Showing papers in "Antioxidants & Redox Signaling in 2004"
TL;DR: Glutaredoxins uniquely reduce mixed disulfides with glutathione via a monothiol mechanism where only an N-terminal low pKa Cys residue is required, by using their glutathionylation site.
Abstract: Most cells contain high levels of glutathione and multiple glutaredoxins, which utilize the reducing power of glutathione to catalyze disulfide reductions in the presence of NADPH and glutathione reductase (the glutaredoxin system). Glutaredoxins, like thioredoxins, may operate as dithiol reductants and are involved as alternative pathways in cellular functions such as formation of deoxyribonucleotides for DNA synthesis (by reducing the essential enzyme ribonucleotide reductase), the generation of reduced sulfur (via 3′-phosphoadenylylsulfate reductase), signal transduction, and the defense against oxidative stress. The three dithiol glutaredoxins of E. coli with the active-site sequence CPYC and a glutathione binding site in a thioredoxin/glutaredoxin fold display surprisingly different properties. These include the inducible OxyR-regulated 10-kDa Grx1 or the highly abundant 24-kDa glutathione S-transferase-like Grx2 (with Grx3 it accounts for 1% of total protein). Glutaredoxins uniquely reduce mixed dis...
633 citations
TL;DR: In vitro antioxidant activities of the two bile pigments are reviewed with emphasis on the different physiological forms of bilirubin and types of oxidants, and discusses these properties in light of the presence and reactivity other nonproteinaceous antioxidants.
Abstract: Biliverdin and bilirubin are reducing species and hence potential antioxidants formed by the action of heme oxygenase and biliverdin reductase. Indeed, there is increasing evidence for the suggestion that a beneficial role of the potentially toxic bilirubin may be to act as a powerful chain-breaking antioxidant in biological systems, and that bilirubin may contribute to the cellular and tissue protection seen with increased heme oxygenase. This article reviews the in vitro antioxidant activities of the two bile pigments with emphasis on the different physiological forms of bilirubin and types of oxidants, and discusses these properties in light of the presence and reactivity other nonproteinaceous antioxidants. Antioxid. Redox Signal. 6, 841–849.
314 citations
TL;DR: Evidence strongly suggests that lipid peroxidation products, particularly hydroperoxides and 4-HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the Alpha class GSTs through the regulation of the intracellular concentrations of 4- HNE.
Abstract: It has been known that glutathione S-transferases (GSTs) can reduce lipid hydroperoxides through their Se-independent glutathione peroxidase activity and that these enzymes can also detoxify lipid peroxidation end products such as 4-hydroxynonenal (4-HNE). In this article, recent studies suggesting that the Alpha class GSTs provide a formidable defense against oxidative stress are critically evaluated and the role of these enzymes in the regulation of oxidative stress-mediated signaling is reviewed. Available evidence from earlier studies together with results of recent studies in our laboratories strongly suggests that lipid peroxidation products, particularly hydroperoxides and 4-HNE, are involved in the mechanisms of stress-mediated signaling and that it can be modulated by the Alpha class GSTs through the regulation of the intracellular concentrations of 4-HNE.
299 citations
TL;DR: The present review will focus on the involvement of ROS in skin carcinogenesis, especially that induced by ultraviolet (UV) radiation, and it has become clear that genetic diseases such as xeroderma pigmentosum show deficient repair of oxidatively modified DNA lesions.
