Iron as the malignant spirit in successful ageing

Iron enhances the production of the highly reactive and toxic hydroxyl radical, thus stimulating oxidative damage. Iron has been associated with a number of oxidative injury-dependent, age-related conditions and diseases. Indeed, oxidative injury is a major factor of (accelerated) ageing. This commentary reviews part of the existing literature on iron's deleterious effects, particularly in the context of ischemia-reperfusion injury and cardiovascular, brain and muscle diseases as well as skin ageing. Furthermore, the advantages of iron chelation are presented. Indeed, iron chelation or deprivation has been shown to act as a potent anti-oxidant in a variety of animal models of human diseases, preventing oxidative stress to tissues and organs. Iron chelators favor successful ageing in general, and when applied topically, successful skin ageing. It has also been proposed that gender-related differences in iron status are responsible for the increased longevity of women as compared to men. Despite this evidence, the role of iron in ageing and the possibilities of pharmacologically targeting iron have remained essentially unexplored. Iron thus appears as the "malignant spirit" in successful ageing.     

Pro-oxidant effects of normobaric hyperoxia in rat tissues.

Rats were exposed to 100% O2 atmosphere for 12, 36 or 48 h, and their lungs, brain, liver and kidneys were studied for signs of oxidative damage. Oxidative damage at molecular level was estimated by: (1) the appearance of conjugated diene double bonds and (2) the amount of fluorescent chromolipids in lipids extracted from tissues. As important intracellular regulators of oxidative stress, the response of enzymes detoxifying reactive oxygen species was also studied. Macroscopically, the brain and the lungs were most susceptible to oxygen-induced effects. As an indication of oxidative tissue damage, hyperoxia caused accumulation of fluorescent chromolipids in brain and lung tissues, whereas diene conjugation did not reveal any signs of lipid peroxidation. Accumulation of fluorescent chromolipids was most prominent in the brain, where 99 and 138% increases over the control were detected after 36 and 48 h hyperoxia, respectively. Fluorescent chromolipids appeared in urine already before their concentrations were elevated in tissues. The activity of superoxide dismutase in the brain was initially decreased, followed then by a slight induction of activity at the later time-points. Pulmonary and hepatic catalase activities were markedly decreased after prolonged (36 and 48 h) hyperoxia. In conclusion, fluorescent chromolipid formation seems to be a sensitive indicator of hyperoxia-induced oxidative damage in rat tissues. The lipid peroxidation-derived fluorescent chromolipids are eliminated from the body via urinary excretion. Moreover, impaired detoxication of reactive oxygen may be implicated in tissue damage due to hyperoxia.     

Inhibition of phagocytosis and chemiluminescence in human leukocytes by a lipid soluble factor in normal tissues.

Homogenates of normal rat tissues inhibited several functional parameters of normal human peripheral blood leukocytes, including luminol-dependent chemiluminescence induced by both soluble (phorbol myristate acetate) and particulate (Escherichia coli) stimuli; in vitro uptake of radiolabeled E. coli; and in vitro phagocytosis and killing of E. coli. The doses of rat tissue protein that caused a 50% inhibition of leukocyte chemiluminescence were ca. 6.2 micrograms for small intestine, 83 micrograms for kidney; 100 micrograms for heart; 132 micrograms for liver, 190 micrograms for skeletal muscle, and 307 micrograms for brain. The putative phagocytosis inhibitor (PI) in rat liver was more plentiful in particulate fractions than in the cytosol. The PI activity in the original or Miranol-solubilized rat liver homogenate was nondialyzable, and it was reduced substantially by heating at 90 degrees C for 30 min but not at 56 degrees C for 30 min. It was unaffected by aprotinin, a potent inhibitor of proteolytic activity. Treatment of tissues with trypsin did not reduce PI activity, whereas treatment with phospholipase A2 clearly increased it. The bulk (up to 88%) of PI in rat liver or small intestine could be extracted by lipid solvents, e.g., diethyl ether. Purified fatty acids were potent inhibitors of leukocyte chemiluminescence; other lipids had little or no inhibiting activity. The various data suggest that (i) normal tissues contain a potent PI and (ii) that the PI is a lipid moiety.     

