Joseph M. Rifkind

Bio: Joseph M. Rifkind is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Hemoglobin & Nitrite. The author has an hindex of 43, co-authored 137 publications receiving 5644 citations. Previous affiliations of Joseph M. Rifkind include Johns Hopkins University & Indian Institute of Technology Madras.

Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging

Abstract: Red Blood Cells (RBCs) need to deform and squeeze through narrow capillaries. Thus, decreased deformability of RBCs contributes to the elimination of aged or damaged RBCs from the circulation. This process causes impaired oxygen delivery, which has contributed to the pathology of a number of diseases. Studies from our laboratory have shown that oxidative stress plays a significant role in damaging the RBC membrane and impairing deformability. RBCs are continuously exposed to both endogenous and exogenous sources of reactive oxygen species (ROS) like superoxide and hydrogen peroxide (H2O2). While the bulk of the ROS are neutralized by the RBC antioxidant system consisting of both non-enzymatic and enzymatic antioxidants including catalase, glutathione peroxidase and peroxiredoxin-2, the autoxidation of hemoglobin bound to the membrane is relatively inaccessible to cytosolic antioxidants. This process becomes more pronounced under hypoxic conditions when hemoglobin is partially oxygenated resulting in an increased rate of autoxidation and increased affinity for the RBC membrane. We have shown that a fraction of peroxyredoxin-2 present on the RBC membrane may play a major role in neutralizing these ROS. H2O2 that is not neutralized by the RBC antioxidant system can react with the heme producing fluorescent heme degradation products (HDP). We have used the level of these HDP as a measure of RBC Oxidative Stress. Increased levels of HDP are detected during cellular aging and various diseases. The negative correlation (pWhile decreased deformability contributes to the removal of RBCs from circulation, the uptake of RBCs by macrophages can also involve other processes like caspase-3 activation,which also directly involve oxidative stress. RBC oxidative stress, therefore, plays a significant role in inducing RBC aging.

Heme degradation by reactive oxygen species.

Abstract: Heme proteins play a major role in various biological functions, such as oxygen sensing, electron transport, signal transduction, and antioxidant defense enzymes. Most of these reactions are carried out by redox reactions of heme iron. As the heme is not recycled, most cells containing heme proteins have the microsomal mixed function oxygenase, heme oxygenase, which enzymatically degrades heme to biliverdin, carbon monoxide, and iron. However, the red cell with the largest pool of heme protein, hemoglobin, contains no heme oxygenase, and enzymatic degradation of the red cell heme occurs only after the senescent red cells are removed by the reticuloendothelial system. Therefore, only nonenzymatic heme degradation initiated when the heme iron undergoes redox reactions in the presence of oxygen-producing reactive oxygen species takes place in the red cell. Unlike enzymatic degradation, which specifically attacks the α-methene bridge, reactive oxygen species randomly attack all the carbon methene bridges of t...

Reaction of Hydrogen Peroxide with Ferrylhemoglobin: Superoxide Production and Heme Degradation

Abstract: The reaction of Fe(II) hemoglobin (Hb) but not Fe(III) hemoglobin (metHb) with hydrogen peroxide results in degradation of the heme moiety. The observation that heme degradation was inhibited by compounds, which react with ferrylHb such as sodium sulfide, and peroxidase substrates (ABTS and o-dianisidine), demonstrates that ferrylHb formation is required for heme degradation. A reaction involving hydrogen peroxide and ferrylHb was demonstrated by the finding that heme degradation was inihibited by the addition of catalase which removed hydrogen peroxide even after the maximal level of ferrylHb was reached. The reaction of hydrogen peroxide with ferrylHb to produce heme degradation products was shown by electron paramagnetic resonance to involve the one-electron oxidation of hydrogen peroxide to the oxygen free radical, superoxide. The inhibition by sodium sulfide of both superoxide production and the formation of fluorescent heme degradation products links superoxide production with heme degradation. The inability to produce heme degradation products by the reaction of metHb with hydrogen peroxide was explained by the fact that hydrogen peroxide reacting with oxoferrylHb undergoes a two-electron oxidation, producing oxygen instead of superoxide. This reaction does not produce heme degradation, but is responsible for the catalytic removal of hydrogen peroxide. The rapid consumption of hydrogen peroxide as a result of the metHb formed as an intermediate during the reaction of reduced hemoglobin with hydrogen peroxide was shown to limit the extent of heme degradation.

The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics

Abstract: The inorganic anions nitrate (NO3-) and nitrite (NO2-) were previously thought to be inert end products of endogenous nitric oxide (NO) metabolism However, recent studies show that these supposedly inert anions can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states This Review discusses the emerging important biological functions of the nitrate-nitrite-NO pathway, and highlights studies that implicate the therapeutic potential of nitrate and nitrite in conditions such as myocardial infarction, stroke, systemic and pulmonary hypertension, and gastric ulceration

Conformational parameters for amino acids in helical, beta-sheet, and random coil regions calculated from proteins.

Abstract: The helix, s Applequist, 1963) in which the Zimm-Bragg parameters u and s are defined respectively as the cooperativity factor for helix initiation, and the equi- librium constant for converting a coil residue to a helical ~~~~

Racism as a Determinant of Health: A Systematic Review and Meta-Analysis

Abstract: Despite a growing body of epidemiological evidence in recent years documenting the health impacts of racism, the cumulative evidence base has yet to be synthesized in a comprehensive meta-analysis focused specifically on racism as a determinant of health. This meta-analysis reviewed the literature focusing on the relationship between reported racism and mental and physical health outcomes. Data from 293 studies reported in 333 articles published between 1983 and 2013, and conducted predominately in the U.S., were analysed using random effects models and mean weighted effect sizes. Racism was associated with poorer mental health (negative mental health: r = -.23, 95% CI [-.24,-.21], k = 227; positive mental health: r = -.13, 95% CI [-.16,-.10], k = 113), including depression, anxiety, psychological stress and various other outcomes. Racism was also associated with poorer general health (r = -.13 (95% CI [-.18,-.09], k = 30), and poorer physical health (r = -.09, 95% CI [-.12,-.06], k = 50). Moderation effects were found for some outcomes with regard to study and exposure characteristics. Effect sizes of racism on mental health were stronger in cross-sectional compared with longitudinal data and in non-representative samples compared with representative samples. Age, sex, birthplace and education level did not moderate the effects of racism on health. Ethnicity significantly moderated the effect of racism on negative mental health and physical health: the association between racism and negative mental health was significantly stronger for Asian American and Latino(a) American participants compared with African American participants, and the association between racism and physical health was significantly stronger for Latino(a) American participants compared with African American participants. Protocol PROSPERO registration number: CRD42013005464.

Pharmacological and Clinical Aspects of Heme Oxygenase

Abstract: This review is intended to stimulate interest in the effect of increased expression of heme oxygenase-1 (HO-1) protein and increased levels of HO activity on normal and pathological states. The HO system includes the heme catabolic pathway, comprising HO and biliverdin reductase, and the products of heme degradation, carbon monoxide (CO), iron, and biliverdin/bilirubin. The role of the HO system in diabetes, inflammation, heart disease, hypertension, neurological disorders, transplantation, endotoxemia and other pathologies is a burgeoning area of research. This review focuses on the clinical potential of increased levels of HO-1 protein and HO activity to ameliorate tissue injury. The use of pharmacological and genetic probes to manipulate HO, leading to new insights into the complex relationship of the HO system with biological and pathological phenomena under investigation, is reviewed. This information is critical in both drug development and the implementation of clinical approaches to moderate and to alleviate the numerous chronic disorders in humans affected by perturbations in the HO system.