scholarly journals Labile plasma iron in iron overload: redox activity and susceptibility to chelation

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2670-2677 ◽  
Author(s):  
Breno P. Esposito ◽  
William Breuer ◽  
Pornpan Sirankapracha ◽  
Pensri Pootrakul ◽  
Chaim Hershko ◽  
...  
Keyword(s):  
Iron Overload ◽  
Oral Treatment ◽  
Oxidation Products ◽  
Redox Activity ◽  
Iron Chelators ◽  
Plasma Iron ◽  
Redox Active ◽  
Reactive Radicals

Abstract Plasma non-transferrin-bound-iron (NTBI) is believed to be responsible for catalyzing the formation of reactive radicals in the circulation of iron overloaded subjects, resulting in accumulation of oxidation products. We assessed the redox active component of NTBI in the plasma of healthy and β-thalassemic patients. The labile plasma iron (LPI) was determined with the fluorogenic dihydrorhodamine 123 by monitoring the generation of reactive radicals prompted by ascorbate but blocked by iron chelators. The assay was LPI specific since it was generated by physiologic concentrations of ascorbate, involved no sample manipulation, and was blocked by iron chelators that bind iron selectively. LPI, essentially absent from sera of healthy individuals, was present in those of β-thalassemia patients at levels (1-16 μM) that correlated significantly with those of NTBI measured as mobilizer-dependent chelatable iron or desferrioxamine chelatable iron. Oral treatment of patients with deferiprone (L1) raised plasma NTBI due to iron mobilization but did not lead to LPI appearance, indicating that L1-chelated iron in plasma was not redox active. Moreover, oral L1 treatment eliminated LPI in patients. The approach enabled the assessment of LPI susceptibility to in vivo or in vitro chelation and the potential of LPI to cause tissue damage, as found in iron overload conditions. (Blood. 2003;102:2670-2677)

The Iron Chelator L1 Potentiates Oxidative DNA Damage in Iron-Loaded Liver Cells

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 632-638 ◽  
Author(s):  
Louise Cragg ◽  
Robert P. Hebbel ◽  
Wesley Miller ◽  
Alex Solovey ◽  
Scott Selby ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Iron Overload ◽  
Oxidative Dna Damage ◽  
Iron Chelator ◽  
Liver Cells ◽  
Iron Chelators

Abstract Iron-mediated carcinogenesis is thought to occur through the generation of oxygen radicals. Iron chelators are used in attempts to prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron overload, we studied the generation of iron-catalyzed oxidative DNA damage and the influence of iron chelators, including L1, on such damage. Iron loading of HepG2 cells was found to greatly exacerbate hydrogen peroxide–mediated DNA damage. Desferrithiocin was protective against iron/hydrogen peroxide–induced DNA damage; deferoxamine had no effect. In contrast, L1 exposure markedly potentiated hydrogen peroxide–mediated oxidative DNA damage in iron-loaded liver cells. However, when exposure to L1 was maintained during incubation with hydrogen peroxide, L1 exerted a protective effect. We interpret this as indicating that L1's potential toxicity is highly dependent on the L1:iron ratio. In vitro studies examining iron-mediated ascorbate oxidation in the presence of L1 showed that an L1:iron ratio must be at least 3 to 1 for L1 to inhibit the generation of free radicals; at lower concentrations of L1 increased oxygen radical generation occurs. In the clinical setting, such potentiation of iron-catalyzed oxidative DNA damage at low L1:iron ratios may lead to long-term toxicities that might preclude administration of L1 as an iron chelator. Whether this implication in fact extends to the in vivo situation will have to be verified in animal studies.