Muscle mechano growth factor is preferentially induced by growth hormone in growth hormone-deficient lit/lit mice

Two muscle insulin-like growth factor-I (IGF-I) mRNA splice variants (IGF-IEa and IGF-IEb) have been identified in rodents. IGF-IEb, also called mechano growth factor (MGF) has been found to be upregulated by exercise or muscle damage. Growth hormone (GH) is the principal regulator of  IGF-I expression in several tissues including skeletal muscle. Therefore, we investigated the effect of chronic GH excess or disruption of GH receptor (GHR) signalling, and the acute effect of GH administration on expression of muscle IGF-I isoforms using transgenic mice that express bovine GH (bGH), GHR gene-disrupted (GHR–/–) mice and GH-deficient lit/lit mice before and after exogenous GH administration. MGF mRNA in skeletal muscle was increased in bGH mice whereas it was decreased in GHR–/– mice compared with control animals. Exogenous GH administration to dwarf lit/lit mice significantly increased muscle MGF but not IGF-IEa mRNA 4 h after treatment. Twelve hours after GH treatment, both MGF and IGF-IEa mRNAs in muscle were increased compared with vehicle-treated lit/lit mice. In contrast in GH-sufficient lit/+ mice, both MGF and IGF-IEa mRNAs were increased 4 h after and returned to the basal level 12 h after GH treatment. Hepatic IGF-I isoforms were regulated in parallel by GH. Thus, our results demonstrated that: (1) MGF mRNA in skeletal muscle is expressed in parallel with GH action; (2) MGF mRNA in muscle is produced preferentially in the situation of GH deficiency in contrast to the pattern in the GH-sufficient state; and (3) the induction of IGF-I isoforms by GH is tissue-specific.     

Body fluid derived exosomes as a novel template for clinical diagnostics

Background

GH and IGFs serum levels decline with age. Age-related changes appear to be associated to decreases in these anabolic hormones. We have previously demonstrated that IGF-I replacement therapy improves insulin resistance, lipid metabolism and reduces oxidative damage (in brain and liver) in aging rats. Using the same experimental model, the aim of this work was to study whether the exogenous administration of IGF-II, at low doses, acts analogous to IGF-I in aging rats.

Methods

Three experimental groups were included in this study: young healthy controls (yCO, 17 weeks old); untreated old rats (O, 103 weeks old); and aging rats treated with IGF-II (O+IGF-II, 2 μg * 100 g body weight^-1 * day^-1) for 30 days. Analytical parameters were determined in serum by routine laboratory methods using an autoanalyzer (Cobas Mira; Roche Diagnostic System, Basel, Switzerland). Serum levels of hormones (testosterone, IGF-I and insulin) were assessed by RIA. Serum Total Antioxidant Status was evaluated using a colorimetric assay. Mitochondrial membrane potential was evaluated using rhodamine 123 dye (adding different substrates to determine the different states). ATP synthesis in isolated mitochondria was determined by an enzymatic method.

Results

Compared with young controls, untreated old rats showed a reduction of IGF-I and testosterone levels with a decrease of serum total antioxidant status (TAS). IGF-II therapy improved serum antioxidant capability without modifying testosterone and IGF-I circulating concentrations. In addition, IGF-II treatment reduced oxidative damage in brain and liver, improving antioxidant enzyme activities and mitochondrial function. IGF-II was also able to reduce cholesterol and triglycerides levels increasing free fatty acids concentrations.

Conclusions

We demonstrate that low doses of IGF-II induce hepatoprotective, neuroprotective and metabolic effects, improving mitochondrial function, without affecting testosterone and IGF-I levels.     

