scholarly journals Inhibition of myeloperoxidase-mediated hypochlorous acid production by nitroxides

2009 ◽  
Vol 421 (1) ◽  
pp. 79-86 ◽  
Author(s):  
Martin D. Rees ◽  
Steven E. Bottle ◽  
Kathryn E. Fairfull-Smith ◽  
Ernst Malle ◽  
John M. Whitelock ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Oxidative Damage ◽  
Hypochlorous Acid ◽  
Inflammatory Diseases ◽  
Antioxidant Compounds ◽  
Protective Effects ◽  
Compound I ◽  
Chloride System ◽  
Ic50 Values ◽  
Compound Ii

Tissue damage resulting from the extracellular production of HOCl (hypochlorous acid) by the MPO (myeloperoxidase)-hydrogen peroxide-chloride system of activated phagocytes is implicated as a key event in the progression of a number of human inflammatory diseases. Consequently, there is considerable interest in the development of therapeutically useful MPO inhibitors. Nitroxides are well established antioxidant compounds of low toxicity that can attenuate oxidative damage in animal models of inflammatory disease. They are believed to exert protective effects principally by acting as superoxide dismutase mimetics or radical scavengers. However, we show here that nitroxides can also potently inhibit MPO-mediated HOCl production, with the nitroxide 4-aminoTEMPO inhibiting HOCl production by MPO and by neutrophils with IC50 values of approx. 1 and 6 μM respectively. Structure–activity relationships were determined for a range of aliphatic and aromatic nitroxides, and inhibition of oxidative damage to two biologically-important protein targets (albumin and perlecan) are demonstrated. Inhibition was shown to involve one-electron oxidation of the nitroxides by the compound I form of MPO and accumulation of compound II. Haem destruction was also observed with some nitroxides. Inhibition of neutrophil HOCl production by nitroxides was antagonized by neutrophil-derived superoxide, with this attributed to superoxide-mediated reduction of compound II. This effect was marginal with 4-aminoTEMPO, probably due to the efficient superoxide dismutase-mimetic activity of this nitroxide. Overall, these data indicate that nitroxides have considerable promise as therapeutic agents for the inhibition of MPO-mediated damage in inflammatory diseases.

scholarly journals Superoxide modulates the activity of myeloperoxidase and optimizes the production of hypochlorous acid

1988 ◽  
Vol 252 (2) ◽  
pp. 529-536 ◽  
Author(s):  
A J Kettle ◽  
C C Winterbourn
Keyword(s):  
Superoxide Dismutase ◽  
Xanthine Oxidase ◽  
Hypochlorous Acid ◽  
Direct Reaction ◽  
Chlorination Reaction ◽  
Inactive Compound ◽  
Physiological Conditions ◽  
Oxidant Damage ◽  
Form Compound ◽  
Compound Ii

Myeloperoxidase catalyses the conversion of H2O2 and Cl- to hypochlorous acid (HOCl). It also reacts with O2- to form the oxy adduct (compound III). To determine how O2- affects the formation of HOCl, chlorination of monochlorodimedon by myeloperoxidase was investigated using xanthine oxidase and hypoxanthine as a source of O2- and H2O2. Myeloperoxidase was mostly converted to compound III, and H2O2 was essential for chlorination. At pH 5.4, superoxide dismutase (SOD) enhanced chlorination and prevented formation of compound III. However, at pH 7.8, SOD inhibited chlorination and promoted formation of the ferrous peroxide adduct (compound II) instead of compound III. We present spectral evidence for a direct reaction between compound III and H2O2 to form compound II, and for the reduction of compound II by O2- to regenerate native myeloperoxidase. These reactions enable compound III and compound II to participate in the chlorination reaction. Myeloperoxidase catalytically inhibited O2- –dependent reduction of Nitro Blue Tetrazolium. This inhibition is explained by myeloperoxidase undergoing a cycle of reactions with O2-, H2O2 and O2-, with compounds III and II as intermediates, i.e., by myeloperoxidase acting as a combined SOD/catalase enzyme. By preventing the accumulation of inactive compound II, O2- enhances the activity of myeloperoxidase. We propose that, under physiological conditions, this optimizes the production of HOCl and may potentiate oxidant damage by stimulated neutrophils.