The Iron Chelator L1 Potentiates Oxidative DNA Damage in Iron-Loaded Liver Cells

Blood ◽  
1998 ◽  
Vol 92 (2) ◽  
pp. 632-638 ◽  
Author(s):  
Louise Cragg ◽  
Robert P. Hebbel ◽  
Wesley Miller ◽  
Alex Solovey ◽  
Scott Selby ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Damage ◽  
Iron Overload ◽  
Oxidative Dna Damage ◽  
Iron Chelator ◽  
Liver Cells ◽  
Iron Chelators

Iron-mediated carcinogenesis is thought to occur through the generation of oxygen radicals. Iron chelators are used in attempts to prevent the long term consequences of iron overload. In particular, 1,2-dimethyl-3-hydroxypyrid-4-one (L1), has shown promise as an effective chelator. Using an established hepatocellular model of iron overload, we studied the generation of iron-catalyzed oxidative DNA damage and the influence of iron chelators, including L1, on such damage. Iron loading of HepG2 cells was found to greatly exacerbate hydrogen peroxide–mediated DNA damage. Desferrithiocin was protective against iron/hydrogen peroxide–induced DNA damage; deferoxamine had no effect. In contrast, L1 exposure markedly potentiated hydrogen peroxide–mediated oxidative DNA damage in iron-loaded liver cells. However, when exposure to L1 was maintained during incubation with hydrogen peroxide, L1 exerted a protective effect. We interpret this as indicating that L1's potential toxicity is highly dependent on the L1:iron ratio. In vitro studies examining iron-mediated ascorbate oxidation in the presence of L1 showed that an L1:iron ratio must be at least 3 to 1 for L1 to inhibit the generation of free radicals; at lower concentrations of L1 increased oxygen radical generation occurs. In the clinical setting, such potentiation of iron-catalyzed oxidative DNA damage at low L1:iron ratios may lead to long-term toxicities that might preclude administration of L1 as an iron chelator. Whether this implication in fact extends to the in vivo situation will have to be verified in animal studies.

Redox active plasma iron in C282Y/C282Y hemochromatosis

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4527-4531 ◽  
Author(s):  
Caroline Le Lan ◽  
Olivier Loréal ◽  
Tally Cohen ◽  
Martine Ropert ◽  
Hava Glickstein ◽  
...  
Keyword(s):  
Iron Overload ◽  
Oxygen Radicals ◽  
Active Component ◽  
Transferrin Saturation ◽  
Alcoholic Cirrhosis ◽  
Healthy Controls ◽  
Plasma Iron ◽  
Redox Active ◽  
Genetic Hemochromatosis

Abstract Labile plasma iron (LPI) represents the redox active component of non–transferrin-bound iron (NTBI). Its presence in thalassemic patients has been recently reported. The aim of the present study was to quantify LPI in HFE genetic hemochromatosis (GH) and to characterize the mechanisms accounting for its appearance. We studied 159 subjects subdivided into the following groups: (1) 23 with iron overloaded GH; (2) 14 with iron-depleted GH; (3) 26 with dysmetabolic hepatosiderosis; (4) 33 with alcoholic cirrhosis; (5) 63 healthy controls. Both NTBI and LPI were substantially higher in patients with iron-overloaded GH than in those with iron-depleted GH or in healthy controls. LPI was significantly correlated with serum transaminase increase in this group. LPI was elevated in the alcoholic cirrhosis subgroup of severely affected patients. LPI was found essentially when transferrin saturation exceeded 75%, regardless of the etiologic condition. Transferrin saturation above 75% was related to iron overload in GH and to liver failure in alcoholic cirrhosis. LPI is present in C282Y/C282Y hemochromatosis and may be a marker of toxicity due to its potential for catalyzing the generation of reactive oxygen radicals in vivo.

scholarly journals Are Mangiferin and Mangiferin-Containing Plant Extracts Helpful for Iron-Loaded Transfusion-Dependent and Non-Transfusion-Dependent Thalassaemia Patients?

2018 ◽  
Vol 11 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Ari Estuningtyas ◽  
Klaus Zwicker ◽  
Tri Wahyuni ◽  
Purnama Fajri ◽  
Pustika Amalia Wahidiyat ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Complex ◽  
Blood Levels ◽  
Plasma Iron ◽  
Gastric Tubes ◽  
Oral Doses ◽  
Great Burden ◽  
Iron Excretion