Abstract: Reactive oxygen species (ROS) are associated not only with initiation, but also with promotion and progression in the multistage carcinogenesis model. In the present review, we will focus on the involvement of ROS in skin carcinogenesis, especially that induced by ultraviolet (UV) radiation. UV-specific DNA damage has been well studied thus far. However, recent reports have revealed the previously unknown participation of oxidative stress in UV-induced skin carcinogenesis. Indeed, in addition to transition-type mutations at dipyrimidine sites, G:C to T:A transversions, which may be induced by the presence of 8-oxoguanine during DNA replication, are frequently observed in the ras oncogene and p53 tumor suppressor gene in human skin cancers of sun-exposed areas and in UV-induced mouse skin cancers. Recent studies have shown that not only UV-B, but also UV-A is involved in UV-induced carcinogenesis. A wide variety of biological phenomena other than direct influence by UV, such as inflammatory and immunological responses and oxidative modifications of DNA and proteins, appear to play roles in UV-induced skin carcinogenesis. Furthermore, it has become clear that genetic diseases such as xeroderma pigmentosum show deficient repair of oxidatively modified DNA lesions. The involvement of ROS in skin carcinogeneisis caused by arsenic and chemical carcinogens will also be discussed.
249 citations
TL;DR: This review describes some of the advantages as well as some experimental considerations of this technique and how it can be applied to biological systems to measure oxidative stress.
Abstract: Electron paramagnetic resonance spin trapping has become an indispensable tool for the specific detection of reactive oxygen free radicals in biological systems. In this review we describe some of the advantages as well as some experimental considerations of this technique and how it can be applied to biological systems to measure oxidative stress.
201 citations
TL;DR: This review focuses on the literature related to nonenzymatic heme degradation with special emphasis on hemoglobin, the dominant red cell heme protein.
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...
197 citations
TL;DR: This study identifies a novel natural compound that could be used for therapeutic purposes as a potent inducer of HO-1 for the protection of brain cells against oxidative and neurodegenerative conditions.
Abstract: In the CNS, the heme oxygenase (HO) system has been reported to be active and to operate as a fundamental defensive mechanism for neurons exposed to an oxidant challenge. We have recently shown that both curcumin and caffeic acid phenethyl ester, two phenolic natural compounds, potently induce HO-1 expression and activity in rat astrocytes. We have extended our previous findings examining the effects of two other plant-derived phenolic compounds, with analogous chemical structures, in rat astrocytes and neurons. Ethyl ferulate (ethyl 4-hydroxy-3-methoxycinnamate) (EFE), the naturally occurring ester of ferulic acid, was able to induce HO-1 protein expression. Maximal expression of HO-1 mRNA and protein and a significant increase in HO activity were detected after 6 h of incubation with 15 microM EFE in astrocytes and 5 microM EFE in neurons. Higher concentrations of EFE (50 microM) caused a substantial cytotoxic effect with no change in HO-1 protein expression and activity. Exposure of astrocytes to resveratrol, a phytoalexin derived from grapes, resulted in an increase of HO-1 mRNA, but it was not able to induce HO-1 protein expression and activity. Interestingly, preincubation (12 h) of neurons with EFE resulted in an enhanced cellular resistance to glucose oxidase-mediated oxidative damage; this cytoprotective effect was considerably attenuated by zinc protoporphyrin IX, an inhibitor of HO activity. This study identifies a novel natural compound that could be used for therapeutic purposes as a potent inducer of HO-1 for the protection of brain cells against oxidative and neurodegenerative conditions.
183 citations
TL;DR: The current knowledge of different levels of TrxR1 regulation in diverse cell types and in response to growth and signaling events is summarized.
Abstract: Reactive oxygen species (ROS) are generated as toxic by-products of aerobic metabolism, but are also essential biomolecules in cell signaling. The thioredoxin (Trx) system is a major enzymatic system modulating ROS levels and is important for redox regulation of cellular function. It consists of Trx and thioredoxin reductase (TrxR), which reduces Trx using NADPH. Most, if not all, of the functions of Trx depend on the activity of TrxR. Mammalian TrxR enzymes are selenoproteins with broad substrate specificities, and alteration of cytosolic TrxR1 expression and activity is likely to be an important determinant for the control of cellular redox regulation. TrxR1 activity in cells seems to be modulated by an intricate interplay, involving a housekeeping type promoter in combination with alternative splice variants and transcriptional start sites, posttranscriptional regulation through AU-rich elements, inactivation by electrophilic agents and by itself modulating the effects of several key signaling molecules. TrxR1 activity is also intimately linked with several aspects of selenium metabolism, and hence selenoprotein function in general. Here, we summarize the current knowledge of these different levels of TrxR1 regulation in diverse cell types and in response to growth and signaling events.
