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PubMed2001

Quantitative analysis of cell death and ferritin expression in response to cortical iron: implications for hypoxia-ischemia and stroke.

Iron that is not bound to storage proteins can catalyse the generation of toxic hydroxyl radicals. Iron can be released from brain storage proteins by hypoxic conditions, such as those that accompany stroke, and the situation can be compounded by iron released from hemoglobin in extravasated blood cells. Despite the neurotoxicity of iron, there is little quantitative data concerning the spatio-temporal extent of its toxicity in vivo. The present study measures the effects of a pathologically relevant concentration of iron (1.0 mM) on neuronal death and on ferritin expression in vivo. Injection of iron (1 microl ferric ammonium citrate) into rat parietal cortex resulted in 7.9-fold more ferritin-labeled cells than did control injections of ammonium citrate at 1 day post-injection. This elevated expression continued for at least 1 week. One day after injection, the mean number of Fluoro-Jade-labeled degenerating neurons in 100 microm sections passing through the center of ferric ammonium citrate injection sites was 664+/-64. This value was 4.5-fold higher than at ammonium citrate injection sites, and this difference increased to 56-fold by day three. By 5 days post-injection, few dying neurons were observed at the control sites, but neurodegeneration continued beyond a week at the iron-injected sites. Thus, iron released during a brief episode of hypoxia-ischemia or during a stroke may be neurotoxic for a protracted period. Therefore, our findings indicate that it may be beneficial to target iron-induced peroxidation throughout the first few weeks following an intracerebral hemorrhage or an hypoxic-ischemic episode.

Animals↗
PubMed1984

Freeze-drying of oxyhemoglobin: protection against oxidation in the presence of EDTA salts, sulfonic acid buffers, and pantothenic acid derivatives.

Hemoglobin was freeze-dried in the presence of salts of EDTA, sulfonic acids used as buffers, or derivatives of pantothenic acid. At 0.25 M most of the compounds effectively inhibited the formation of methemoglobin. The various model compounds used (sodium zinc EDTA, tris(hydroxymethyl) methylaminopropanesulfonic acid, and DL-pantothenol) produced similar decreases in methemoglobin formation as a function of the concentration of protective agent between 0.01 and 0.20 M. Experiments on the storage of the freeze-dried materials revealed substantial denaturation of oxyhemoglobin after 12 months at 4 degrees C. On the whole, these compounds were less effective than amino acid salts, during both desiccation and storage. The multiplicity of compounds that inhibit the denaturation of hemoglobin during freeze-drying indicates that their mode of action is nonspecific.

Buffers↗
PubMed1981

Stimulation of hemoglobin synthesis in murine erythro-leukemia cells by low molecular weight ketones, aldehydes, acids, alcohols and ethers.

The effects of short chain (C1-C5) aldehydes, ketones, acids alcohols and ethers on murine erythroleukemia (MEL) cells were examined to determine which particular chemical moieties and some of their combinations stimulated hemoglobin synthesis in these cells. The C4 series of compounds was active at lower concentrations than homologs of shorter chain lengths. Within an homologous series the potency and efficacy of the alcohol was always less then that of the acid and aldehyde compounds. Though hepanoic acid was found to be an inducer of hemoglobin synthesis in MEL cells, the 4,6-dioxoheptanoic acid analog is a potent inhibitor of hemoglobin synthesis. Analysis of porphyrin content of MEL cells incubated with the inducers 2-butanone, 2-methoxyethanol, acetone and methanol, showed that increased hemoglobin synthesis was always accompanied by the accumulation of porphyrins, most of which was protoporphyrin. These studies suggest that low molecular ketones, aldehydes, acids, ethers and alcohol can correct the defect in erythroid differentiation exhibited by MEL cells and they further suggest that the physiological trigger for inducing hemoglobin synthesis in these cells is less discriminating than previously recognized.

Alcohols↗
PubMed1984

Post-translational modifications of hemoglobin.