Insulin-like growth factor-I stimulates erythropoiesis when administered enterally

BACKGROUND: Insulin-like growth factors I and II (IGF-I and IGF-II) are potent growth factors involved in development. IGF-I stimulates proliferation of erythropoietic progenitors and parenteral IGF-I administration stimulates in vivo erythropoiesis in animals. IGF-I and IGF-II are both present in mammalian milks and when milk-borne, are resistant to neonatal gastrointestinal degradation. Whether milk-borne IGF-I or IGF-II regulates neonatal erythropoiesis in not known. We hypothesized that physiological doses of enteral IGFs stimulate erythropoiesis in suckling rats. METHODS: Eight day-old Sprague Dawley rats were artificially fed for 4 days with rat milk substitute (RMS) or RMS supplemented with physiological levels of IGF-I or IGF-II. Rats fed IGF-I and IGF-II were compared to control RMS. Blood and marrow were collected; measures of red cell mass, measures of erythropoietic stimulus, and indices of iron status were measured. RESULTS: Rats fed IGF-I had higher hemoglobin (Hb) levels (100 +/- 10 g/l), compared to those fed RMS (94 +/- 9) or IGF-II (91 +/- 6), p < 0.001. After IGF-I supplementation, red blood cell counts (RBC) (p < 0.04) and hematocrits (p < 0.002) were also higher. Plasma erythropoietin (Epo) levels, reticulocytes, plasma iron and erythrocyte iron incorporation were similar. CONCLUSION: Intact enteral IGF-I reaches distal erythropoietic tissue resulting in greater red cell mass, but not by increasing plasma Epo levels or by altering cellular iron transport.     

Pro-oxidant effects of normobaric hyperoxia in rat tissues

Rats were exposed to 100% O₂ atmosphere for 12, 36 or 48 h, and their lungs, brain, liver and kidneys were studied for signs of oxidative damage. Oxidative damage at molecular level was estimated by: (1) the appearance of conjugated diene double bonds and (2) the amount of fluorescent chromolipids in lipids extracted from tissues. As important intracellular regulators of oxidative stress, the response of enzymes detoxifying reactive oxygen species was also studied. Macroscopically, the brain and the lungs were most susceptible to oxygen-induced effects. As an indication of oxidative tissue damage, hyperoxia caused accumulation of fluorescent chromolipids in brain and lung tissues, whereas diene conjugation did not reveal any signs of lipid peroxidation. Accumulation of fluorescent chromolipids was most prominent in the brain, where 99 and 138% increases over the control were detected after 36 and 48 h hyperoxia, respectively. Fluorescent chromolipids appeared in urine already before their concentrations were elevated in tissues. The activity of superoxide dismutase in the brain was initially decreased, followed then by a slight induction of activity at the later time-points. Pulmonary and hepatic catalase activities were markedly decreased after prolonged (36 and 48 h) hyperoxia. In conclusion, fluorescent chromolipid formation seems to be a sensitive indicator of hyperoxia-induced oxidative damage in rat tissues. The lipid peroxidation-derived fluorescent chromolipids are eliminated from the body via urinary excretion. Moreover, impaired detoxication of reactive oxygen may be implicated in tissue damage due to hyperoxia.     

新生大鼠缺氧缺血性脑病脑内脂质过氧化物的变化

本文测定生后６－７天大鼠氧缺血性脑病（ＨＩＥ）时脑组织内脂质过氧化物（ＬＰＯ）的动态变化，以及ＨＩＥ后吸不同浓度氧对脑组织（ＬＰＯ）的影响。结果显示，ＨＩＥ发生后２ｈ脑内ＬＰＯ即明显增高，１２ｈ达到高峰，２４ｈ后开始下降，到７２ｈ恢复正常。表明ＨＩＥ时脑内自由基产生增加，由其引发的脂质过氧化损伤主要发生在发病初期，特别是病后２４ｈ之内。ＨＩＥ大鼠吸入不同浓度Ｏ２后测定脑组织中ＬＰＯ变化，结果吸纯Ｏ     

Ferritin and desferrioxamine attenuate xanthine oxidase-dependent leak in isolated perfused rat lungs

