Enzymatic defense systems
1. Introduction
Oxidative stress is thought to contribute to the development of a wide range of diseases including neurodegenerative (Alzheimer, Parkinson, Amyotrophic Lateral Sclerosis…), diabetes, cancer, rheumatoid arthritis, cardiovascular and liver diseases several of them are related with low levels of IGFs such as degenerative and aging disorders [1-8].
Oxidative stress represents an imbalance between the production of ROS/RNS and a biological system's ability to detoxify the reactive intermediates or to repair the resulting damage. In normal conditions ROS are reduced into water. For these reason cells are protected against oxidative stress by an interacting network of antioxidant enzymes. This detoxification pathway is the result of several enzymes, with Superoxide Dismutase (SOD, EC 1.15.1.1) catalyzing the first step O2 into H2O2 and Catalase (CAT; EC. 1.11.1.6) and Glutathione Peroxidase (GSH-Px; EC 1.11.1.9) removing H2O2 into H2O by two different pathways. Disturbances in the normal redox state of tissues can cause toxic effects through the production of peroxides and free radicals exert deleterious effects on cell through direct attack on DNA, proteins or membrane lipids (including mitochondrial lipids). These oxidative damages lead to the cellular death. The mechanisms of oxidative cellular damage are summarized in Fig. 1.
The main sources of ROS/RNS are: exogenous (γ irradiation, UV irradiation, drugs, xenobiotics, and toxin metabolism) and endogenous (metabolic pathways, mitochondrial respiration, oxidative burst, fagocytosis, enzyme activities, aging and diseases).
Although the exposure of the organism to ROS/RNS is extremely high from exogenous sources, the exposure to endogenous sources is much more important and extensive, because it is a continuous process during the life span of every cell in the organism.
Mitochondria are the major endogenous source of ROS underphysiologycal conditions, because 2% to 3% of the O2 consumed is converted to O2-. Intramitochondrial ROS production increases after peroxidation of intramitochondrial membrane lipids. Furthermore mitochondria are particularly sensitive to ROS/RNS-induced injury in the pathogenesis of disease. Oxidative stress exerts deleterious effects on mitochondria function by directly impairing oxidative phosphorylation through direct attack of proteins or membrane lipids. ROS/RNS can also induce mitochondrial DNA deletions and mitochondrial membrane permeability transition (MMPT). MMP pore opening activates caspases, which is an endpoint to initiate cell death. Recently, a large number of studies have associated mitochondrial dysfunction caused by ROS/RNS to both accidental cell death (necrosis) and programmed cell death (apoptosis).
Continuous exposure to various types of oxidative stress from numerous sources has led the cell and the entire organism to develop defense mechanisms for protection against reactive metabolites. Mitochondrial like a source of ROS are summarized in Fig. 2.
Understanding that mitochondria are the most important cellular targets of IGF-I [5, 6, 7] and it is the main intracellular source of ROS our results show a novel mechanism for oxidative stress regulation through mitochondrial protection and normalization of antioxidants enzymes activities by IGFs signaling pathways.
2. Oxidative Stress: Mitochondrial damage and antioxidant denfences
2.1. Mitochondrial damage
Mitochondria play a central role in many cellular functions including energy production, respiration, heme synthesis, and lipids synthesis, metabolism of amino acids, nucleotides, and iron, and maintenance of intracellular homeostasis of inorganic ions, cell motility, cell proliferation and apoptosis [8, 9]. Mitochondria contain their own DNA (mtDNA). The mtDNA occurs in small clusters called nucleoids or chondriolites. The number of mtDNA molecules in nucleoids varies in size and numbers in response to physiological conditions. While nuclear DNA encodes the majority of the mitochondrial proteins only a few of these proteins are encoded by mitochondrial DNA. A recent mitochondrial proteomic study in S. cerevisiae identified at least 750 mitochondrial proteins that perform mitochondrial function [10]. The last decade has witnessed an increased interest in mitochondria, not only because mitochondria were recognized to play a central role in apoptosis but also since mitochondrial genetic defects were found to be involved in the pathogenesis of a number of human diseases [9,11].