Post-translational modifications of hemoglobin can provide special insights into metabolic disorders. A variety of small molecules in health and disease can form covalent adducts with hemoglobin. The most abundant and best understood of these nonenzymatic modifications is the glycosylation of hemoglobin at the N-terminus of the beta chain (Hb AIc) as well as at the N-terminus of the alpha chain and at certain lysine residues. Glycosylated hemoglobins are elevated in diabetics and offer a useful way of monitoring diabetic control. Moreover, non-enzymatic glycosylation of other tissues may contribute significantly to the long term complications of diabetes. Additional minor hemoglobin components can be formed from other small reactive compounds. For example, cyanate, a breakdown product of urea, reacts with hemoglobin to form distinct minor components in red cells of uremic patients. Acetaldehyde can form hemoglobin adducts in red cells of alcoholics. Thus, hemoglobin can be viewed as a "reporter molecule", revealing metabolic perturbations in a variety of diseases.

Blood Protein Electrophoresis↗
PubMed1998

Hemoglobin binding of bicyclic aromatic amines.

Aromatic diamino compounds, e.g., 4,4'-methylenebis(2-chloroaniline) (MOCA) and 4,4'-methylenedianiline (MDA), are used as curing agents in the production of elastomers. Since MOCA and MDA are mutagenic and carcinogenic, substitutes are of great commercial interest. For benzidine it has been shown that ortho substitution with methyl groups yields the nonmutagenic 3,3',5,5'-tetramethylbenzidine. Therefore, MDA analogues with large substituents in the ortho position have been synthesized. The substituents are supposed to inhibit the formation of the N-hydroxyarylamines which are the putative genotoxic intermediates. We investigated the biological availability of the N-hydroxylamines of ortho-substituted diamines and of known carcinogenic diamines in female Wistar rats, by determining hemoglobin (Hb) adducts. Hb from rats dosed with 0.5 mmol/kg diamine and from controls was isolated and hydrolyzed in base. The released diamine and monoacetyldiamine were quantified by HPLC with electrochemical detection and/or GC/MS. MDA, 4,4'-oxydianiline (ODA), 4,4'-ethylenedianiline, and 4,4'-thiodianiline (TDA) bound to hemoglobin as diamine and as monoacetyl-diamine. 4,4'-Methylenebis(2,6-dimethylaniline), 4,4'-methylenebis(2,6-diethylaniline), MOCA, and 4,4'-sulfonyldianiline (dapsone) bound only as diamine to Hb. 4,4'-Methylenebis(2,6-dichloroaniline) did not bind to Hb. Thus, the presence of two substituents in the ortho position and the presence of electron-withdrawing groups in the para position to the amino group drastically reduced the formation of Hb adducts. The amount of hemoglobin adducts was compared to their carcinogenic potency. The extent of hemoglobin binding of the bicyclic diamines (dapsone, 3,3'-dichlorobenzidine, MDA, MOCA, TDA, ODA, and benzidine) increases with their carcinogenic potency.

Amines↗
PubMed2003

Antimalarial activities of novel synthetic cysteine protease inhibitors.

Among promising new targets for antimalarial chemotherapy are the cysteine protease hemoglobinases falcipain-2 and falcipain-3. We evaluated the activities of synthetic peptidyl aldehyde and alpha-ketoamide cysteine protease inhibitors against these proteases, against cultured Plasmodium falciparum parasites, and in a murine malaria model. Optimized compounds inhibited falcipain-2 and falcipain-3, blocked hemoglobin hydrolysis, and prevented the development of P. falciparum at nanomolar concentrations. The compounds were equally active against multiple strains of P. falciparum with varied sensitivities to standard antimalarial agents. The peptidyl inhibitors were consistently less active against vinckepain-2, the putative falcipain-2 and falcipain-3 ortholog of the rodent malaria parasite Plasmodium vinckei. The lead compound morpholinocarbonyl-leucine-homophenylalanine aldehyde, which blocked P. falciparum development at low nanomolar concentrations, was tested in a murine P. vinckei model. When infused continuously at a rate of 30 mg/kg of body weight/day, the compound delayed the progression of malaria but did not eradicate infections. Our data demonstrate the potent antimalarial activities of novel cysteine protease inhibitors. Additionally, they highlight the importance of consideration of the specific enzyme targets of animal model parasites. In the case of falcipains, differences between P. falciparum and rodent parasites complicate the use of the rodent malaria model in the drug discovery process.