Iron, through its participation in reactions that generate reactive oxygen species, may contribute to the oxidative lung injury observed in patients with acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). A number of investigators have shown that the endogenous iron storage protein ferritin increases in the blood of patients with and at-risk for ALI and ARDS, but the significance of these increases are not known. In the present investigation, we measured lung tissue levels of thiobarbituric acid reactive substances (TBARS) and lung leak in isolated rat lungs perfused with xanthine oxidase (XO) and purine, an enzymatic system which generates reactive oxygen species. We found that adding ferritin (100 ng/mL) or desferrioxamine (DFO, 10 mM), an iron chelator, to the vascular perfusate solution decreased oxidant-induced leak in isolated rat lungs perfused with XO and purine. Addition of ferritin or DFO also decreased TBARS in isolated rat lungs perfused with XO and purine; neither ferritin nor DFO, however, decreased XO activity in vitro. Our results suggest that oxidative lung leak may be altered by the availability of reactive iron and that ferritin may contribute to protection against oxidative lung injury.     

The protective properties of melatonin against aluminium‐induced neuronal injury

Aluminium (Al) toxicity is closely linked to the pathogenesis of Alzheimer's disease (AD). This experimental study investigated the neuroprotective effect of melatonin (Mel; 10 mg/kg bwt) on aluminium chloride (AlCl₃; 34 mg/kg bwt) induced neurotoxicity and oxidative stress in rats. Adult male albino Wistar rats were injected with AlCl₃ for 7 days. The effect on brain structure, lipid peroxidation (LPO), nitric oxide (NO) levels, glutathione (GSH) content, antioxidant enzymes (SOD, CAT, GPx and GR), apoptotic proteins (Bax and Bcl‐2) and an apoptotic enzyme (caspase‐3) was investigated. No apparent changes occurred following the injection of melatonin. Melatonin pretreatment of the AlCl₃‐administered rats reduced brain damage, and the tissues appeared like those of the control rats. Compared to treatment with AlCl₃, pretreatment with melatonin decreased LPO and NO levels and increased the GSH content and antioxidant enzyme activity. Moreover, melatonin increased the levels of the anti‐apoptotic protein, Bcl‐2, decreased the levels of the pro‐apoptotic protein, Bax, and inhibited caspase‐3 activity. Therefore, our results indicate that melatonin may provide therapeutic value against aluminium‐induced oxidative stress and histopathological alternations in the rat brain and that these effects may be related to anti‐apoptotic and antioxidant activities.     

New antidepressant drugs that do not cross the blood-brain barrier

Stimulation of neurogenesis in the adult brain (i.e. in the hippocampus) has recently been proposed as a putative mechanism of antidepressant action of drugs. This effect of antidepressants may not be achieved by their primary action on proliferating cells, but may involve the drug-triggered mobilization of trophic factors, such as brain-derived neurotrophic factor (BDNF), glia-derived protein S100 beta, or insulin-like growth factor I (IFG-I). Whereas BDNF and S100 beta are produced in the brain, IGF-I is primarily released from peripheral tissues. Administered peripherally, IGF-I increases hippocampal neurogenesis in the adult rat. Because synthesis and release of IGF-I appear to be stimulated by serotonergic mechanisms, we propose that antidepressants that affect serotonergic mechanisms might be rendered more effective by mobilizing IGF-I. Moreover, we suggest that new antidepressant drugs could be designed that would not enter into the brain but would stimulate peripheral mediators such as IGF-I.     

Ameliorative effect of Opuntia ficus indica juice on ethanol-induced oxidative stress in rat erythrocytes

The aim of the present study was to investigate the efficacy of Opuntia ficus indica f. inermis fruit juice (OFIj) on reversing oxidative damages induced by chronic ethanol intake in rat erythrocytes. OFIj was firstly analyzed with HPLC for phenolic and flavonoids content. Secondly, 40 adult male Wistar rats were equally divided into five groups and treated for 90 days as follows: control (C), ethanol-only 3 g/kg body weight (b.w) (E), low dose of OFIj 2 ml/100 g b.w + ethanol (Ldj + E), high dose of OFIj 4 ml/100 g b.w + ethanol (Hdj + E), and only a high dose of OFIj 4 ml/100 g b.w (Hdj). HPLC analysis indicated high concentrations of phenolic acids and flavonoids in OFIj. Ethanol treatment markedly decreased the activities of erythrocyte superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and the level of reduced glutathione (GSH). Changes in the erythrocyte's antioxidant ability were accompanied by enhanced oxidative modification of lipids (increase of malondialdeyde level) and proteins (increase in carbonyl groups). Interestingly, pre-administration of either 2 ml/100 g b.w or 4 ml/100 g b.w of OFIj to ethanol-intoxicated rats significantly reversed decreases in enzymatic as well as non enzymatic antioxidants parameters in erythrocytes. Also, the administration of OFIj significantly protected lipids and proteins against ethanol-induced oxidative modifications in rat erythrocytes. The beneficial effect of OFIj can result from the inhibition of ethanol-induced free radicals chain reactions in rat erythrocytes or from the enhancement of the endogenous antioxidants activities.     