A variety of cellular systems, including NADPH oxidase, xanthine oxidase, uncoupled eNOS (endothelial NO synthase) and cytochrome P450 enzymes, can generate ROS, but, in most mammalian cells, mitochondria are the principal organelles for ROS production. The production of mitochondrial ROS is a consequence of oxidative phosphorylation at the respiratory chain complexes I and III where electrons derived from NADH and FADH can directly react with oxygen or other electron acceptors and generate free radicals [12-14]. Indeed, the increase of the redox potential at complex I and complex III induces ROS generation [15, 16]. Mitochondria are also a major site for the accumulation of low molecular weight Fe2+ complexes, which promote the oxidative damage of membrane lipids [17-19].
Mitochondria do not only represent the major source of ROS production but they are also the major targets for their damaging effects. Mitochondrial DNA (mtDNA) seems to be highly vulnerable to oxidative challenges compared to nuclear DNA for three main reason: 1) its close proximity to the electron transport chain (ETC), 2) it is continuously exposed to ROS generated during oxidative phosphorylation (it is estimated that up to 4% of the oxygen consumed by cells is converted to ROS under physiological conditions) [20] and 3) its limited capacity of DNA repair strategies and the lack of protection by histones [21]. ROS also produce more than 20 types of mutagenic base modifications in DNA [22]. These DNA lesions cause mutations in mtDNA that can lead to impairment of mitochondrial function [23]. Taken together, this makes clear that mtDNA is extremely susceptible to mutation by ROS-induced damage. Given that mitochondria are the major producer of ATP, it is also likely that mitochondrial dysfunction leads to the reduction in ATP level that may affect ATP-dependent pathways involved in transcription, DNA replication, DNA repair, and DNA recombination. Mitochondria are intimately involved in deoxyribose nucleoside triphosphate (dNTP) biosynthesis [24]. It is conceivable that mitochondrial damage contributes to muta-genesis of the nuclear genome in part due to impaired nucleotide biosynthesis. In fact, it is well established that an imbalance in the dNTP pool is mutagenic to cells [25]. Studies demonstrate that a dNTP pool imbalance can induce nucleotide insertion, frame-shift mutation [25] sister chromatid exchange, recombination and double-strand break [26].
Mitochondria also play a key role in regulation of apoptosis under a variety of pathological conditions, including ischemia, hypoxia, and myocardial infarction [27-30]. The electrochemical potential across mitochondrial membrane, MMP, is known to be highly sensitive to apoptotic stimulation. As an index of mitochondrial function in living cells, MMP can be measured with an indicator dye, e.g., rhodamine 123 (Rh123), which fluoresces in direct proportion to MMP [31]. Decreased MMP occurs in cells undergoing apoptosis induced by oxidative agents, such as H2O2 in primary neuronal cultures [32]. Injured mitochondria can release cytochrome-c into the cytoplasm when cells are treated with proapoptotic stimuli [33]. Cytochrome-c activates the apoptosome containing the caspase-activating protein Apaf-1 and subsequently the caspase cascade that induce apoptosis [34].
Because macromolecules in mitochondria (including mtDNA) are particulary susceptible to oxidative damage of mitochondrial turnover is critical for the maintenance of a healthy mitochondrial phenotype, normal energy production, and the promotion of healthy aging [35]. Mitochondria are highly dynamic organelles, and deregulation of mitochondrial turnover is likely one of the intrinsic causes of mitochondrial dysfunction, which contributes to deregulation of cell metabolism, oxidative stress, and altered signal transduction during the aging process.
Autophagy is a catabolic process that contributes to the maintenance of cellular homeostasis through the degradation of damaged mitochondria in lysosomes. The available evidence suggests that there is an age-dependent decline in autophagic function, which likely contributes to the accumulation of damaged non-functional mitochondria. In addition, dysfunction of the proteasomes [36] may be also contributed to the accumulation of damaged mitochondrial proteins in the age diseases.