181 citations
TL;DR: The present study shows the impaired induction of TRX in tissues from genetically hypertensive rats despite the relative increment of oxidative stress, which may play a crucial role in the development and pathogenesis of hypertension.
Abstract: As oxidative stress plays a crucial role in the development and pathogenesis of hypertension, we analyzed the redox (reduction/oxidation) status in tissues from Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP). Expressions of 8-hydroxy-2'-deoxyguanosine, a marker for oxidative stress-induced DNA damage, and protein carbonylation, a marker for oxidation status of proteins, were enhanced in aorta, heart, and kidney from SHR and SHRSP compared with WKY. The expression of redox regulating protein, thioredoxin (TRX), estimated by immunohistochemistry and western blot, and expression of TRX gene estimated by real-time RT-PCR were markedly suppressed in those tissues from SHR and SHRSP compared with WKY. Induction of TRX was impaired after angiotension II treatment in peripheral blood mononuclear cells isolated from SHR and SHRSP compared with those isolated from WKY. Although previous reports have shown that TRX is induced by a variety of oxidative stress in tissues, the present study shows the impaired induction of TRX in tissues from genetically hypertensive rats despite the relative increment of oxidative stress. Redox imbalance in essential organs may play a crucial role in the development and pathogenesis of hypertension.
172 citations
TL;DR: This review focuses on the peroxide-induced formation of radicals, their assignment to specific protein residues, and the pseudoperoxidase and prooxidant activities of the heme proteins.
Abstract: Recent research has shown that myoglobin and hemoglobin play important roles in the pathology of certain disease states, such as renal dysfunction following rhabdomyolysis and vasospasm following subarachnoid hemorrhages. These pathologies are linked to the interaction of peroxides with heme proteins to initiate oxidative reactions, including generation of powerful vasoactive molecules (the isoprostanes) from free and membrane- bound lipids. This review focuses on the peroxide-induced formation of radicals, their assignment to specific protein residues, and the pseudoperoxidase and prooxidant activities of the heme proteins. The discovery of heme to protein cross-linked forms of myoglobin and hemoglobin in vivo, definitive markers of the participation of these heme proteins in oxidative reactions, and the recent results from heme oxygenase knockout/knockin animal model studies, indicate that higher oxidation states (ferryl) of heme proteins and their associated radicals play a major role in the mechanisms of pathology.
153 citations
TL;DR: Elucidation of IPC-mediated complex signaling processes will help in the development of more effective pharmacological approaches for prevention of myocardial ischemia/reperfusion injury.
Abstract: Ischemic preconditioning (IPC) is a most powerful endogenous mechanism for myocardial protection against ischemia/reperfusion injury. It is now apparent that reactive oxygen species (ROS) generated in the mitochondrial respiratory chain act as a trigger of IPC. ROS mediate signal transduction in the early phase of IPC through the posttranslational modification of redox-sensitive proteins. ROS-mediated activation of Src tyrosine kinases serves a scaffold for interaction of proteins recruited by G protein-coupled receptors and growth factor receptors that is necessary for amplification of cardioprotective signal transduction. Protein kinase C (PKC) plays a central role in this signaling cascade. A crucial target of PKC is the mitochondrial ATP-sensitive potassium channel, which acts as a trigger and a mediator of IPC. Mitogen-activated protein (MAP) kinases (extracellular signal-regulated kinase, p38 MAP kinase, and c-Jun NH2-terminal kinase) are thought to exist downstream of the Src-PKC signaling module, ...
TL;DR: The role of LOOHs in photooxidative signaling, like other stress-associated lipid metabolites/peroxidation products (e.g., arachidonate, diacylglycerol, ceramide, 4-hydroxynonenal, may act as signaling molecules), is focused on.