Aldehydes↗
PubMed2004

Adducts of N-terminal valines in hemoglobin with isoprene diepoxide, a metabolite of isoprene.

Isoprene (2-methylbuta-1,3-diene) is a multi-site carcinogen in rodents. To evaluate the role of the diepoxide metabolite (1,2:3,4-diepoxy-2-methylbutane) in carcinogenesis, measurements of in vivo doses of the diepoxide are needed. The in vivo dose may be inferred from levels of reaction products with hemoglobin (Hb adducts). This report presents in vitro studies of the adduct formation by the diepoxide of isoprene with valinamide and oligopeptides as model compounds of N-terminal valines in hemoglobin (Hb). In the reaction with valinamide it was shown that isoprene diepoxide forms as the main product a ring-closed adduct, which is a pyrrolidine derivative [N,N-(2,3-dihydroxy-2-methyl-1,4-butadiyl)valinamide, MPyr-Val]. The analysis was performed by gas chromatography/mass spectrometry (GC/MS) (EI and PICI) after acetylation. The ring-closed adduct was also identified by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI-MS) as the main product in the reaction between isoprene diepoxide and standard hepta- or (2H8)octapeptides, corresponding to the N-terminal peptides of the alpha-chains in mouse and rat Hb. These peptides, alkylated with isoprene diepoxide, to be used as internal standards and calibration standards for quantification of MPyr-adduct levels in vitro and in vivo, were analyzed with respect to the degree of MPyr-alkylation by two independent methods, amino acid analysis and HPLC-UV; similar results were obtained using these methods. A method for measurement of Hb adducts as modified peptides, used earlier to measure a similar adduct to N-terminal valines in Hb from the diepoxide of 1,3-butadiene, has in the present work been tested for application to isoprene diepoxide. The method is based on tryptic degradation of globin and LC/ESI-MS analysis of N-terminal Pyr-heptapeptides of the Hb alpha-chain enriched by HPLC. MPyr-adduct levels in isoprene diepoxide alkylated hemolysate from mouse erythrocytes incubated with different concentrations of isoprene diepoxide (2 and 10 mM) for 1 h were quantified. The adduct level was about 50 nmol/g alpha-chain Hb per mM x h. From the adduct levels the rate constant of isoprene diepoxide for reaction with N-terminal valine was calculated to be about 1.6 times faster than for diepoxybutane.

Alkylation↗
PubMed2005

Nucleotide -88 (C-T) promoter mutation is a common beta-thalassemia mutation in the Jat Sikhs of Punjab, India.

A study of beta-gene mutations in Jat Sikhs, a subcaste of Punjabis, revealed a very high prevalence (46%: 41/88) of the mild beta++ promoter region mutation -88 (C-T). Sixteen individuals presenting in homozygous form were clinically mild. Un-transfused patients had characteristic hematological findings: high Hb F (38.1-68.6%, mean 47.4%), high Hb A2 (5.7-9.8%, mean 6.88%), and the rest had adult hemoglobin. The 19 subjects with compound heterozygosity for -88 (C-T) and another beta-gene mutation presented both as thalassemia intermedia (four cases) and as thalassemia major (15 cases). One of the four patients with the milder phenotype had a second mild mutation, CAP+1 (beta++). In the other three cases with the milder phenotype, the second mutation was associated with the presence of the XmnI Ggamma polymorphism. Notably, the XmnI Ggamma was negative in all the -88 (C-T) alleles. None of the patients had associated alpha-thalassemia even in the thalassemia intermedia group. Haplotype analysis of the -88 (C-T) homozygous cases showed a single haplotype (+ - - - - + -) in all but two individuals. This haplotype is distinct from those described in the Africans with homozygous -88 (C-T), suggesting that the mutation in our population occurred independently.

Adolescent↗
PubMed1999

Activation of soluble guanylate cyclase by carbon monoxide and nitric oxide: a mechanistic model.