Mitochondria are important cellular targets of IGF-I [5, 6], different groups have described that IGF-I decreases mitochondrial superoxide production [37] and low levels of IGF-I have been linked to increase in oxidative stress damage [3, 5, 40-42]. IGF-I also acts as an anti-apoptosis factor of multiple cell types, and its anti-apoptotic effects occur through engagement with IGF-I receptor (IGF-IR) and thought to activate an intracellular signal transduction pathway that may modulate the mitochondria, cytochrome c and caspase pathway [38, 39]. Recent studies show that treatment of aged rodents with IGF-I confer mitochondrial protection, including an attenuation of mitochondrial ROS generation in the liver [40-42]. The available data suggest that treatments that increase circulating IGF-I levels exert citoprotective effects in aging and degenerative diseases [1-3, 5-7, 42]. Thus, further studies are necessary to determine the role of mitochondrial mechanisms in beneficial effects of IGF-I treatment, including the effects of IGF-I on autophagy of dysfunctional mitochondria and apoptosis.
2.2. Antioxidant defenses
ROS and RNS consist of radicals and other reactive oxygen/nitrogen factors that can react with other substrates. Examples of ROS and RNS are superoxide, nitric oxide, peroxynitrite and hydrogen peroxide. Under physiological conditions, these are counterbalanced by an array of defense pathways, and it needs to be emphasized that ROS and RNS have many physiological roles that include signaling. In excess, or in situations where defenses are compromised, ROS and RNS may react with fatty acids, proteins and DNA, thereby causing damage to these substrates. Under normal conditions, antioxidant defenses include the enzymatic and non-enzymatic defense systems regulate the ROS and RNS produced. Antioxidants regulate oxidative and nitrosative reactions in the body and may remove ROS and RNS through scavenging radicals, decreasing the production of ROS and RNS, thus preventing the damage caused by ROS and RNS.
Enzymatic defense systems.
Enzymatic defense systems such as Superoxide Dismutases (SOD), Catalases (CAT), Glutathione Peroxidases (GPx), Glutation Reductases (GSR or GR; EC 1.8.1.7) and Glutathione Transferases (GST; EC 2.5.1.18) protect mitochondria and DNA from oxidative stress. It has been proposed that polymorphisms in these enzymes are associated with DNA damage and subsequently the individual’s risk of wide range of diseases susceptibility [42, 43].
CAT is a homotetramer encoded by
Genetic polymorphisms in catalase and its altered expression and activity are associated with oxidative DNA damage and subsequently the individual’s risk of cancer susceptibility [56]. A few polymorphisms have been described for the catalase-encoding gene; these are normally related with the development of mental disorders [57]. Humans with low catalase levels (acatalasemia) have an increased risk for diabetes mellitus; while the clinical features of acatalasemia are oral gangrene, altered lipid, carbohydrate, homocysteine metabolism and the increased risk of diabetes mellitus [58] and lower levels of catalase activity in other tissues, seem to be asymptomatic.
For every mole of oxidized glutathione (GSSG), one mole of NADPH is required to reduce GSSG to GSH. The enzyme forms a FAD-bound homodimer. Human
Cytosolic GSTs of mammals have been particularly well characterized, and were originally classified into Alpha, Mu, Pi, Theta, Zeta and Omega classes on the basis of a substrate/inhibitor specificity, primary and tertiary structure similarities and immunological identity [88]. The alpha class genes (
Non-enzymatic defense systems.
Examples of non-enzymatic defense systems are scavenger antioxidants (coenzyme Q10, vitamin C and E, and glutathione) and some proteins which act as antioxidants by binding ROS and RNS, e.g. thioredoxin (Trx), SS-peptides and acute phase proteins such as albumin, transferrin, haptoglobin and ceruloplasmin. These antioxidant systems thus protect the tissues against ROS and RNS.