Abstract: Photosensitized peroxidation of membrane lipids has been implicated in skin pathologies such as phototoxicity, premature aging, and carcinogenesis, and may play a role in the antitumor effects of photodynamic therapy. Lipid hydroperoxides (LOOHs) are prominent early products of photoperoxidation that typically arise via singlet oxygen ((1)O(2)) attack. Nascent LOOHs can have several possible fates, including (i) iron-catalyzed one-electron reduction to chain-initiating free radicals, which exacerbate peroxidative damage, (ii) selenoperoxidase-catalyzed two-electron reduction to relatively innocuous alcohols, and (iii) translocation to other membranes, where reactions noted in (i) or (ii) might take place. In addition, LOOHs, like other stress-associated lipid metabolites/peroxidation products (e.g., arachidonate, diacylglycerol, ceramide, 4-hydroxynonenal), may act as signaling molecules. Intermembrane transfer of LOOHs may greatly expand their signaling range. When photogenerated rapidly and site-specifically, e.g., in mitochondria, LOOHs may act as early mediators of apoptotic cell death. This review will focus on these various aspects, with special attention to the role of LOOHs in photooxidative signaling.
TL;DR: A large amount of hemoglobin is degraded daily to heme and globin and is replenished by biosynthesis in the bone marrow erythroblasts and has the potential to be toxic because it catalyzes the production of reactive oxygen species.
Abstract: A large amount of hemoglobin is degraded daily to heme and globin and is replenished by biosynthesis in the bone marrow erythroblasts. "Free heme" can be dissociated from apohemoglobin in vitro and, conversely, native hemoglobin can be renatured from them. Then why does heme need to be degraded to iron, biliverdin IXalpha, and carbon monoxide in vivo? Free heme, i.e., a protein-unbound heme, exists in cells at a very minute concentration and exerts regulatory functions such as the repression of nonspecific delta-aminolevulinate synthase expression and the induction of microsomal heme oxygenase-1 (HO-1). The latter gene expression occurs by way of free heme-mediated derepression of Bach1, a mammalian heme-responsive transcription factor that suppresses the activation of the HO-1 gene. All these events occur at free heme concentrations below 1 microM. In contrast, free heme concentration greater than 1 microM can be toxic because it catalyzes the production of reactive oxygen species. To cope with this problem, the body is equipped with various defense mechanisms against high free heme concentrations. HO is one of the major players in these mechanisms, and it catabolizes free heme to iron, biliverdin IXalpha, and carbon monoxide. These three metabolites of heme by HO reactions have additional important functions and are involved in various critical cellular events. Thus, the breakdown of heme to smaller elements has its own significance in essential cellular metabolism.
TL;DR: Exogenous TRX exerts distinct cytoprotective effects on cerebral ischemia/reperfusion injury in mice by means of its redox-regulating activity, and was detected in the ischemic hemisphere by western blot analysis, suggesting that rhTRX was able to permeate the blood-brain barrier in theIschemic Hemisphere.
Abstract: Thioredoxin (TRX) is induced by a variety of oxidative stimuli and shows cytoprotective roles against oxidative stress. To clarify the possibility of clinical application, we examined the effects of intravenously administered TRX in a model of transient focal cerebral ischemia in this study. Mature male C57BL/6j mice received either continuous intravenous infusion of recombinant human TRX (rhTRX) over a range of 1-10 mg/kg, bovine serum albumin, or vehicle alone for 2 h after 90-min transient middle cerebral artery occlusion (MCAO). Twenty-four hours after the transient MCAO, the animals were evaluated neurologically and the infarct volumes were assessed. Infarct volume, neurological deficit, and protein carbonyl contents, a marker of protein oxidation, in the brain were significantly ameliorated in rhTRX-treated mice at the dose of 3 and 10 mg/kg versus these parameters in control animals. Moreover, activation of p38 mitogen-activated protein kinase, whose pathway is involved in ischemic neuronal death, was suppressed in the rhTRX-treated mice. Further, rhTRX was detected in the ischemic hemisphere by western blot analysis, suggesting that rhTRX was able to permeate the blood-brain barrier in the ischemic hemisphere. These data indicate that exogenous TRX exerts distinct cytoprotective effects on cerebral ischemia/reperfusion injury in mice by means of its redox-regulating activity.