scholarly journals Protective Effect of PPARγAgonists on Cerebellar Tissues Oxidative Damage in Hypothyroid Rats

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Yousef Baghcheghi ◽  
Farimah Beheshti ◽  
Hossein Salmani ◽  
Mohammad Soukhtanloo ◽  
Mahmoud Hosseini
Keyword(s):  
Nitric Oxide ◽  
Superoxide Dismutase ◽  
Drinking Water ◽  
Oxidative Damage ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Group I ◽  
Biochemical Measurements ◽  
Thiol Content

The aim of the current study was to investigate the effects of peroxisome proliferator-activated receptor gamma (PPARγ) agonists on cerebellar tissues oxidative damage in hypothyroid rats. The animals included seven groups: group I (control), the animals received drinking water; group II, the animals received 0.05% propylthiouracil (PTU) in drinking water; besides PTU, the animals in groups III, IV, V, VI, and VII, were injected with 20 mg/kg vitamin E (Vit E), 10 or 20 mg/kg pioglitazone, and 2 or 4 mg/kg rosiglitazone, respectively. The animals were deeply anesthetized and the cerebellar tissues were removed for biochemical measurements. PTU administration reduced thiol content, superoxide dismutase (SOD), and catalase (CAT) activities in the cerebellar tissues while increasing malondialdehyde (MDA) and nitric oxide (NO) metabolites. Vit E, pioglitazone, and rosiglitazone increased thiol, SOD, and CAT in the cerebellar tissues while reducing MDA and NO metabolites. The results of present study showed that, similar to Vit E, both rosiglitazone and pioglitazone as PPARγagonists exerted protective effects against cerebellar tissues oxidative damage in hypothyroid rats.

Protection by pentoxifylline of malathion-induced toxic stress and mitochondrial damage in rat brain

2010 ◽  
Vol 29 (10) ◽  
pp. 851-864 ◽  
Author(s):  
Akram Ranjbar ◽  
Mohammad Hossein Ghahremani ◽  
Mohammad Sharifzadeh ◽  
Abolfazl Golestani ◽  
Mahmood Ghazi-Khansari ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Oxidative Damage ◽  
Rat Brain ◽  
Manganese Superoxide Dismutase ◽  
Brain Homogenate ◽  
Brain Mitochondria ◽  
Alpha Tocopherol ◽  
Protective Effects ◽  
Whole Brain ◽  
Induced Changes

Objective: The objective of this study was to investigate the possible protective effects of pentoxifylline as a phosphodiesterase-5 inhibitor on malathion-induced oxidative damage to rat brain mitochondria. Methods: Rats received malathion (200 mg/kg/day) and pentoxifylline (PTX, 50 mg/kg/day) in combination or alone. Alpha-tocopherol (AT, 15 mg/kg/day) was used as a positive standard. After 1 week of treatment, blood, whole brain tissue, and brain mitochondria were isolated. The activity of enzymatic scavengers such as glutathione peroxidase (GPx), catalase (CAT), copper-zinc superoxide dismutase (Cu/ZnSOD), and manganese superoxide dismutase (MnSOD) were measured. The extents of cellular lipid peroxidation (LPO), nitrotyrosine (NOx), and the ratio of reduced versus oxidized glutathione (GSH/GSSG) were determined. The protein expression of MnSOD was determined in brain mitochondria. Results: Malathion stimulated activities of CAT, Cu/ZnSOD, GPx, and increased LPO and NOx, and decreased GSH/GSSG in whole brain homogenate. The changes in CAT, LPO, GPx, and GSH/GSSG were restored by PTX and AT. In plasma samples, malathion increased CAT, Cu/ZnSOD, and GPx activities, increased LPO, and decreased GSH/GSSG, while PTX and AT attenuated malathion-induced changes in GPx, Cu/ZnSOD, LPO, and GSH/GSSG. In brain mitochondria, malathion enhanced LPO, NOx, CAT, GPx, and MnSOD and decreased GSH/GSSG as compared to controls, whereas PTX and AT restored malathion-induced changes in GSH/GSSG, NOx, GPx, and CAT. Malathion noticeably enhanced expression of MnSOD protein as compared to controls. Malathion decreased viability of mitochondria that was recovered by AT. It is concluded that oxidative damage is at least in part the mechanism of toxicity of malathion in the mitochondria that can be recovered by PTX comparable to AT.