Several other studies have used MitoQ10 in a variety of animal models of disease [102] and the results indicate that MitoQ10 protects against liver damage in an animal model of sepsis
Subcellular Location | |||||
SOD1 (Cu-Zn SODs) | Cytosol | Chromosome 21 | Familiar Amyotrophic Lateral Sclerosis (ALS) | ||
Superoxide Dismutases | SOD, ss EC 1.15.1.1 | SOD2 (MnSOD) | Mitochondrial | Chromosome 6 | Cancer, asthma and degenerative disease |
SOD3 (Cu-Zn SODs) | Extracellular | Chromosome 4 | Vascular-related diseases, atherosclerosis, hypertension, diabetes, ischemia-reperfusion injury,lung disease, various inflammatory conditions, and neurological diseases | ||
Catalase | CAT, EC.1.11.1.6 | Peroxisome fraction | Chromosome 11 | Mental disorders, Diabetes mellitus. | |
GPx1 | Chromosome 3 | ||||
GPx2 | Chromosome 14 | ||||
GPx3 | Chromosome 5 | Mental disorders | |||
Glutathione Peroxidases | GSH-Px, EC 1.11.1.9 | GPx4 | Cytosol/Mitochondrial | Chromosome 19 | |
GPx5 | Chromosome 6 | ||||
GPx6 | Chromosome 6 | ||||
GPx7 | Chromosome 1 | ||||
GPx8 | Chromosome 5 | ||||
Glutathione Reductase | GSR or GR, EC 1.8.1.7 | Cytosol/Mitochondrial | Chromosome 8 | Red blood diseases | |
Alpha, A1-1 | Chromosome 6 | ||||
Alpha, A2-2 | Chromosome 6 | ||||
Alpha, A3-3 | Cytosol | Chromosome 6 | |||
Alpha, A4-4 | Chromosome 6 | ||||
Alpha, A5-5 | Chromosome 6 | ||||
Mu, M1-1 | Chromosome 1 | ||||
Mu, M2-2 | Chromosome 1 | ||||
Mu, M3-3 | Chromosome 1 | ||||
Glutathione Transferases | GST; EC 2.5.1.18 | Mu, M4-4 | Chromosome 1 | Neurodegenerative, liver diseases and cancer | |
Mu, M5-5 | Chromosome 1 | ||||
Pi, P1-1 | Chromosome 11 | ||||
Theta, T1-1 | Chromosome 22 | ||||
Theta, T2-2 | Chromosome 22 | ||||
Zeta, Z1-1 | Chromosome 14 | ||||
Omega, O1-1 | Chromosome 10 | ||||
Omega, O2-2 | Chromosome 10 | ||||
Kappa, K1-1 | Mitochondrial/peroxisome | Chromosome 7 | |||
gp I, MGST2 | Chromosome 4 | ||||
gp I, FLAP | Chromosome 4 | ||||
gp I, LTC4S | Microsomal | Chromosome 1 | |||
gp II, MGST3 | Chromosome 1 | ||||
gp IV, MGST1 | Chromosome 12 | ||||
gp IV, PGES1 | Chromosome 9 |
[103], contributes to the aetiology of the metabolic syndrome and atherosclerosis in a mouse model [104] protects pancreatic
Antioxidant defense systems against mitochondrial ROS formation.