Long-term treatment with SMS 201–995 in resistant acromegaly: Effectiveness of high doses and continuous subcutaneous infusion

Summary Seventeen patients (8 women and 9 men) resistant to all other forms of therapy were treated with the somatostatin analogue SMS 201-995 (octreotide, Sandostatin^®). The duration of treatment ranged from 1 to 5 years. Mean GH levels of only 4 patients were suppressed under 5 g/L during an 8 h serum profile with the standard dose of 0.1 mg 2 or 3 times daily. This standard dose suppressed mean GH levels in 10 other patients more than 50% of baseline, but for optimal effect higher doses up to 1.5 mg, 4 daily injections or continuous subcutaneous infusion (CSI) were needed. Octreotide had no influence on GH secretion in 3 patients. Suppression of mean GH levels under 5 g/L was achieved in 10 patients. Normalization of insulin-like growth factor I (IGF-I) occured in only 5 patients. Altogether, therapy with SMS 201-995 reduced GH levels from 23.8±32.2 g/L (mean±SD) to 6.7±5.0 g/L by 71.8% and IGF-I levels from 7.9±3.1 U/ml to 3.2±1.6 U/ml by 59.5%.We conclude that 1) treatment with SMS 201-995 in patients resistant to other forms of therapy may be less successful than previously reported for heterogenous groups of patients; 2) the dose regimen must be adapted to the individual patient for optimal effect and most of our patients needed higher doses than 300 g daily; 3) 4 or maybe more daily injections or CSI seem to be most effective; and 4) in a minority of patients SMS has no influence on GH-secretion.Abbreviations CSI continuous subcutaneous infusion - CT computerized tomography - GH growth hormone - IGF-I insulin-like growth factor I=Somatomedin-C - IRMA immunoradiometric assay - MRI magnetic resonance imaging - PRL prolactin - RIA radioimmunoassay - SD standard deviation - SMS octreotide=Sandostatin^® - TSH thyreoidea stimulating hormone - T4 thyroxine This work was supported by the Deutsche Forschungsgemeinschaft (Mue 585/3-3). Parts of this work were presented on the 34. Symposium Deutsche Gesellschaft für Endokrinologie Hannover, March 1990 (Acta Endocrinologica Suppl. 1 Vol. 122 (1990), 14)     

Somatotroph response to periodical IGF-I administration to male rats

Insulin-like growth factor I (IGF-I) downregulates growth hormone (GH) expression in pituitary cell cultures. However, in vivo different results were found depending on the experimental protocol used. We determined the kinetics of changes of pituitary and serum GH concentrations after subcutaneous IGF-I administration (240µg/100 g body weight) to rats every 12h for various periods. These parameters were correlated with changes in the somatotroph cell population. A significant increase in serum GH was registered at 6h after IGF-I injection. At this time, some somatotroph cells exhibited ultrastructurally signs of high secretory activity, whereas adjacent somatotroph cells showed a quiescent appearance with sizeable stores of secretory granules. In contrast, serum GH levels remained unchanged at 1, 2 and 12h after each IGF-I injection. Pituitary GH concentrations were comparable to control levels during the first 48h and declined significantly at 72h and 96h of IGF-I treatment. After these prolonged periods of time of treatment, the size and extension of organelles involved in protein synthesis decreased and mature secretory granules in the cytoplasm increased significantly in GH-secreting cells. The somatotroph cell density remained unchanged even at 96h of treatment. In conclusion, our results suggest that periodical IGF-I administration to rats does not inhibit GH secretion. Interestingly, IGF-I injections induced early and significant increases in serum GH levels. This result may be a consequence of a temporary stimulatory action on somatotroph cells concurrent with increased secretory activity.Key words:     