scholarly journals Influence of superoxide on myeloperoxidase kinetics measured with a hydrogen peroxide electrode

1989 ◽  
Vol 263 (3) ◽  
pp. 823-828 ◽  
Author(s):  
A J Kettle ◽  
C C Winterbourn
Keyword(s):  
Hypochlorous Acid ◽  
Initial Rate ◽  
Electron Donors ◽  
H2o2 Concentration ◽  
Compound I ◽  
Ph Optimum ◽  
Neutral Ph ◽  
High Concentrations ◽  
Compound Ii ◽  
Enzyme Functions

Stimulated neutrophils discharge large quantities of superoxide (O2.-), which dismutates to form H2O2. In combination with Cl-, H2O2 is converted into the potent oxidant hypochlorous acid (HOCl) by the haem enzyme myeloperoxidase. We have used an H2O2 electrode to monitor H2O2 uptake by myeloperoxidase, and have shown that in the presence of Cl- this accurately represents production of HOCl. Monochlorodimedon, which is routinely used to assay production of HOCl, inhibited H2O2 uptake by 95%. This result confirms that monochlorodimedon inhibits myeloperoxidase, and that the monochlorodimedon assay grossly underestimates the activity of myeloperoxidase. With 10 microM-H2O2 and 100 mM-Cl-, myeloperoxidase had a neutral pH optimum. Increasing the H2O2 concentration to 100 microM lowered the pH optimum to pH 6.5. Above the pH optimum there was a burst of H2O2 uptake that rapidly declined due to accumulation of Compound II. High concentrations of H2O2 inhibited myeloperoxidase and promoted the formation of Compound II. These effects of H2O2 were decreased at higher concentrations of Cl-. We propose that H2O2 competes with Cl- for Compound I and reduces it to Compound II, thereby inhibiting myeloperoxidase. Above pH 6.5, O2.- generated by xanthine oxidase and acetaldehyde prevented H2O2 from inhibiting myeloperoxidase, increasing the initial rate of H2O2 uptake. O2.- allowed myeloperoxidase to function optimally with 100 microM-H2O2 at pH 7.0. This occurred because, as previously demonstrated, O2.- prevents Compound II from accumulating by reducing it to ferric myeloperoxidase. In contrast, at pH 6.0, where Compound II did not accumulate, O2.- retarded the uptake of H2O2. We propose that by generating O2.- neutrophils prevent H2O2 and other one-electron donors from inhibiting myeloperoxidase, and ensure that this enzyme functions optimally at neutral pH.

scholarly journals Oxidative Stress in The Hippocampus During Experimental Seizures Can Be Ameliorated With The Antioxidant Ascorbic Acid

2009 ◽  
Vol 2 (4) ◽  
pp. 214-221 ◽  
Author(s):  
Ítala Mônica Sales Santos ◽  
Adriana da Rocha Tomé ◽  
Gláucio Barros Saldanha ◽  
Paulo Michel Pinheiro Ferreira ◽  
Gardenia Carmem Gadelha Militão ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Ascorbic Acid ◽  
Superoxide Dismutase ◽  
Water Soluble ◽  
Control Group ◽  
Antioxidant Compounds ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Adult Rats