The mitochondrial respiratory chain, located in the inner mitochondrial membrane (IM), is composed of four multimeric integral membrane proteins complexes (complexes I-IV), coencymeQ (CoQ), and cytochrome c (cyt c). Complex I accepts electrons from NADH and complex II accepts electrons from succinate. Electrons then move down an electrochemical gradient through CoQ to complex III, from complex III to cyt c, and from cyt c to complex IV, which uses four electrons to reduce molecular oxygen to water (Fig. 3). The production of mitochondrial ROS is a consequence of oxidative phosphorylation at the respiratory chain complexes I and III where electrons derived from NADH can directly react with oxygen or other electron acceptors and generate free radicals [12-14]. Indeed, the increase of the redox potential at complex I and complex III induces ROS generation [15, 16]. Mitochondrial and cell cytosolic antioxidant systems can neutralize excess mitochondrial ROS under most conditions. With the exception of generation at complex III, ROS production in mitochondria is exclusively directed towards the matrix where MnSOD catalyses dismutation to H2O2 [119] which is then reduced to H2O by GSH and Trx systems (Trx2) [120]. As the regeneration of GSH and reduced Trx2 depends on the NADPH/NADP+ redox state, an efficient mitochondrial bioenergetic function is required to maintain antioxidant activity. Matrix ROS can also pass through the MMTP, formed by voltage-dependent anion channel (VDAC), cyclophilin D (cyp D) and the adenine nucleotide translocator (ANT), directly to the cytosol where Cu-Zn SOD catalyses dismutation to H2O2 [119] which is then reduced to H2O by catalase. Complex III generates ROS on both sides of the mitochondrial inner membrane and in the intermembrane space, where Cu-Zn SOD converts O2− into H2O2, which diffuses in the cytosol where catalase reduces it into H2O. Thus the efflux of H2O2 from the mitochondria is relatively modest, but may be modulated by either mitochondrial ROS themselves or changes in antioxidant defenses.
Regulation of enzymatic antioxidant defense systems.
In order to prevent oxidative stress, the cell must respond to ROS by mounting an antioxidant defense system. Antioxidant enzymes play a major role in reducing ROS levels; therefore, redox regulation of transcription factors is significant in determining gene expression profile and cellular response to oxidative stress. There are different transcription factors involved in regulation of antioxidant enzymes and they can be regulated though IGFs signaling and others pathways related with receptors tyrosine kinases (RTKs). The most studied transcription factors are:
The PI3K/Akt/PP2A/GSK3ß and PKC/GSK3 play a role in regulation of Nrf2 and antioxidant gen regulation. PI3K pathway, consisting of p110 cataytic subunit and p85 regulatory subunit, is tighly coupled with RTKs activated by various growth factors such as IGFs, Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor (PDGF), Nerve Growth Factor (NGF), and Vascular Endothelial Growth Factor (VEGF). PI3K is recruited to activate RTK dimers through a SH2 domain in the PI3K p85 regulatory subunit. PI3K catalyzes the synthesis of the second messenger phosphatidylinositol 3,4,5 triphosphate (PIP3) from phosphatidylinositol 4,5 bisphosphate (PIP2), wherein the membrane bound PIP3 serves as a signaling molecule to recruit proteins containing the pleckstrin homology (PH) domain. These PH domain proteins, such as the phosphoinositide-dependent protein kinase (PDK) and protein kinase B (AKT) serine/threonine kinases are thus activated and mediate further downstream signaling events [123]. The synthesis of PIP3 is negatively regulated primarily by the phosphatase and tensin homology (PTEN) phosphatase, which dephosphorylates PIP3 back to PIP2 [124]. Through PTEN, the PI3K pathway is subject to reversible redox regulation by ROS generated by growth factor stimulation. H2O2 was shown to oxidize and inactivate human PTEN through disulfide bond formation between the catalytic domain Cys-124 and Cys-71 residues [125, 126]. It was also demonstrated that endogenously generated ROS following treatment with peptide growth factors such as IGFs, EGF, or PDGF causes oxidation of PTEN leading to the activation of the PI3K pathway [127]. PTEN oxidation is reversed by peroxiredoxin II, a cytoplasmic peroxiredoxin isoform that eliminates H2O2 generated in response to growth factors [125]. It is noteworthy that various oxidants and ROS-producing chemicals activate transcription of a battery of antioxidant genes through a PI3K-NFE2- like 2 (Nrf2)-antioxidant response element (ARE) mechanism, where PTEN knockdown enhances transcription of ARE regulated antioxidant genes [128]. However, it is not known whether these oxidants induce PTEN oxidation and inhibition of phosphatase activity leading to gene activation. This leads to antioxidant gene expression that protects the cell. A role for NRF2 in drug resistance is suggested based on its property to induce detoxifying, drug transport, and antioxidant enzymes.