TL;DR: Modern medical research is confirming the ancient wisdom that therapy of many diseases may reside in an inexpensive beverage in a "teapot" as both black and green tea have very similar beneficial attributes in lowering the risk of many human diseases, including several types of cancer and heart diseases.
Abstract: Tea that contains many antioxidants is a pleasant and safe drink that is enjoyed by people across the globe. Tea leaves are manufactured as black, green, or oolong. Black tea represents approximately 78% of total consumed tea in the world, whereas green tea accounts for approximately 20% of tea consumed. The concept of "use of tea for promotion of human health and prevention and cure of diseases" has become a subject of intense research in the last decade. Diseases for which tea drinkers appear to have lower risk are simple infections, like bacterial and viral, to chronic debilitating diseases, including cancer, coronary heart disease, stroke, and osteoporosis. Initial work on green tea suggested that it possesses human health-promoting effects. In recent years, the research efforts have been expanded to black tea as well. Research conducted in recent years reveals that both black and green tea have very similar beneficial attributes in lowering the risk of many human diseases, including several types of cancer and heart diseases. For cancer prevention, evidence is so overwhelming that the Chemoprevention Branch of the National Cancer Institute has initiated a plan for developing tea compounds as cancer-chemopreventive agents in human trials. Thus, modern medical research is confirming the ancient wisdom that therapy of many diseases may reside in an inexpensive beverage in a "teapot."
TL;DR: In the last few years, a new role of BR as an endogenously produced antioxidant has emerged, and several reports have shown that BR contributes to prevent cell damage mediated by reactive oxygen species, as well as nitric oxide and its congeners.
Abstract: Heme oxygenase (HO) cleaves the tetrapyrrolic ring of cellular heme moieties liberating carbon monoxide (CO) and equimolar amounts of free iron and biliverdin (BV). BV is in turn converted into bilirubin (BR) by the cytosolic enzyme BV reductase. Three HO isoforms have been described to date: HO-1, HO-2, and HO-3. All these isoforms are present in nervous tissue with different localizations and regulation. CO, the gaseous product of HO, exerts its biological effects through the activation of soluble guanylyl cyclase, but alternative signaling pathways, such as the activation of cyclooxygenase, have also been reported in the brain. In vitro and in vivo studies showed that CO, at the hypothalamic level, plays a key role in the modulation of stress response because it inhibits the release of antiinflammatory neuropeptides, such as corticotropin-releasing hormone and arginine vasopressin, and increases body temperature in rodents exposed to psychological stressors (stress fever). In the last few years, a new role of BR as an endogenously produced antioxidant has emerged, and several reports have shown that BR contributes to prevent cell damage mediated by reactive oxygen species, as well as nitric oxide and its congeners.
TL;DR: Although extreme concentrations of the heme oxygenase-1 protein resulting from the opposing phenomena of gene activation and repression have physiological consequences, even minor modulation in the level of this enzyme, as elicited by variations in the length of a dinucleotide repeat region within the human hmox-1 promoter, may be of clinical relevance.
Abstract: Recent investigations into the regulation of heme oxygenase-1 gene (hmox-1) transcription have exposed mechanisms of increasing diversity and complexity worthy of a gene whose expression is modulat...
TL;DR: Manipulation of endogenous cellular defense mechanisms, via the heat shock response, through nutritional antioxidants or pharmacological compounds, may represent an innovative approach to therapeutic intervention in diseases causing tissue damage, such as neurodegeneration.