Soluble guanylate cyclase (GC) from bovine lung is activated 4-fold by carbon monoxide (CO) and 400-fold by nitric oxide (NO). Spectroscopic and kinetic data for ligation of CO and NO with GC are summarized and compared with similar data for myoglobin (Mb), hemoglobin (Hb), and heme model compounds. Kinetic, thermodynamic, and structural data form a basis on which to construct a model for the manner in which the two ligands affect protein structure near the heme for heme proteins in general and for GC in particular. The most significant datum is that although association rates of ligands with GC are similar to those with Mb and Hb, their dissociation rates are dramatically faster. This suggests a delicate balance between five- and six-coordinate heme iron in both NO and CO complexes. Based on these and other data, a model for GC activation is proposed: The first step is formation of a six-coordinate species concomitant with tertiary and quaternary structural changes in protein structure and about a 4-fold increase in enzyme activity. In the second step, applicable to NO, the bond from iron to the proximal histidine ruptures, leading to additional relaxation in the quaternary and tertiary structure and a further 100-fold increase in activity. This is the main event in activation, available to NO and possibly other activators or combinations of activators. It is proposed, finally, that the proximal base freed in step 2, or some other protein base suitably positioned as a result of structural changes following ligation, may provide a center for nucleophilic substitution catalyzing the reaction GTP --> cGMP. An example is provided for a similar reaction in a derivatized protoheme model compound. The reaction mechanism attempts to rationalize the relative enzymatic activities of GC, heme-deficient GC, GC-CO, and GC-NO on a common basis and makes predictions for new activators that may be discovered in the future.

Carbon Monoxide↗
PubMed1996

A cost-effectiveness evaluation of newborn hemoglobinopathy screening from the perspective of state health care systems.

OBJECTIVE: To determine the most cost-effective strategy for newborn hemoglobinopathy screening from the perspective of state health care systems. STUDY DESIGN: Using Alaska as an example, we used decision analysis to compare a policy of no screening to universal or targeted screening with selective follow-up only of infants who are homozygous or compound heterozygous for an abnormal hemoglobin variant and to universal or targeted screening with complete follow-up, including follow-up of infants with clinically insignificant traits. Probabilities and costs were varied over values that might be expected for other states. RESULTS: Among the selective follow-up options, targeted screening would be the most cost-effective strategy for Alaska at a cost of $206,192 per death averted; by contrast, universal screening would prevent 50% more deaths at an incremental cost of $2,040,000 per death averted. Universal would be more cost-effective than targeted screening for several scenarios expected to occur in other states, including a high sickle cell disease prevalence, a low screening test cost, and a high cost per screen associated with racial targeting. Among the complete follow-up options, both targeted and universal screening would cost at least $200,000 per death averted over the range of all variables tested during sensitivity analysis; the incremental cost of universal versus targeted screening would be at least $600,000 per death averted. CONCLUSIONS: Our data suggest each state should determine the most cost-effective option based on state-specific values for sickle cell disease prevalence, test costs and racial targeting costs.

Alaska↗
PubMed2004

Induction of reversible hemolytic anemia in living zebrafish using a novel small molecule.

We used zebrafish to screen and identify small molecules that affect the process of vertebrate hematopoietic development. Zebrafish embryos were exposed to a library of 5000 synthetic compounds and screened for defects in primitive erythropoiesis. Here, we present the characterization of hemolytic anemia induced in zebrafish by the small molecule 5115318 (3-[5-methyl-furan 2-yl]-propionic acid N'-phenyl-hydrazide). This compound is capable of generating hemoglobin aggregates and Heinz bodies in red cells in vivo only. The induced anemia is reversible and treated fish recover in about 4 days. This study shows the feasibility of using zebrafish to screen for small molecules that can modulate the specific process of erythropoiesis.

Anemia, Hemolytic↗
PubMed1984

Metabolism of [75Se]selenite by rhesus monkeys.