Activation of PI3K/PKB signaling decreases FOXO activity and thus the levels of FOXO target genes like MnSOD and catalase [130]. Their regulation via PI-3K/PKB/FOXO signaling therefore implies that insulin, through this signaling cascade, may modulate the cellular ROS level.
Based on oxidative stress is an imbalance between the production of ROS and antioxidative defenses systems, IGF-I decreases mitochondrial ROS production and IGF-I/Akt pathway is involved in Nrf2 and FOXO activity, both transcription factors involved in the antioxidative enzymes regulation. We propose that IGF-I can exert direct effects on cells and can alter in opposite ways the expression of antioxidant enzymes depending on the ROS levels. This regulation may contribute to the citoprotective effects of treatment with low doses of IGF-I in experimental “IGF-I deficiency” conditions [2, 5, 6, 40-42]. This model is summarized in Fig. 4.
3. Aging and others conditions of “IGF-I deficiency” and oxidative stress
Mechanisms that cellular protection against oxidative injure are not well understood. It is known, however, that factors that promote the generation of ROS and/or impair antioxidative processes contribute to oxidative damage. Oxidative damage accumulates with aging and is likely responsible for the progressive decline in physiological systems. The identification of physiological regulators of antioxidative processes is critical to the understanding of degenerative diseases and aging processes. GH, IGF-I, IGF-II concentrations decline with age. The IGF-I is an anabolic hormone produced mainly in the liver in response to GH stimulation [131]. Circulating IGF-I serum levels decline by more than 50% in healthy older adults [132, 133]. Our team results show that exogenous administration of low doses of IGF-I restores IGF-I circulating levels and some age-related changes, improving glucose and lipid metabolisms, increasing testosterone levels and serum total antioxidant capability, and reducing oxidative damage in the brain and liver associated with a normalization of antioxidant enzyme activities and mitochondrial protection [5]. From these results we suggested that aging seems to be an unrecognized condition of “IGF-I deficiency.” The best-known condition of “IGF-I deficiency” is Laron’s dwarfism [134], characterized by an absence of GH receptors in the liver. Another condition of IGF-I deficiency is liver cirrhosis. In cirrhosis the reduction of receptors for GH in hepatocytes and the diminished ability of the hepatic parenchyma to synthesize cause a progressive decrease in serum IGF-I levels [135]. We have also shown previously that short courses of treatment with low doses of IGF-I in rats with carbon tetrachloride-induced cirrhosis had many systemic beneficial effects, and showed hepatoprotective and antioxidant properties, including mitochondrial protection [2, 3, 6, 41].
Oxidative Stress is one of the most important mechanisms of the cellular damage in aging [42,131] and in others “IGF-I deficiency” conditions such as liver cirrhosis where there are a diminution in IGF-I levels but not in GH levels followed of a decrease in liver biosynthetic capacity. In order to reproduce of “IGF-I deficiency” condition and the possible benefices of treatment with low doses of IGF-I, we used two different experimental models:
Experimental model of cirrhosis: Male Wistar rats in which liver cirrhosis was inducted using CCl4. IGF-I therapy or saline was administrated the last 4 weeks [2, 6, 41, 137-139].
Experimental model of aging: Healthy male Wistar rats were divided into two groups according to age: young control of 17 weeks, and aging control rats of 103 weeks. Old animals were randomly assigned to receive either saline or human IGF-I [5, 32,139,140].
In these experimental groups we measured the
Understanding that mitochondria are one of the most important cellular targets of IGF-I [5, 6, 7] and they are the main intracellular ROS sources we studied the
In these conditions of “IGF-I deficiency” low doses of IGF-I induced: a increase in the total serum antioxidant capacity closely related with serum IGF-I levels [40], a correlation between the SODs levels and MDA as shown in Fig. 5, a decrease of oxidative cell damage reducing MDA and PCC and improving antioxidant enzyme activities and a mitochondrial protection improving MMP, proton leak and reducing intramitochondrial ROS production and increasing ATP synthesis (Fig. 6), leading to reduced apoptosis [5, 41, 42].