Abstract: Efficient functioning of maintenance and repair processes seems to be crucial for both survival and physical quality of life. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed “vitagenes,” among these, the heat shock system, a highly conserved mechanism responsible for the preservation and repair of cellular macromolecules, such as proteins, RNAs, and DNA. Recent studies have shown that the heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including ischemia and reperfusion damage, inflammation, cancer, as well as metabolic and neurodegenerative disorders. Recently, the involvement of the heme oxygenase (HO) pathway in antidegenerative mechanisms has received considerable attention, as it has been demonstrated that the expression of HO is closely related to that of amyloid precursor protein. HO induction occurs together with the induction of other heat shock proteins...
TL;DR: Recombinant Trx80 was discovered to be a potent mitogenic cytokine that stimulates growth of resting human peripheral blood mononuclear cells (PBMC) in a synthetic medium, an effect that Trx lacks.
Abstract: Human cytosolic thioredoxin (Trx), which is the 12-kDa protein disulfide reductase with the Cys-Gly-Pro-Cys active site and a key component of cellular redox biochemistry and regulation, acts as cocytokine upon leaderless secretion. A 10-kDa C-terminally truncated thioredoxin (Trx80) comprising the 80 or 84 N-terminal amino acids is also secreted and present in plasma, where it originally was purified and identified as eosinophilic cytotoxicity enhancing factor. Recombinant Trx80 was discovered to be a potent mitogenic cytokine that stimulates growth of resting human peripheral blood mononuclear cells (PBMC) in a synthetic medium, an effect that Trx lacks. Trx80 is very different from Trx because it is a dimer lacking reductase activity and the cytokine activity is not dependent on the Cys residues of the Trx active-site motif. The primary targets of Trx80 in PBMC are monocytes that are activated to proliferate and increase expression of CD14, CD40, CD54, and CD86. Trx80 induces secretion of interleukin (IL)-12 in CD40+ monocytes from PBMC. Trx80 and IL-2 together were strongly synergistic to induce secretion of interferon-gamma in PBMC. Trx80 is a potent cytokine for monocytes directing the immune system to a Th1 response via IL-12 production.
TL;DR: Substantial evidence suggests a role for redox throughout embryonic, fetal, and postnatal development, and diseases of prematurity, such as necrotizing enterocolitis, retinopathy of prem aturity, and chronic lung disease, may be modulated by redox in the premature.
Abstract: In the cell, reducing and oxidizing molecules modulate the redox state. In embryonic and fetal growth, increased oxidative stress may be detrimental, but an oxidized state can also be beneficial. This is because redox may also affect key transcription factors that can alter gene expression during development. In addition, redox may impact on placentation and amniotic membrane integrity during pregnancy. Lastly, diseases of prematurity, such as necrotizing enterocolitis, retinopathy of prematurity, and chronic lung disease, may be modulated by redox in the premature. Because antioxidant therapies have not necessarily modified the outcome of these diseases, some debate exists as to this. Nonetheless, sufficient evidence suggests a role for redox throughout embryonic, fetal, and postnatal development. This evidence will be explored here.
TL;DR: Antioxidant therapy in combination with antiviral therapy may minimize liver damage and aid in the prevention and subsequent development of HCC.
Abstract: Oxidative stress (OS) plays a major role in chronic hepatitis C. Various OS markers have been found to be elevated in hepatitis C virus (HCV)-related liver disease. This study detected the presence of OS in serum and liver biopsy specimens of HCV patients. Reactive oxygen molecules (ROM) in sera of 54 HCV patients were compared with 23 controls. OS markers 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal, malondialdehyde, and thioredoxin were measured in liver biopsy specimens of 18 HCV patients with fibrosis staging F1 (six); F2 (two), F3 (four), and F4 (six). The interferon (IFN) response and hepatocellular carcinoma (HCC) occurrence in the presence of OS markers were also evaluated. The level of ROM in HCV patients was 318 ± 56.7 Carr compared with 248 ± 40.8 Carr in controls (p = 0.032). Multivariate analysis found age (p = 0.0236) to be the only independent variable associated with increase in ROM in sera. In liver biopsy specimens, OS markers were found mainly around the area of piecemeal necro...