Treatment of iron overload in thalassaemia is still a great burden for patients, their families and the health care system in developing countries like Indonesia, because of expensiveness and unwanted side effects of chemical iron-chelating therapeutics. This animal study investigates an extract from the leaves of Mangifera foedica L (EMF) and its major active compound, mangiferin, for chelating and antioxidant treatment of iron overload. Sixty rats were randomly divided into 10 groups: control, iron overload (IO), and IO with mangiferin doses between 50 and 200 mg/g BW or 2390 mg of EMF, applied via gastric tubes. For comparison, deferiprone (DFP) was used. Iron overload was induced by intraperitoneal iron dextran resembling two models, transfusion-dependent (TDT) or nontransfusion-dependent thalassaemia (NTDT). Increasing oral doses of mangiferin and EMF did not result in higher mangiferin plasma levels; however, mangiferin administered for four weeks roughly doubled blood levels compared to two weeks. In the TDT model, mangiferin significantly lowered ferritin levels by 21% and plasma iron levels by 60% (EMF by 50%), almost like DFP (by 70%) and increased iron excretion 6-fold via urine (DFP 15-fold, EMF 2-fold). In the NTDT model mangiferin and EMF decreased ferritin levels significantly by about 30%, without significantly decreasing excess plasma iron. Mangiferin increased iron excretion via urine 4-fold (EMF 2-fold) and tended to diminish Fe accumulation in liver and heart. Iron chelating effects of EMF were weaker than of mangiferin, but its in vivo antioxidant activity was stronger. In vitro, both mangiferin and the mangiferin/FeIII complex are potent superoxide radical scavengers, the iron complex being superior.

scholarly journals Characterization of Weissella viridescens UCO-SMC3 as a Potential Probiotic for the Skin: Its Beneficial Role in the Pathogenesis of Acne Vulgaris

2021 ◽  
Vol 9 (7) ◽  
pp. 1486
Author(s):  
Marcela Espinoza-Monje ◽  
Jorge Campos ◽  
Eduardo Alvarez Villamil ◽  
Alonso Jerez ◽  
Stefania Dentice Maidana ◽  
...  
Keyword(s):  
Immune Response ◽  
Oral Treatment ◽  
Acne Vulgaris ◽  
Topical Administration ◽  
In Vivo Studies ◽  
Mice Model ◽  
Cutibacterium Acnes ◽  
Snail Helix Aspersa

Previously, we isolated lactic acid bacteria from the slime of the garden snail Helix aspersa Müller and selected Weissella viridescens UCO-SMC3 because of its ability to inhibit in vitro the growth of the skin-associated pathogen Cutibacterium acnes. The present study aimed to characterize the antimicrobial and immunomodulatory properties of W. viridescens UCO-SMC3 and to demonstrate its beneficial effect in the treatment of acne vulgaris. Our in vitro studies showed that the UCO-SMC3 strain resists adverse gastrointestinal conditions, inhibits the growth of clinical isolates of C. acnes, and reduces the adhesion of the pathogen to keratinocytes. Furthermore, in vivo studies in a mice model of C. acnes infection demonstrated that W. viridescens UCO-SMC3 beneficially modulates the immune response against the skin pathogen. Both the oral and topical administration of the UCO-SCM3 strain was capable of reducing the replication of C. acnes in skin lesions and beneficially modulating the inflammatory response. Of note, orally administered W. viridescens UCO-SMC3 induced more remarkable changes in the immune response to C. acnes than the topical treatment. However, the topical administration of W. viridescens UCO-SMC3 was more efficient than the oral treatment to reduce pathogen bacterial loads in the skin, and effects probably related to its ability to inhibit and antagonize the adhesion of C. acnes. Furthermore, a pilot study in acne volunteers demonstrated the capacity of a facial cream containing the UCO-SMC3 strain to reduce acne lesions. The results presented here encourage further mechanistic and clinical investigations to characterize W. viridescens UCO-SMC3 as a probiotic for acne vulgaris treatment.

scholarly journals Bioinspired organometallic chemistry

2002 ◽  
Vol 74 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Lanny S. Liebeskind ◽  
Jiri Srogl ◽  
Cecile Savarin ◽  
Concepcion Polanco
Keyword(s):  
Organometallic Chemistry ◽  
Refractory Metal ◽  
Redox Active ◽  
The Stability ◽  
New Procedures ◽  
Sulfur Containing ◽  
Insight Into

