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Induced Toxicity (induced + toxicity)
Selected AbstractsProtective effect of CPUX1, a progesterone, on hydrogen peroxide-induced oxidative damage in PC12 cells,DRUG DEVELOPMENT RESEARCH, Issue 8 2008Bian-sheng Ji Abstract The protective effect of CPUX1, a novel progesterone analog, on hydrogen peroxide (H2O2)-induced oxidative damage was investigated in rat pheochromocytoma (PC12) cells. Following the exposure of PC12 cells to H2O2, there was a reduction in cell survival and activities of superoxide dismutase (SOD) and mitochondrial membrane potential (MMP) accompanied by increased levels of lactate dehydrogenase (LDH) release, malondialdehyde (MDA) production, and intracellular reactive oxygen species (ROS) and intracellular [Ca2+]i levels. Preincubation of cells with CPUX1 prior to H2O2 exposure attenuated all these changes mentioned and had a protective effect against H2O2 -induced toxicity in PC12 cells, indicating that the compound may have potential therapeutic benefit for CNS disorders influenced by oxidative damage. Drug Dev Res 69: 2008 ©2008 Wiley-Liss, Inc. [source] Docosahexaenoic acid stabilizes soluble amyloid-, protofibrils and sustains amyloid-,-induced neurotoxicity in vitroFEBS JOURNAL, Issue 4 2007Ann-Sofi Johansson Enrichment of diet and culture media with the polyunsaturated fatty acid docosahexaenoic acid has been found to reduce the amyloid burden in mice and lower amyloid-, (A,) levels in both mice and cultured cells. However, the direct interaction of polyunsaturated fatty acids, such as docosahexaenoic acid, with A,, and their effect on A, aggregation has not been explored in detail. Therefore, we have investigated the effect of docosahexaenoic acid, arachidonic acid and the saturated fatty acid arachidic acid on monomer oligomerization into protofibrils and protofibril fibrillization into fibrils in vitro, using size exclusion chromatography. The polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid at micellar concentrations stabilized soluble A,42 wild-type protofibrils, thereby hindering their conversion to insoluble fibrils. As a consequence, docosahexaenoic acid sustained amyloid-,-induced toxicity in PC12 cells over time, whereas A, without docosahexaenoic acid stabilization resulted in reduced toxicity, as A, formed fibrils. Arachidic acid had no effect on A, aggregation, and neither of the fatty acids had any protofibril-stabilizing effect on A,42 harboring the Arctic mutation (A,E22G). Consequently, A,Arctic-induced toxicity could not be sustained using docosahexaenoic acid. These results provide new insights into the toxicity of different A, aggregates and how endogenous lipids can affect A, aggregation. [source] Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development,HEPATOLOGY, Issue 2 2008Silke Marhenke In tyrosinemia type 1 (HT1), accumulation of toxic metabolites results in oxidative stress and DNA damage, leading to a high incidence of hepatocellular carcinomas. Nuclear factor erythroid-2 related factor 2 (Nrf2) is a key transcription factor important for cellular protection against oxidative stress and chemical induced liver damage. To specifically address the role of Nrf2 in HT1, fumarylacetoacetate hydrolase (Fah)/Nrf2,/, mice were generated. In acute HT1, loss of Nrf2 elicited a strong inflammatory response and dramatically increased the mortality of mice. Following low grade injury, Fah/Nrf2,/, mice develop a more severe hepatitis and liver fibrosis. The glutathione and cellular detoxification system was significantly impaired in Fah/Nrf2,/, mice, resulting in increased oxidative stress and DNA damage. Consequently, tumor development was significantly accelerated by loss of Nrf2. Potent pharmacological inducers of Nrf2 such as the triterpenoid analogs 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole have been developed as cancer chemoprevention agents. Pretreatment with 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole dramatically protected Fah,/, mice against fumarylacetoacetate (Faa)-induced toxicity. Our data establish a central role for Nrf2 in the protection against Faa-induced liver injury; the Nrf2 regulated cellular defense not only prevents acute Faa-induced liver failure but also delays hepatocarcinogenesis in HT1. (HEPATOLOGY 2008;48:487,496.) [source] Altered distribution of mitochondria impairs calcium homeostasis in rat hippocampal neurons in cultureJOURNAL OF NEUROCHEMISTRY, Issue 1 2003Guang Jian Wang Abstract The specificity of Ca2+ signals is conferred in part by limiting changes in cytosolic Ca2+ to subcellular domains. Mitochondria play a major role in regulating Ca2+ in neurons and may participate in its spatial localization. We examined the effects of changes in the distribution of mitochondria on NMDA-induced Ca2+ increases. Hippocampal cultures were treated with the microtubule-destabilizing agent vinblastine, which caused the mitochondria to aggregate and migrate towards one side of the neuron. This treatment did not appear to decrease the energy status of mitochondria, as indicated by a normal membrane potential and pH gradient across the inner membrane. Moreover, electron microscopy showed that vinblastine treatment altered the distribution but not the