like fluorogenic cleavage, and Western blot analysis demonstrated that huperzine A reduced Abeta25-35-induced ROS formation in a dose-dependent manner, and 1 microM of huperzine A attenuated Abeta25-35-induced caspase-3 activity at 6, 12, 24, and 48 hr posttreatment. Our results provide the first direct evidence that huperzine A protects neurons against Abeta25-35-induced apoptosis via the inhibition of ROS formation and caspase-3 activity.
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PMID:Huperzine A attenuates amyloid beta-peptide fragment 25-35-induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase-3 activation. 1175 78

Programmed cell death plays an integral role in neurodegenerative diseases such as Alzheimer's disease (AD). Acetylcholinesterase (AChE) was suggested to be neurotoxic in vivo and in vitro and accelerate assembly of amyloid peptide into Alzheimer's fibrils. In our experiments, we found increased AChE expression in apoptotic neuroblastoma SK-N-SH cells after long-term culture. Our results first showed that in apoptotic SK-N-SH cells, AChE aggregated in the nucleus and suppression of AChE expression with antisense oligonucleotide could save the cells from apoptosis. It was also found that caspase-3 activity was parallel with AChE activation in apoptotic SK-N-SH cells. These results suggest that AChE plays an important role in the procession of neuroblastoma cell apoptosis and favor the association between AChE and neuronal apoptosis in AD.
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PMID:Increased expression of intranuclear AChE involved in apoptosis of SK-N-SH cells. 1198 78

While acute organophosphorous compound poisoning due to inhibition of acetylcholinesterase is a well-established clinical entity, the existence of chronic poisoning due to exposure to low levels of organophosphorous compounds (below the threshold required for cholinergic clinical symptoms) is a hotly debated issue. In this study, we have evaluated the effects of noncholinergic doses of malathion (0.01-20 microM) on apoptosis of murine L929 fibroblasts. Employing flow cytometric and caspase activation analyses we demonstrate that malathion induces apoptosis in L929 cells in a dose- and time-dependent manner. The initiator caspases (caspase-8 and caspase-9) as well as the effector caspase (caspase-3) were activated by the treatment of L929 cells with malathion. Exposure of L929 cells to malathion in the presence of a general inhibitor of caspase, z-VAD-FMK abolished the apoptotic effect of the compound. In addition, malathion induced an increase in the expression of the pro-apoptotic protein p53. However, the induction of p53 expression was subsequent to activation of the caspase cascades. The present findings suggest, that the cytotoxicity of malathion at noncholinergic doses is mediated through caspase-dependent apoptosis.
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PMID:Effect of malathion on apoptosis of murine L929 fibroblasts: a possible mechanism for toxicity in low dose exposure. 1250 48

The acute effects of poisoning with organophosphorus compounds (OPCs) are well known and have been described extensively. Most of the clinical symptoms are due to inhibition of acetylcholinesterase. Although acute OPC poisoning is a well-established clinical entity, the existence of chronic poisoning due to exposure to low levels of OPC (below the threshold required for cholinergic clinical symptoms) is a hotly debated issue. Recent studies have suggested the involvement of OPCs in apoptotic processes. However, the mechanisms by which they modulate this process are poorly investigated. In the present study we evaluated the toxic effect of different concentrations of paraoxon (POX) and parathion (PAT) in murine EL4 T lymphocytes. We examined cellular responses, including induction of apoptosis, involvement of a caspase cascade, the activity of effector caspase (caspase-3) and the biochemical and morphological changes that are the hallmarks of classical apoptosis. The results of our study indicate that at doses below IC(50) POX is a potent inducer of apoptosis, as opposed to PAT that shows little apoptotic effect.
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PMID:Influence of paraoxon (POX) and parathion (PAT) on apoptosis: a possible mechanism for toxicity in low-dose exposure. 1251 33

Dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP) is an organophosphorus (OP) insecticide and acaricide extensively used to treat external parasitic infections of farmed fish. In previous studies we have demonstrated the importance of the glutathione (GSH) metabolism in the resistance of the European eel (Anguilla anguilla L.) to thiocarbamate herbicides. The present work studied the effects of the antioxidant and glutathione pro-drug N-acetyl-L-cysteine (NAC) on the survival of a natural population of A. anguilla exposed to a lethal concentration of dichlorvos, focusing on the glutathione metabolism and the enzyme activities of acetylcholinesterase (AChE) and caspase-3 as biomarkers of neurotoxicity and induction of apoptosis, respectively. Fish pre-treated with NAC (1 mmol kg(-1), i.p.) and exposed to 1.5 mg l(-1) (the 96-h LC85) of dichlorvos for 96 h in a static-renewal system achieved an increase of the GSH content, GSH/GSSG ratio, hepatic glutathione reductase (GR), glutathione S-transferase (GST), glutamate:cysteine ligase (GCL), and gamma-glutamyl transferase (gammaGT) activities, which ameliorated the glutathione loss and oxidation, and enzyme inactivation, caused by the OP pesticide. Although NAC-treated fish presented a higher survival and were two-fold less likely to die within the study period of 96 h, Cox proportional hazard models showed that hepatic GSH/GSSG ratio was the best explanatory variable related to survival. Hence, tolerance to a lethal concentration of dichlorvos can be explained by the individual capacity to maintain and improve the hepatic glutathione redox status. Impairment of the GSH/GSSG ratio can lead to excessive oxidative stress and inhibition of caspase-3-like activity, inducing cell death by necrosis, and, ultimately, resulting in the death of the organism. We therefore propose a reconsideration of the individual effective dose or individual tolerance concept postulated by Gaddum 50 years ago for the log-normal dose-response relationship. In addition, as NAC increased the tolerance to dichlorvos, it could be a potential antidote for OP poisoning, complementary to current treatments.
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PMID:Fish tolerance to organophosphate-induced oxidative stress is dependent on the glutathione metabolism and enhanced by N-acetylcysteine. 1456 51