Given the stability of the bond between a mercaptide ligand and various redox-active metals, it is of interest that Nature has evolved significant metalloenzymatic processes that involve key interactions of sulfur-containing functionalities with metals such as Ni, Co, Cu, and Fe. From a chemical perspective, it is striking that these metals can function as robust biocatalysts in vivo, even though they are often "poisoned" as catalysts in vitro through formation of refractory metal thiolates. Insight into the nature of this chemical discrepancy is under study in order to open new procedures in synthetic organic and organometallic chemistry.

scholarly journals In vivo and In vitro Antioxidant Activities of Aqueous and Ethanol Stem Bark Extracts of Vitex doniana on Doxorubicin-induced Oxidative Stress in Rats

2021 ◽  
pp. 44-55
Author(s):  
Mohammed Aliyu Sulaiman ◽  
Daniel Dahiru ◽  
Mohammed Auwal Ibrahim ◽  
Ahmed Ibrahim Hayatu
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Activities ◽  
Ischemia Reperfusion ◽  
Oral Treatment ◽  
Stem Bark ◽  
Albino Rats ◽  
Associated Diseases ◽  
Vitex Doniana

Background: Oxidative stress is involved in the pathogenesis of hypertension, myocardial ischemia-reperfusion injury, atherosclerosis, muscular dystrophy, aging and other associated diseases. Vitex doniana is used in Adamawa, northern Nigeria to treat oxidative stress associated diseases. However, the antioxidative effects of the plant have not been scientifically examined in oxidative stress experimental animal models. The aim of this study is to investigate the in vitro and in vivo antioxidant activities of aqueous and ethanol stem bark extracts of Vitex doniana in oxidative stress model of rats. Methods: The study used 35 adult albino rats weighing 175 ± 25 g, of which 30 were induced with oxidative stress by intraperitoneal injection of doxorubicin (10 mg/kg) for three consecutive days. Animals were treated by oral administration of silymarin (100 mg/kg) and Vitex doniana aqueous or ethanol extract (100 mg/kg and 200 mg/kg) for 14 consecutive days before they were sacrificed on the 15th day and blood was analyzed for biochemical indices of oxidative stress. Results: The results of the phytochemistry showed the presence of alkaloids, tannins, flavonoids, steroids, phenols, saponins, terpenoids, glycosides: and total flavonoids (52.70 ± 1.60 mg/ml and 75.40 ± 0.80 mg/ml), total phenols (21.45 ± 1.54 mg/ml and 26.50 ± 1.22 mg/ml) for aqueous and ethanol stem bark extracts respectively. The extracts scavenged DPPH radical, reduced Fe3+ and inhibited lipid peroxidation. Doxorubicin significantly (p<0.05) lowered the levels of SOD, CAT, GR and TAS and significantly (p<0.05) but, increased the level of LPO. Oral treatment with Vitex doniana extracts significantly (p<0.05) increased the activities of CAT, GR, SOD and TAS while LPO was significantly (p<0.05) lowered. Vitex doniana stem bark extracts significantly (p<0.05) improved the biochemical derangements observed in the induced untreated animals in comparable manner to that of Silymarin. Conclusion: The present study provides the scientific rationale for the use of Vitex doniana stem bark in traditional medicine and has a viable antioxidative capacity both in vitro and in vivo.

FimH Antagonists for the Oral Treatment of Urinary Tract Infections: From Design and Synthesis to in Vitro and in Vivo Evaluation

2010 ◽  
Vol 53 (24) ◽  
pp. 8627-8641 ◽  
Author(s):  
Tobias Klein ◽  
Daniela Abgottspon ◽  
Matthias Wittwer ◽  
Said Rabbani ◽  
Janno Herold ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Urinary Tract Infections ◽  
Oral Treatment ◽  
In Vivo Evaluation ◽  
Design And Synthesis ◽  
Tract Infections

Abstract 064: The Lipoxigenase Inhibitor Nordihydroguaiaretic Acid Prevents the Development of Hypoxia-Induced Pulmonary Hypertension in Mice

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Andrea Iorga ◽  
Gabriel Wong ◽  
Denise Mai ◽  
Jingyuan Li ◽  
Salil Sharma ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Smooth Muscle Actin ◽  
Nordihydroguaiaretic Acid ◽  
Treated Group ◽  
Oxidation Products ◽  
Lipoxygenase Inhibitor ◽  
Human Pulmonary Artery