TL;DR: This review summarizes the current state of the art on bacterial heme oxygenase research and the various biological roles of this enzyme in prokaryotes and their biochemical properties will be discussed.
Abstract: The importance of heme oxygenases in heme catabolism, iron utilization, and cellular signaling has been recognized for many years and is a well studied process in eukaryotes. Through the accessibility of an increasing number of bacterial genomes, it has become evident that heme oxygenases are also widespread in prokaryotes. In these organisms, the heme oxygenase reaction serves a similar function as in eukaryotes. A major role of bacterial heme oxygenases has been attributed to acquisition of iron in prokaryotic pathogens, but other functions, such as involvement in phytobilin biosynthesis, have been described. This review summarizes the current state of the art on bacterial heme oxygenase research. The various biological roles of this enzyme in prokaryotes and their biochemical properties will be discussed. Antioxid. Redox Signal. 6, 825–834.
TL;DR: Diseases associated with premature infants, including bronchopulmonary dysplasia, periventricular leukomalacia, intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis, have been linked to free radical-mediated cell and tissue injury.
Abstract: Free radicals have been implicated in the pathogenesis of a wide spectrum of human diseases. Premature infants are probably developmentally unprepared for extrauterine life in an oxygen-rich environment and exhibit a unique sensitivity to oxidant injury. Diseases associated with premature infants, including bronchopulmonary dysplasia, periventricular leukomalacia, intraventricular hemorrhage, retinopathy of prematurity, and necrotizing enterocolitis, have been linked to free radical-mediated cell and tissue injury. With the advent of therapies designed to combat the injurious effects of free radicals, the role of these highly reactive chemical molecules in the pathogenesis of neonatal diseases needs to be fully determined.
TL;DR: This review will focus on the mammalian testis-specific thioredoxin system that comprises threeThioredoxins exclusively expressed in spermatids and an additional thiOREDoxin highly expressed in testis, but also present in lung and other ciliated tissues (Txl-2).
Abstract: Redox control of cell physiology is one of the most important regulatory mechanisms in all living organisms. The thioredoxin system, composed of thioredoxin and thioredoxin reductase, has emerged as a key player in cellular redox-mediated reactions. For many years, only one thioredoxin system had been described in higher organisms, ubiquitously expressed in the cytoplasm of eukaryotic cells. However, during the last decade, we and others have identified and characterized novel thioredoxin systems with unique properties, such as organelle-specific localization in mitochondria or endoplasmic reticulum, tissue-specific distribution mostly in the testis, and features novel for thioredoxins, such as microtubule-binding properties. In this review, we will focus on the mammalian testis-specific thioredoxin system that comprises three thioredoxins exclusively expressed in spermatids (named Sptrx-1, Sptrx-2, and Sptrx-3) and an additional thioredoxin highly expressed in testis, but also present in lung and other ciliated tissues (Txl-2). The implications of these findings in the context of male fertility and testicular cancer, as well as evolutionary aspects, will be discussed.
TL;DR: It is hypothesized that species-selective alterations in redox microenvironment caused by free radical production from thalidomide results in attenuation of the NF-kappaB-mediated gene expression that is responsible for limb outgrowth.
Abstract: Several hypotheses have been proposed to explain the mechanisms of thalidomide teratogenesis, although none adequately accounts for the observed malformations and explains the basis for species specificity. Recent observations that thalidomide increases the production of free radicals and elicits oxidative stress, coupled with new insights into the redox regulation of nuclear transcription factors, lead to the suggestion that thalidomide may act through redox misregulation of the limb outgrowth pathways. Oxidative stress, as marked by glutathione depletion/oxidation and a shift in intracellular redox potential toward the positive, occurs preferentially in limbs of thalidomide-sensitive rabbits, but not in resistant rats. DNA binding of nuclear factor κ-B (NF-κB), a redox-sensitive transcription factor and key regulator of limb outgrowth, was shown to be significantly attenuated in rabbit limb cells and could be restored following the addition of a free radical spin-trapping agent, phenyl N-tert-butyl nitr...