ultrastructure of mitochondria. NMDA (200 µm, 1 min) evoked a greater increase in cytosolic Ca2+ in vinblastine-treated cells than in untreated cells. This increase did not result from impaired Ca2+ efflux, enhanced Ca2+ influx, opening of the mitochondrial permeability transition pore or altered function of endoplasmic reticulum Ca2+ stores. Ca2+ uptake into mitochondria was reduced by 53% in vinblastine-treated cells, as reported by mitochondrially targeted aequorin. Thus, the distribution of mitochondria maintained by microtubules is critical for buffering Ca2+ influx. A subset of mitochondria close to a Ca2+ source may preferentially regulate Ca2+ microdomains, set the threshold for Ca2+ -induced toxicity and participate in local ATP production. [source] Melatonin protects against endosulfan-induced oxidative tissue damage in ratsJOURNAL OF PINEAL RESEARCH, Issue 4 2008Gülden Z. Omurtag Abstract:, Endosulfan is a chlorinated cyclodiene insecticide which induces oxidative stress. In this study, we investigated the possible protective effect of melatonin, an antioxidant agent, against endosulfan (Endo)-induced toxicity in rats. Wistar albino rats (n = 8) were administered endosulfan (22 mg/kg/day orally) followed by either saline (Endo group) or melatonin (10 mg/kg/day, Endo + Mel group) for 5 days. In other rats, saline (control group) or melatonin (10 mg/kg/day, Mel group) was injected for 5 days, following corn oil administration (vehicle of endosulfan). Measurement of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content were performed in liver and kidney. Furthermore, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine levels, lactate dehydrogenase (LDH) activity were measured in the serum samples, while tumor necrosis factor-, (TNF-,), interleukin-, (IL-,) and total antioxidant capacity (AOC) were assayed in plasma samples. Endosulfan administration caused a significant decrease in tissue GSH and plasma AOC, which was accompanied with significant rises in tissue MDA and collagen levels and MPO activity. Moreover, the proinflammatory mediators (TNF-, and IL-,), LDH activity, AST, ALT, creatinine and BUN levels were significantly elevated in the endosulfan-treated rats. On the other hand, melatonin treatment reversed all these biochemical alterations induced by endosulfan. Our results suggest that oxidative mechanisms play an important role in endosulfan-induced tissue damage and melatonin, by inhibiting neutrophil infiltration, balancing oxidant,antioxidant status and regulating the generation of inflammatory mediators, ameliorates oxidative organ injury as a result of endosulfan toxicity. [source] Effects of anthocyanins and other phenolics of boysenberry and blackcurrant as inhibitors of oxidative stress and damage to cellular DNA in SH-SY5Y and HL-60 cellsJOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE, Issue 5 2006Dilip Ghosh Abstract There is growing interest both from consumers and researchers in the role that berries play in human health. The objective of this study was to investigate whether anthocyanins and other phenolics present in boysenberries and blackcurrants are effective in protecting cells against the oxidative damage induced by hydrogen peroxide (H2O2). The concentrations of polyphenols used were within the human physiological range. The data showed that SH-SY5Y human neuroblastoma cells were protected against H2O2 -induced toxicity by the anthocyanins and phenolic fractions. The concurrent addition of either fractions of these berries with H2O2 significantly inhibited the increase in intracellular reactive oxygen species (ROS) production. Pre-incubation of cells with the same concentrations had no effect on the ROS level,a result that may be due to the metabolic conversion to inactive compounds. Anthocyanins and phenolic fractions of blackcurrant were better at protecting DNA of HL-60 human promyelocytic cells from damage than similar fractions from boysenberry. The phenolic extract of blackcurrant demonstrated the highest protective effect against H2O2 -induced neurotoxicity, oxidative stress and DNA damage and may be a good candidate for inclusion into a processed functional food. Copyright © 2006 Society of Chemical Industry [source] Neuroprotective effect of luteolin on amyloid , protein (25,35)-induced toxicity in cultured rat cortical neuronsPHYTOTHERAPY RESEARCH, Issue S1 2010Hao-Yuan Cheng Abstract The present study was carried out to investigate the neuroprotective effect of luteolin on amyloid , (A,) (25,35)-induced neurotoxicity using cultured rat cortical neurons. After exposure of primary cultures of rat cortical cells to 10 ,M A, (25,35) for 48 h, cortical cell cultures exhibited marked apoptotic death. Pretreatment with luteolin (1, 10 ,M) significantly protected cortical cell cultures against A, (25,35)-induced toxicity. Luteolin (1, 10 ,M) showed a concentration-dependent inhibition on 10 ,M A, (25,35)-induced apoptotic neuronal death, as assessed by MTT assay. Furthermore, luteolin reduced apoptotic characteristics by DAPI staining. For Western blot analysis, the results showed that the protective effect of luteolin on A, (25,35)-induced neurotoxicity was mediated by preventing of ERK-p, JNK, JNK-p, P38-p and caspase 3 activations in rat primary