The metabolism of [75Se]selenite was studied in rhesus monkeys. In blood samples taken various times after injection, Sephadex G-150 gel filtration revealed that the majority of the 75Se was associated with hemoglobin and low-molecular-weight compounds in erythrocytes up to 24 hours after selenium injection. Subsequently a gradual increase of 75Se occurred in glutathione peroxidase (GSH-Px) with a concurrent decrease of label with hemoglobin. In contrast to the erythrocytes, over 80% of the labeled selenium in plasma was associated with one peak 3 hours and later after injection. This major protein eluted at a position similar to GSH-Px on gel filtration, but subsequent chromatography on diethylaminoethyl (DEAE)-Sephacel separated the radiolabeled protein from GSH-Px. Gel filtration of heart, muscle, brain and pancreas cytosol revealed two major selenium-containing proteins, whereas one was predominant in liver and kidney. The major selenium peak was associated with GSH-Px in liver but not in the kidney. GSH-Px activity with either organic or inorganic peroxides as substrates and glutathione transferase activity were higher in liver than kidney.

Animals↗
PubMed2002

Effects of porphyrins and inorganic iron on the growth of Prevotella intermedia.

We demonstrated earlier that hemin-iron-containing compounds which include hemin, human hemoglobin, bovine hemoglobin, and bovine catalase stimulate the growth of Prevotella intermedia [Leung, Subramaniam, Okamoto, Fukushima, Lai, FEMS Microbiol. Lett. 162 (1998) 227-233]. However, the contributions of tetrapyrrole porphyrin ring in these hemin-iron sources as well as inorganic iron for the growth of this organism have not been determined. The purpose of this study was to examine the effects of porphyrins, host iron-binding proteins, and various inorganic iron sources on the growth of hemin-iron depleted P. intermedia. Protoporphyrin IX and protoporphyrin IX-zinc, either in the presence or absence of supplemented ferrous or ferric iron, promoted the growth of P. intermedia at a rate that was comparable to that of the hemin control. On the other hand, neither the host iron proteins, transferrin and lactoferrin, nor the inorganic iron sources which included ferrous chloride, ferric chloride, ferric citrate, ferric nitrate, and ferric ammonium citrate at concentrations up to 200 microM stimulated the growth of hemin-iron-restricted P. intermedia. The results suggest that P. intermedia only use iron in a specific form and that the porphyrin-ring structure is essential for the growth of P. intermedia as in the case of other related organisms.

Culture Media↗
PubMed1988

Liposome/heme as a totally synthetic oxygen carrier.

We synthetically derived protoheme (oxygen-binding site of hemoglobin) to an amphiphilic heme compound and embedded it in the phospholipid bilayer of liposomes, not in an aqueous inside region of liposomes. This liposome/heme transports oxygen efficiently under physiological conditions. Characteristics of our totally synthetic liposome/heme as an artificial oxygen carrier, are summarized as follows. (i) Oxygen-binding is reversible and very rapid. (ii) The oxygen volume dissolved in the fluid is similar or superior to that of blood. (iii) The oxygen-binding affinity is close to that of blood. (iv) The particle size is smaller than 0.1 micron. (v) It is physically and mechanically stable under shear stress and storage. (vi) The components are synthetic derivatives of protoheme and phospholipid originated in nature. The advantages (i)-(iii) and brilliant red color of the solution are derived from the fact that our totally synthetic liposome/heme, transports oxygen in the same principle of red blood cells. When the liposome/heme solution was mixed with human blood, the liposome/heme delivered oxygen to blood in the mixture system. The oxygen-exchanging of the liposome/heme with blood was also tested ex-vivo using an artificial lung apparatus. The oxy liposome/heme was circulated through A-V of a dog leg, and the oxygen concentration was kept at a high level. This demonstrates the fact that the synthetic liposome/heme transports and delivers oxygen to the muscle tissue. Application to extracorporeal circulation and transfusion test will also be reported.

Animals↗
PubMedDate not supplied

Clinical applications of capillary electrophoresis.