TL;DR: NADPH oxidase in platelets seems to play a major role as an intracellular signaling mechanism in the activation of platelets, which suggests platelets enhance ROS production by neutrophils and possibly their cytotoxic potential via the release of TXA2, which in turn in platelet is not affected by the extracellular release of free radicals.
Abstract: Involvement of phagocyte NADPH oxidase in host defense response is well established. In contrast, little is known about the functional role of NADPH oxidase in platelets. In this study, we analyzed...
TL;DR: Free heme, an entity that can be generated by UVA irradiation of cells, also appears to be a critical intermediate that can directly influence both the transcriptional activation and repression of the HO-1 gene.
Abstract: Ultraviolet A (UVA: 320-380 nm) radiation is an oxidizing carcinogen that has proved an ideal agent for demonstrating the oxidant inducibility of the mammalian heme oxygenase-1 (HO-1) gene. The UVA response in cultured human skin fibroblasts and other cell types is mediated by singlet oxygen and is strongly influenced by cellular reducing equivalents. Free heme, an entity that can be generated by UVA irradiation of cells, also appears to be a critical intermediate that can directly influence both the transcriptional activation and repression of the HO-1 gene. Heme release is likely to be of central importance to the inflammatory response in skin and its abrogation by HO.
TL;DR: An understanding of the processes involved in lung growth, especially in alveolarization and vascularization, as well as in repair of injured lung tissue, may facilitate development of strategies to enhance these processes.
Abstract: Preterm neonates with respiratory distress are exposed not only to the relative hyperoxia ex utero, but also to life-saving mechanical ventilation with high inspired oxygen (O2) concentrations, whi...
TL;DR: It is suggested that further studies using potent and specific augmentation of HO-1 gene expression by viral vectors, as well as targeted, specific inhibition ofHO-1 expression, are required to elucidate fully the complex role of this enzymatic pathway in angiogenesis.
Abstract: Angiogenesis occurring during reparative or pathological processes is driven by various inflammatory mediators that influence the synthesis of growth factors. It has been recognized recently that reactive oxygen species (ROS) and nitric oxide (NO) are important modulators of the synthesis and activity of vascular endothelial growth factor (VEGF), a major angiogenic molecule. Moreover, heme oxygenase-1 (HO-1), a ubiquitous stress-inducible enzyme that is induced by ROS and NO, was recently discovered to be involved in angiogenesis. Genetic overexpression of HO-1 enhanced VEGF synthesis and augmented formation of vascular capillaries, improving the blood flow in ischemic tissues. In addition, by-products of HO-1 exert numerous effects that can also influence angiogenesis in both positive and negative ways. Therefore, the antiinflammatory effects of HO-1 can attenuate the excess formation of blood vessels in inflammatory angiogenesis. In this review, the recent data on the role of HO-1 in angiogenesis are cr...
TL;DR: APC presents a safe mode to apply preconditioning to human hearts, and major developments in a field that is exciting to clinicians and basic scientists alike are summarized.
Abstract: Volatile anesthetic agents, such as halothane, isoflurane, and sevoflurane, are the drugs most commonly used to maintain the state of general anesthesia They have long been known to provide some protection against the effects of cardiac ischemia and reperfusion Several mechanisms likely contribute to this cardioprotection, including coronary vasodilation, reduced contractility with corresponding decreased metabolic demand, and a direct effect to decrease myocardial Ca2+ entry through L-type Ca2+ channels Recently, a memory phase to cardioprotection has been observed by these agents, which is inhibited by ATP-sensitive potassium channel inhibition These features suggest a pathway that shares components with those required for ischemic preconditioning, despite the remarkable differences between these two stimuli, and the term anesthetic preconditioning (APC) has been adopted Scavengers of reactive oxygen species (ROS) abrogate APC, suggesting an effect of anesthetic agents to cause ROS formation Such