cortical cultures. Taken together, the results suggest that luteolin prevents A, (25,35)-induced apoptotic neuronal death through inhibiting the protein level of JNK, ERK and p38 MAP kinases and caspase 3 activations. Copyright © 2009 John Wiley & Sons, Ltd. [source] Hepatoprotective and antioxidant effects of Alnus japonica extracts on acetaminophen-induced hepatotoxicity in ratsPHYTOTHERAPY RESEARCH, Issue 12 2004Sang Tae Kim Abstract The stem bark of the Betulaceae plant Alnus japonica, which is indigenous to Korea, has been used as a popular folk medicine for hepatitis and cancer. In this study, the antioxidant activity of the crude extract and the hepatoprotective activities on acetaminophen (AAP)-induced toxicity in the rat liver were evaluated. We investigated the effect of the methanol (AJM) and solvent fracton of the stem bark of Alnus japonica (AJ) on AAP-induced hepatotoxicity in rats. In rat hepatocyte culture, pretreatment with AJM (50, 100, 150 and 200 µg[sol ]ml) significantly decreased the cytotoxicity of AAP in a dose-dependent manner. The pretreated with EtOAc and BuOH fraction led to an increase in free radical scavenging activity and a decrease in inhibition of lipid peroxidation, both superoxide dismutase and catalase prevent the hepatotoxicity by AAP in the treatment of A. japonica fraction. We conclude that AJ is an important antioxidant in AAP-induced live hepatotoxicity and that extract of AJM plays a hepatoprotective effects in the against AAP-induced cytotoxicity in cultured rat hepatocytes in vitro. Pending more evaluation for safety and efficacy, AJ can potentially be used in mitigating AAP-induced hepatotoxicity. Copyright © 2004 John Wiley & Sons, Ltd. [source] Dopamine melanin-loaded PC12 cells: a model for studies on pigmented neuronsPIGMENT CELL & MELANOMA RESEARCH, Issue 4 2005Anna Östergren Summary The most conspicuous feature in idiopathic parkinsonism is the degeneration of pigmented neurons in the substantia nigra. A major problem for the study of the significance of neuromelanin for the development of parkinsonism is that common experimental animals lack neuromelanin in substantia nigra. The aim of this study was to develop an in vitro model that could be used to study the role of neuromelanin in chemically induced toxicity in dopaminergic cells. Cultured neuron-like PC12 cells were exposed to synthetic dopamine melanin (0,1.0 mg/ml) for 48 h, resulting in uptake of dopamine melanin particles into the cells. The intracellular distribution of dopamine melanin granules was similar to that found in neuromelanin-containing neurons. Dopamine melanin, up to 0.5 mg/ml, had negligible effects on ultrastructure, induction of the endoplasmic reticulum-stress protein glucose regulating protein 78, activation of caspase-3 and cell viability. The decreased cell viability in response to the cytotoxic peptide amyloid- ,25,35 was similar in melanin-loaded cells and in control cells without melanin. The results of the studies suggest that melanin-loaded PC12 cells can serve as an in vitro model for studies on the role of neuromelanin for the toxicity of chemicals, in particular neurotoxicants with melanin affinity, in pigmented neurons. [source] Positive allosteric modulation of ,7 neuronal nicotinic acetylcholine receptors: lack of cytotoxicity in PC12 cells and rat primary cortical neuronsBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2009Min Hu Background and purpose:, ,7-Nicotinic acetylcholine receptors (,7 nAChRs) play an important role in cognitive function. Positive allosteric modulators (PAMs) amplify effects of ,7 nAChR agonist and could provide an approach for treatment of cognitive deficits in neuropsychiatric diseases. PAMs can either predominantly affect the apparent peak current response (type I) or increase both the apparent peak current response and duration of channel opening, due to prolonged desensitization (type II). The delay of receptor desensitization by type II PAMs raises the possibility of Ca2+ -induced toxicity through prolonged activation of ,7 nAChRs. The present study addresses whether type I and II PAMs exhibit different cytotoxicity profiles. Experimental approach:, The present studies evaluated cytotoxic effects of type I PAM [N-(4-chlorophenyl)]-,-[(4-chloro-phenyl)-aminomethylene]-3-methyl-5-isoxazoleacet-amide (CCMI) and type II PAM 1-[5-chloro-2,4-dimethoxy-phenyl]-3-[5-methyl-isoxazol-3-yl]-urea (PNU-120596), or 4-[5-(4chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulphonamide (A-867744). The studies used cultures of PC12 cells and primary cultures of rat cortical neuronal cells. Key results:, Our results showed that neither type I nor type II PAMs had any detrimental effect on cell integrity or cell viability. In particular, type II PAMs did not affect neuron number and neurite outgrowth under conditions when ,7 nAChR activity was measured by Ca2+ influx and extracellular signal-regulated kinases 1 and 2 phosphorylation, following exposure to ,7 nAChR agonists. Conclusions and implications:, This study demonstrated that both type I and type II ,7 nAChR selective PAMs, although exhibiting differential electrophysiological profiles, did not exert cytotoxic effects in cells endogenously expressing ,7 nAChRs. [source] | ||||||||||||||||