Ascorbic acid has many nonenzymatic actions and is a powerful water-soluble antioxidant. It protects low density lipoproteins from oxidation and reduces harmful oxidants in the central nervous system. Pilocarpine-induced seizures have been suggested to be mediated by increases in oxidative stress. Current studies have suggested that antioxidant compounds may afford some level of neuroprotection against the neurotoxicity of seizures. The objective of the present study was to evaluate the neuroprotective effects of ascorbic acid (AA) in rats, against the observed oxidative stress during seizures induced by pilocarpine. Wistar rats were treated with 0.9% saline (i.p., control group), ascorbic acid (500 mg/kg, i.p., AA group), pilocarpine (400 mg/kg, i.p., pilocarpine group), and the association of ascorbic acid (500 mg/kg, i.p.) plus pilocarpine (400 mg/kg, i.p.), 30 min before of administration of ascorbic acid (AA plus pilocarpine group). After the treatments all groups were observed for 6 h. The enzyme activities as well as the lipid peroxidation and nitrite concentrations were measured using spectrophotometric methods and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of ascorbic acid were also evaluated on the same parameters. In pilocarpine group there was a significant increase in lipid peroxidation and nitrite level. However, no alteration was observed in superoxide dismutase and catalase activities. Antioxidant treatment significantly reduced the lipid peroxidation level and nitrite content as well as increased the superoxide dismutase and catalase activities in hippocampus of adult rats after seizures induced by pilocarpine. Our findings strongly support the hypothesis that oxidative stress in hippocampus occurs during seizures induced by pilocarpine, proving that brain damage induced by the oxidative process plays a crucial role in seizures pathogenic consequences, and also imply that a strong protective effect could be achieved using ascorbic acid.

Melatonin reduces high levels of lipid peroxidation induced by potassium iodate in porcine thyroid

2019 ◽  
pp. 1-7 ◽  
Author(s):  
Paulina Iwan ◽  
Jan Stepniak ◽  
Malgorzata Karbownik-Lewinska
Keyword(s):  
Lipid Peroxidation ◽  
Oxidative Damage ◽  
Membrane Lipids ◽  
Chemical Properties ◽  
Iodine Concentration ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Protective Effects ◽  
Potassium Iodate ◽  
Hormone Synthesis

Abstract. Iodine is essential for thyroid hormone synthesis. Under normal iodine supply, calculated physiological iodine concentration in the thyroid is approx. 9 mM. Either potassium iodide (KI) or potassium iodate (KIO3) are used in iodine prophylaxis. KI is confirmed as absolutely safe. KIO3 possesses chemical properties suggesting its potential toxicity. Melatonin (N-acetyl-5-methoxytryptamine) is an effective antioxidant and free radical scavenger. Study aims: to evaluate potential protective effects of melatonin against oxidative damage to membrane lipids (lipid peroxidation, LPO) induced by KI or KIO3 in porcine thyroid. Homogenates of twenty four (24) thyroids were incubated in presence of either KI or KIO3 without/with melatonin (5 mM). As melatonin was not effective against KI-induced LPO, in the next step only KIO3 was used. Homogenates were incubated in presence of KIO3 (200; 100; 50; 25; 20; 15; 10; 7.5; 5.0; 2.5; 1.25 mM) without/with melatonin or 17ß-estradiol. Five experiments were performed with different concentrations of melatonin (5.0; 2.5; 1.25; 1.0; 0.625 mM) and one with 17ß-estradiol (1.0 mM). Malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA) concentration (LPO index) was measured spectrophotometrically. KIO3 increased LPO with the strongest damaging effect (MDA + 4-HDA level: ≈1.28 nmol/mg protein, p < 0.05) revealed at concentrations of around 15 mM, thus corresponding to physiological iodine concentrations in the thyroid. Melatonin reduced LPO (MDA + 4-HDA levels: from ≈0.97 to ≈0,76 and from ≈0,64 to ≈0,49 nmol/mg protein, p < 0.05) induced by KIO3 at concentrations of 10 mM or 7.5 mM. Conclusion: Melatonin can reduce very strong oxidative damage to membrane lipids caused by KIO3 used in doses resulting in physiological iodine concentrations in the thyroid.