Mitochondrial damage induced by fetal hyperphenylalaninemia in the rat brain and liver: its prevention by melatonin, Vitamin E, and Vitamin C

Abnormal oxidative stress was observed in hyperphenylalaninemia and other inborn errors of intermediary metabolism, owing to the accumulation of toxic metabolites, free radical production and increased LPO products. In our model of maternal hyperphenylalaninemia, pregnant rats were injected with 300 mg/kg BW l-phenylalanine (PHE) and 50 mg/kg BW p-chlorophenylalanine (PCPA) dissolved in saline. In this research study, we measured LPO-by-products, i.e., malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) and we demonstrated that maternal hyperphenylalaninemia increased both markers of oxidative stress in the brain and liver mitochondria of the pups. We also demonstrated that administration of melatonin, Vitamin E, and Vitamin C, in this order of potency, prevented the oxidative damage to the mitochondria, especially in the brain. We therefore conclude that maternal hyperphenylalaninemia induces a clear state of oxidative stress that is somehow directly involved in brain and liver impairment, which can be prevented by melatonin, Vitamin E, and Vitamin C.     

On the benefit of galls of Quercus brantii Lindl. in murine colitis: the role of free gallic acid

Introduction

In this study we investigated the effect of gall of Quercus brantii Lindl., a traditional Iranian medicine, in a murine model of experimental colitis induced in male rats by rectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS).

Material and methods

Quantification of the main active components was done for estimation of total phenolic content and free gallic acid. Gall of Quercus brantii Lindl. in two forms (gall powder and gall hydro alcoholic extract) was gavaged for 10 days (500 mg/kg). Ten days after induction of colitis, colonic status was examined by macroscopic, microscopic and biochemical analyses. Colonic tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were analyzed as biomarkers of inflammatory condition. To determine the role of oxidative stress (OS) in colitis, the levels of cellular lipid peroxidation (LPO), total antioxidant power (TAP) and myeloperoxidase (MPO) were measured in colon tissues.

Results

TNBS-induced colitis exhibited a significant increase in colon MPO activity and concentrations of cellular LPO, TNF-α and IL-1β, while TAP was significantly reduced. Microscopic evaluations of the colonic damage in the colitis group revealed multifocal degenerative changes in the epithelial lining and areas of necrosis, extensive mucosal and sub-mucosal damage with congested blood vessels, edema and hemorrhages along with extensive infiltration of inflammatory cells. Parameters including macroscopic and microscopic scores, TNF-α, IL-1β, LPO, TAP and MPO improved by both gall extract and gall powder of Quercus brantii Lindl. and reached close to normal levels. The level of total phenols (GAE/100 g of sample) and free gallic acid were estimated to be 88.43 ±7.23 (mean ± SD) and 3.74% of dry weight, respectively.

Conclusions

The present study indicates that the gall of Quercus brantii Lindl. is able to exert antioxidative and anti-inflammatory effects on the biochemical and pathological parameters of colitis.     

Concentration of iron and distribution of iron and transferrin after experimental iron overload in rat tissues in vivo: study of the liver, the spleen, the central nervous system and other organs