Pulmonary hypertension (PH) is a chronic lung disease characterized by progressively elevated pulmonary arterial pressures and severe pulmonary vascular remodeling resulting from interactions between oxidized lipoprotein deposition and increased endothelial proliferation. Previously we have shown increased plasma levels of biological oxidation products such as hydroxyoctadecadienoic acids (HODEs) and hydroxyeicosatetraenoic acids (HETEs) in the rat monocrotaline model of PH. Here we investigated the role of HETEs and HODEs in the development of PH and whether their inhibition with the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) attenuates the progression of PH. Mice were placed in a hypoxic chamber with O2 concentrations of ≤10% for 21 days and either left untreated to develop PH (n=7) or treated with NDGA daily (10mg/kg/day, i.p., n=4) from day 1. Direct RV catheterization was terminally performed to record RV pressure (RVP). Pulmonary arteriolar thickening and oxidized lipid deposition were assessed by staining lung sections with Masson’s Trichrome or with α-smooth muscle actin and E-06 (marker for oxidized low-density lipoproteins). In vitro, human pulmonary artery smooth muscle cell (hPASMC) proliferation was assessed by MTT assays in the absence or presence of 12-HETE (100ng/ml), 9-HODE (1µg/ml) and 13-HODE (1µg/ml) alone or together with NDGA (10, 25 and 50µM). In-vitro, HETE/HODE treatment increased hPASMC proliferation ~ 2-fold when compared to untreated cells and NDGA significantly inhibited the proliferative effects of all three oxidized lipids. In-vivo, NDGA treatment prevented the development of PH. RVP was lower in the NDGA-treated group vs. the PH group (24.01±1.39mmHg vs. 36.91±5.74mmHg, p<0.05) and was comparable to control normoxic mice (20.93±2.52mmHg). RV hypertrophy index was significantly elevated in the PH mice versus control mice (0.38±0.03 vs. 0.28±0.02 (p<0.001), while NDGA treatment completely prevented the development of RV hypertrophy (0.28±0.04). Lung sections demonstrated arteriolar thickening and E-06 positive deposits in the PH group, which was prevented by NDGA therapy. We conclude that oxidized fatty acid deposition and accumulation might play a role in the development of PH.

scholarly journals The effect of N-alkyl modification on the antimalarial activity of 3- hydroxypyridin-4-one oral iron chelators

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 637-643 ◽  
Author(s):  
C Hershko ◽  
EN Theanacho ◽  
DT Spira ◽  
HH Peter ◽  
P Dobbin ◽  
...  
Keyword(s):  
Antimalarial Activity ◽  
Iron Chelators ◽  
Lipid Solubility ◽  
Lipophilic Compounds ◽  
Labile Iron Pool ◽  
Ring Nitrogen ◽  
Iron Pool ◽  
Chelating Compounds

Abstract The antimalaria effect of iron chelators is attributed to their interaction with a labile iron pool within parasitised erythrocytes, and it was postulated that increased affinity to iron as well as increased lipophilicity may improve antimalarial activity. In the present study we have examined the antimalarial effect of 3- hydroxypyridin-4-ones, a family of bidentate orally effective iron chelators whose lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. A significant dose-related suppression of Plasmodium falciparum cultures was observed with all drugs tested in vitro at concentrations of 5 mumol/L or higher. In contrast, there was a clear segregation of the in vivo effect on P berghei in rats (300 mg/kg/d subcutaneous) into two categories: compounds CP20, 38, and 40 failed to suppress malaria, whereas CP51, 94, and 96 had a strong antimalarial effect, similar or better than deferoxamine. There was a close linear correlation between the suppression of peak parasite counts and the reduction in hepatic nonheme iron induced by the various drugs tested (r = .9837). The most lipophilic compounds were also the most effective in suppressing malaria and in depleting hepatic iron stores. These data indicate that 3-hydroxypyrydin-4-ones are able to suppress malaria in vivo and in vitro. Because lipid solubility is an important determinant of antimalarial action, our study provides useful information regarding the selection of orally effective iron-chelating compounds that may be suitable for clinical application as antimalarial agents.

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