Discovery of New Phosphoinositide 3-kinase Delta (PI3Kδ) Inhibitors via Virtual Screening using Crystallography-derived Pharmacophore Modelling and QSAR Analysis

2019 ◽  
Vol 15 (6) ◽  
pp. 588-601 ◽  
Author(s):  
Mahmoud A. Al-Sha'er ◽  
Rua'a A. Al-Aqtash ◽  
Mutasem O. Taha
Keyword(s):  
Virtual Screening ◽  
Inflammatory Diseases ◽  
Qsar Model ◽  
Qsar Analysis ◽  
Pharmacophore Modelling ◽  
Physicochemical Descriptors ◽  
Qsar Modelling ◽  
Ic50 Values ◽  
Phosphoinositide 3 Kinase ◽  
Pharmacophore Models

<P>Background: PI3K&#948; is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3K&#948; inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3K&#948; binding. </P><P> Methods: Seventeen PI3K&#948; crystallographic complexes were used to extract 94 pharmacophore models. QSAR modelling was subsequently used to select the superior pharmacophore(s) that best explain bioactivity variation within a list of 79 diverse inhibitors (i.e., upon combination with other physicochemical descriptors). </P><P> Results: The best QSAR model (r2 = 0.71, r2 LOO = 0.70, r2 press against external testing list of 15 compounds = 0.80) included a single crystallographic pharmacophore of optimal explanatory qualities. The resulting pharmacophore and QSAR model were used to screen the National Cancer Institute (NCI) database for new PI3Kδ inhibitors. Two hits showed low micromolar IC50 values. </P><P> Conclusion: Crystallography-based pharmacophores were successfully combined with QSAR analysis for the identification of novel PI3K&#948; inhibitors.</P>

Pyrrolizines as Potential Anticancer Agents: Design, Synthesis, Caspase-3 activation and Micronucleus (MN) Induction

2019 ◽  
Vol 18 (15) ◽  
pp. 2124-2130
Author(s):  
Amany Belal
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Caspase 3 ◽  
Assay Method ◽  
Breast Adenocarcinoma ◽  
Compound I ◽  
Design Synthesis ◽  
Ic50 Values ◽  
New Compounds

Background: For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized. Methods: Structures of the new compounds were confirmed by IR, 1H-NMR, 13C-NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method. Result: Compounds 2, 3 and 5 were the most potent on colon cancer cells, their IC50 values were less than 5 µM. Compounds 2, 3 and 8 were the most potent on liver cancer cells, their IC50 values were less than 10 µM. As for MCF7, compounds 2, 7, 8 and 9 were the most active with IC50 values less than 10 µM. We can conclude that combining pyrrolizine scaffold with urea gave abroad spectrum anticancer agent 2 against the three tested cell lines. Micronucleus assays showed that compounds 2, 3, 8 are mutagenic and can induce apoptosis. In addition, caspase-3 activation was evaluated and compound 2 showed increase in the level of caspase-3 (9 folds) followed by 3 (8.28 folds) then 8 (7.89 folds). Conclusion: The obtained results encourage considering these three compounds as novel anticancer prototypes.