Huangqi (Astragalus membranaceus), a traditional Chinese medicine, has been used to ameliorate side effects of cancer chemotherapy in China. However, little is known about its molecular mechanisms. Here we show that induction of K562 or HEL cells with 1.5 mg/ml of Huangqi (Hex) (Components extracted from Huangqi) for 3-5 d results in the expression of beta-globin gene in both cell lines and leads to terminal differentiation. Moreover, the apoptosis in HEL cells can be induced by increasing concentration of Huangqi (Hex) to 4.5 mg/ml for 3-5 d. Upregulation of Apaf-1, caspase-3 and acetylcholinesterase (AChE) in HEL cells may play a crucial role in the process of apoptosis. The prospect of inducing expression of adult (beta) globin gene and apoptosis selectively in cancer cells is obviously attractive from a therapeutic point of view.
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PMID:Effects of Huangqi (Hex) on inducing cell differentiation and cell death in K562 and HEL cells. 1520 6

Carbofuran is an anti-acetylcholinesterase insecticide regarded as a relatively safe chemical based on extensive toxicological data. However, the N-nitroso metabolite of carbofuran has been reported to be genotoxic. We previously observed that N-nitrosocarbofuran (NOCF) induces apoptosis and cell cycle arrest in Chinese hamster lung (CHL) fibroblasts. To extend our initial observations, we investigated the molecular mechanism of NOCF-induced apoptosis. Treatment of cells with NOCF caused dose-dependent upregulation of cytosolic factors, such as Bax and Bid, and release of cytochrome c, which were accompanied by activation of caspase-9. We also observed activation of caspase-8 and caspase-3, and subsequent cleavage of poly(ADP-ribose) polymerase. A broad-spectrum caspase inhibitor and a caspase-8-specific inhibitor completely blocked caspase-3 activation and cell death induced by NOCF. These results suggest that the mitochondrial pathway is primarily involved in the NOCF-induced apoptosis of CHL cells.
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PMID:N-nitroso metabolite of carbofuran induces apoptosis in CHL cells by cytochrome c-mediated activation of caspases. 1529 19

Huperzine A (HupA), isolated from Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase. It has been found to reverse or attenuate cognitive deficits in a broad range of animal models. Clinical trials in China have demonstrated that HupA significantly relieves memory deficits in aged subjects, patients with benign senescent forgetfulness, Alzheimer's disease (AD) and vascular dementia (VD), with minimal peripheral cholinergic side effects compared with other AChEIs in use. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53 and caspase-3, protect mitochondria, and interfere with APP metabolism. Antagonizing effects on NMDA receptors and potassium currents may contribute to the neuroprotection as well. It is also possible that the non-catalytic function of AChE is involved in neuroprotective effects of HupA. The therapeutic effects of HupA on AD or VD are probably exerted via a multi-target mechanism.
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PMID:Neuroprotective effects of huperzine A. A natural cholinesterase inhibitor for the treatment of Alzheimer's disease. 1595 16

MicroRNAs (miRNAs) are abundant small regulatory RNAs with multiple roles in cell fate determination. The processes regulating cellular miRNA levels are still unclear and experimental oligonucleotide tools to readily mimic their effects are not yet available. Here, we report that thapsigargin-induced intracellular Ca(++) release suppressed pre-miR-181a levels in human promegakaryotic Meg-01 cells, induced differentiation-associated nuclear endoreduplication and caspase-3 activation and replaced the acetylcholinesterase 3' splice variant AChE-S with AChE-R. AChE, PKC and PKA inhibitors all attenuated the pre-miR-181a decline and the induced differentiation. AChmiON, a synthetic 23-mer 2'-oxymethylated oligonucleotide mimicking the miR-181a sequence, blocked the calcium-induced differentiation while elevating cellular pre-miR-181a levels and inducing DNA fragmentation and cell death. Moreover, when added to RW 264.7 macrophages, AChmiON at 100 nM induced nitric oxide production with efficiency close to that of bacterial endotoxin, demonstrating physiologically relevant activities also in blood-born monocytes/macrophages. The stress-induced modulation of hematopoietic miR-181a levels through AChE, PKC and PKA cascade(s) suggests using miRNA mimics for diverting the fate of hematopoietic tumor cells towards differentiation and/or apoptosis.
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PMID:MicroRNA modulation of megakaryoblast fate involves cholinergic signaling. 1624 78

Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase(AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.
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PMID:Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. 1636 7


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