Capillary electrophoresis (CE) is a new powerful separation technique that often exhibits higher resolution and shorter analysis times than high performance liquid chromatography (HPLC) or agarose electrophoresis (AE). The separation can be accomplished based on charge as well as on size, hydrophobicity, and stereospecificity. In addition to high resolution, the most significant features of CE are ease of use, low cost of operation, and the speed of the analysis thus suitable for stat work. Examples of the application of CE in the field of clinical diagnosis which are discussed include: therapeutic drug monitoring, proteins (serum, urinary and cerebrospinal fluid), and hemoglobins. This technique can reveal compounds which are not routinely analyzed in the lab thus opening a new area for the clinical investigator.

Blood Proteins↗
PubMed1995

Oxytocin-induced penile erection. Role of nitric oxide.

In order to investigate the mechanism of action by which oxytocin induces penile erection, the effect of NG-nitro-L-arginine methyl ester (NAME) and NG-monomethyl-L-arginine (NMMA), inhibitors of nitric oxide (NO) synthase, injected into the paraventricular nucleus of the hypothalamus (PVN) on the response to oxytocin injected into the PVN was studied in male rats. NAME and NMMA, but not NG-mono-methyl-D-arginine (D-NMMA), which does not inhibit NO-synthase, prevented in a dose-dependent manner the response to oxytocin. NAME was 4-5 times more potent than NMMA. NAME prevention of the oxytocin effect was not observed when NAME was given together with L-arginine but not with D-arginine. Oxytocin-induced penile erection was prevented by the oxytocin antagonist d(CH2)5Tyr(Me)-Orn8-vasotocin and by methylene blue, an inhibitor of guanylate cyclase, but not reduced hemoglobin, a NO scavenger, given intracerebroventricularly (i.c.v.). In contrast, both methylene blue and hemoglobin were ineffective when injected into the PVN, unlike d(CH2)5Tyr(Me)-Orn8-vasotocin. Penile erection was induced also by sodium nitroprusside and hydroxylamine, two NO donors, injected into the PVN. Like the oxytocin effect, the NO donor response was prevented by i.c.v. d(CH2)5Tyr(Me)-Orn8-vasotocin and methylene blue, but not hemoglobin. In contrast, the three compounds were ineffective in preventing the NO donor response when injected into the PVN. The present results suggest that oxytocin induces penile erection by activating NO synthase in the PVN. NO in turn activates oxytocinergic neurons projecting to extra-hypothalamic areas that control the expression of this male sexual function by a guanosine cyclic 3':5'-monophosphate (cGMP) independent mechanism at least in the PVN.

Animals↗
PubMed2005

Hemolytic effects of sodium selenite and mercuric chloride in human blood.

Many works have reported the interaction between selenium and mercury in the mammalian body and that chalcogen seems to have a protective effect against mercury toxicity. The aim of this study was to investigate the hemolytic effects of sodium selenite and/or mercuric chloride in human blood under in vitro conditions. For this, total venous blood from healthy subjects (males and females) was heparinized and incubated at 37 degrees C for 90 min with different concentrations of sodium selenite and/or mercuric chloride. The hemolytic effects of compounds were evaluated by measuring plasma hemoglobin concentration after centrifugation. In addition, 2-thiobarbituric acid reactive substances (TBARS) from plasma and erythrocytes, as well as erythrocyte nonprotein thiols (NPSH), were also evaluated in order to investigate molecular mechanisms related to selenite- or mercury-induced hemolysis. Mercuric chloride and sodium selenite, alone (400 microM), promoted a small in vitro hemolytic effect in human erythrocytes. However, when blood was exposed to both compounds (200 microM of each), there was an extremely high synergistic hemolytic effect. The exposure of blood to sodium selenite (400 microM), mercuric chloride (400 microM), and both compounds (200 microM each) did not alter erythrocyte TBARS levels. Sodium selenite presented a high oxidant effect toward erythrocyte NPSH; however, this effect was inhibited by mercuric chloride. The current results point to a synergistic hemolytic effect of sodium selenite and mercuric chloride in human blood, suggesting new understanding on the selenium-mercury antagonism. Moreover, this observed hemolysis seems to be not related to lipoperoxidation or thiol depletion.

Adult↗