The purpose of this study was to estimate the iron concentration in the liver, spleen and brain of control rats and rats overloaded with iron and to determine the distribution of iron and of transferrin (TF). Iron was administered to Wistar rats by food supplemented with 3% carbonyl iron for 3 months, or intraperitoneally, or intraveneously as iron polymaltose for 4 months (total administered dose: 300 or 350 mg/rat, respectively). Iron concentration was estimated by atomic absorption spectrophotometry and iron- and TF-distribution histochemically and immunohistochemically, respectively. In control rats the organ with the highest iron content was the spleen, followed by the liver and brain. After iron loading the increase of iron in the liver was greater than that of the spleen; iron concentration in the brain did not change significantly. Distribution of iron in the liver was in Kupffer cells throughout the lobule and in hepatocytes at its periphery. No difference in the number of positive cells or staining intensity for TF was observed between control rats and iron overloaded animals in the liver or central nervous system (CNS); the spleen was negative for TF. Distribution of TF in the liver showed a centrilobular localisation in hepatocytes. TF reaction in the brain occurred in oligodendrocytes, vessel walls, choroid plexus epithelial cells and some neurons. In conclusion, experimental iron overload in rats leads to iron uptake mainly by reticuloendothelial (RE) cells and hepatocytes, indicating that hepatocytes are of particular importance for iron metabolism. Iron uptake by the brain was not significant, probably because the brain is protected against iron overload. Iron overload did not influence location and quantity of TF in the liver and CNS, whereas the visualisation of iron and TF did not coincide. This indicates that TF may have other functions beyond iron transport.     

Iron storage diseases in birds

Parenteral iron is toxic to many species but, because the uptake of iron from the diet is regulated in the intestine, acute intoxication is not seen under natural conditions. Chronic ingestion of large amounts of absorbable iron in the diet can lead to the storage of iron in the liver in many species, including humans. The excess iron is stored within hepatocytes as haemosiderin and can be quantitatively assessed by liver biopsy or at necropsy using special stains such as Perls iron stain and/or biochemical tests. Iron may also be found within the Kupffer cells in the liver and the macrophage cells of the spleen especially where concurrent diseases are present such as haemolytic anaemia, septicaemia, neoplasia and starvation. Iron accumulation in the liver, also known as haemosiderosis, may not always be associated with clinical disease although in severe cases hepatic damage may occur. It is probable that concurrent disease conditions are largely responsible for the degree and nature of the pathological changes described in most cases of haemosiderosis. In some human individuals there may be a genetic predisposition to iron storage disease, haemochromatosis, associated with poor regulation of iron uptake across the intestine. In severe cases iron pigment will be found in the liver, spleen, gut wall, kidney and heart with subsequent development of ascites, heart failure and multisystem pathology. Clinical disease associated with accumulation of iron in the liver, and other tissues, has been reported in many species of bird although it is most commonly reported in Indian hill mynas ( Gracula religiosa ) and toucans ( Ramphastos sp ). It is likely that the tolerance to the build up of tissue iron varies in individual species of bird and that the predominant predisposing factors may differ, even within closely related taxonomic groups.     

Are lipid peroxidation processes induced by changes in the cell wall structure and how are these processes connected with diseases?

Apparently nature uses the unique sensitivity of polyunsaturated fatty acids (PUFAs) versus oxygen to generate chemical signals if the surface of a cell is influenced by an outside or inside event; for instance the attack of microorganisms, proliferation, aging or by treatment of isolated cells with surfactants. It seems that mammalian and plant cells respond equally to such changes in their structures by transformation of polyunsaturated fatty acids localized in the phospholipid layer of the cell wall to lipidhydroperoxides (LOOHs). These lipid peroxidation (LPO) processes involve all PUFAs, not only arachidonic acid.Slight physiological changes of the cell wall for instance by proliferation seem to activate enzymes, e.g., phospholipases and lipoxygenases (LOX). When an outside impact (for instance by attack of microorganisms) exceeds a certain level LOX commit suicide and liberate iron ions. These start a nonenzymatic LPO. Enzymatic and nonenzymatic LPO distinguish fundamentally which has not been recognized in the past. In the enzymatic LPO processes peroxyl radicals generated as intermediates cannot leave the enzyme complex. In contrast in a nonenzymatic LPO process peroxyl radicals are not trapped. They attack nearly any kind of biological molecules, for instance proteins. Thus only the amount of an outside impact decides if proliferation, apoptosis, or necrosis is started.Some evidence indicates that cancer might be the consequence of a low response of cells to induce apoptotic LPO processes. In contrast to high level of LPO processes induces diseases combined with inflammation, for instance rheumatic arthritis. After consumption of food rich in linoleic acid its LPO products become increased in low density lipoprotein (LDL). This LDL is able to enter endothelial cells and damage cells from inside, long before an inflammatory response is detectable.