Compounds from Ilex paraguariensis extracts have antioxidant effects in the brains of rats subjected to chronic immobilization stress

2017 ◽  
Vol 42 (11) ◽  
pp. 1172-1178 ◽  
Author(s):  
Ana C. Colpo ◽  
Maria Eduarda de Lima ◽  
Marisol Maya-López ◽  
Hemerson Rosa ◽  
Cristina Márquez-Curiel ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Immobilization Stress ◽  
Brain Regions ◽  
Protective Role ◽  
Ilex Paraguariensis ◽  
Protective Effects ◽  
Species Formation ◽  
Lipid And Protein Oxidation ◽  
Response To Stress ◽  
Chronic Immobilization Stress

Immobilization induces oxidative damage to the brain. Ilex paraguariensis extracts (Mate) and their major natural compound, chlorogenic acid (CGA), exert protective effects against reactive oxygen species formation. Here, the effects of Mate and CGA on oxidative damage induced by chronic immobilization stress (CIS) in the cortex, hippocampus, and striatum were investigated. For CIS, animals were immobilized for 6 h every day for 21 consecutive days. Rats received Mate or CGA by intragastric gavage 30 min before every restraint session. Endpoints of oxidative stress (levels of lipid peroxidation, protein carbonylation, and reduced (GSH) and oxidized (GSSG) forms of glutathione) were evaluated following CIS. While CIS increased oxidized lipid and carbonyl levels in all brain regions, CGA (and Mate to a lesser extent) attenuated lipid and protein oxidation as compared with control groups. GSH/GSSG balance showed a tendency to increase in all regions in response to stress and antioxidants. Taken together, our results support a protective role of dietary antioxidants against the neuronal consequences of stress.

scholarly journals Structural Characterization and Assessment of Anti-Inflammatory and Anti-Tyrosinase Activities of Polyphenols from Melastoma normale

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3913
Author(s):  
Rui-Jie He ◽  
Jun Li ◽  
Yong-Lin Huang ◽  
Ya-Feng Wang ◽  
Bing-Yuan Yang ◽  
...  
Keyword(s):  
Enzyme Inhibitors ◽  
Enzyme Inhibitor ◽  
Structure Identification ◽  
No Production ◽  
Protective Effects ◽  
Successful Isolation ◽  
Ic50 Values ◽  
Development And Utilization ◽  
Inhibitory Activities ◽  
Anti Inflammatory

Polyphenols, widely distributed in the genus Melastoma plants, possess extensive cellular protective effects such as anti-inflammatory, anti-tyrosinase, and anti-obesity, which makes it a potential anti-inflammatory drug or enzyme inhibitor. Therefore, the aim of this study is to screen for the anti-inflammatory and enzyme inhibitory activities of compounds from title plant. Using silica gel, MCI, ODS C18, and Sephadex LH-20 column chromatography, as well as semipreparative HPLC, the extract of Melastoma normale roots was separated. Four new ellagitannins, Whiskey tannin C (1), 1-O-(4-methoxygalloyl)-6-O-galloyl-2,3-O-(S)-hexahydroxydiphenoyl-β-d-glucose (2), 1-O-galloyl-6-O-(3-methoxygalloyl)-2,3-O-(S)-hexahydroxydiphenoyl-β-d-glucose (3), and 1-O-galloyl-6-O-vanilloyl-2,3-O-(S)-hexahydroxydiphenoyl-β-d-glucose (4), along with eight known polyphenols were firstly obtained from this plant. The structures of all isolates were elucidated by HRMS, NMR, and CD analyses. Using lipopolysaccharide (LPS)-stimulated RAW2 64.7 cells, we investigated the anti-inflammatory activities of compounds 1–4, unfortunately, none of them exhibit inhibit nitric oxide (NO) production, their IC50 values are all > 50 μM. Anti-tyrosinase activity assays was done by tyrosinase inhibition activity screening model. Compound 1 showed weak tyrosinase inhibitory activity with IC50 values of 426.02 ± 11.31 μM. Compounds 2–4 displayed moderate tyrosinase inhibitory activities with IC50 values in the range of 124.74 ± 3.12–241.41 ± 6.23 μM. The structure–activity relationships indicate that hydroxylation at C-3′, C-4′, and C-3 in the flavones were key to their anti-tyrosinase activities. The successful isolation and structure identification of ellagitannin provide materials for the screening of anti-inflammatory drugs and enzyme inhibitors, and also contribute to the development and utilization of M. normale.

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