All these data together provide evidence of the beneficial effect of IGF-I replacement therapy inducing anabolic [139] and antioxidant [5, 40, 41,139] actions in both experimental “IGF-I deficiency” conditions: cirrhosis and aging and experimental basis for further studies at exploring the potential IGF-I like a bioprotector due to its antioxidant, hepatoprotective and neuoroprotective effects. Recently, we have also shown that IGF-II exerts similar effects [139,140]. The IGF-II is a peptide hormone that belongs to the family of IGFs. It plays an important role in the embryology development but the physiological function of IGF-II in the adult life are not fully understood [139,140]. IGF-II concentration decline with the age. Recently, we have also shown that low doses of IGF-II in aging rats exerts similar hepatoprotector and neuroprotector effects than IGF-I low doses therapy.
4. Conclusions
Our results show that the cytoprotective effect of IGFs is closely related to a mitochondrial protection, leading to the reduction of intramitocondrial free radical production, oxidative damage, and apoptosis, increased ATP production and a normalization of antioxidant enzyme activities. Further studies are necessary to elucidate all mechanisms involved in the IGFs mitochondrial protection, including the effects of IGF-I on autophagy of dysfunctional mitochondria and apoptosis. In agreement with these results, it has been reported that IGF-I differentially regulates Bcl-xL and Bax. Previously, we reported that low doses of IGF-I restored the expression of several protease inhibitors such us the serine protease inhibitor 2 in cirrotic rats [137], which could contribute to the described mitochondrial protection. Our work provides new evidence of beneficial effect of IGF-I replacement therapy in degenerative diseases including aging.
Abbreviations
Adenine Nucleotide Translocator (ANT)
Amyotrophic Lateral Sclerosis (ALS)
Antioxidants response elements (ARE)
Catalase (CAT)
Coenzyme Q10 (CoQ10)
Copper and Zinc SOD (Cu-Zn SODs)
Cytochrome c (cyt c)
Deoxyribose nucleoside triphosphate (dNTP)
Electron Transport Chain (ETC)
Glutathione (GSH)
Glutathione Peroxidase (GSP)
Glutathione Ttransferases (GST).
Glutation Reductases (GSR)
Growth factor hormone (GH),
IGF-I receptor (IGF-1R)
Inner mitochondrial membrane (IM),
Insulin-like growth factor I (IGF-I)
Manganese SOD (MnSOD)
Mitochondrial DNA (mtDNA).
Mitochondrial Membrane Permeability Transition (MMPT)
Nerve Growth Factor (NGF)
Nuclear Factor κ B (NFκB)
Pentose phosphate pathway (PPP)
Phosphatidylinositol 3, 4, 5 triphosphate (PIP3)
Phosphatidylinositol 4, 5 bisphosphate (PIP2)
Platelet-Derived Growth Factor (PDGF)
Protein Carboxyl Content (PCC)
Reactive Nitrogen Species (RNS)
Reactive oxygen species (ROS)
Rhodamine 123 (Rh123)
Superoxide Dismutase (SOD)
Szeto-Schiller (SS)
Thioredoxin (Trx)
Tripenylphoshonium ion (TPP+)
Tyrosine Kinases (RTKs)
Vascular Endothelial Growth Factor (VEGF)
Voltage-Dependent Anion Channel (VDAC)
References
- 1.
J, Castilla-Cortázar I, Santidrián S, Prieto J.”Low doses of insulin-like growth factor-I improve nitrogen retention and food efficiency in rats with early cirrosis”. J Hepatol.Picardi A. de Oliveira A. C. Muguerza B. Tosar A. Quiroga J. Castilla-Cortázar I. Santidrián S. Prieto J.”. Low doses. of insulin-like. growth-I factor. improve nitrogen. retention food efficiency. in rats. with early. cirrosis” 1997 Jan;26 1 191 202 - 2.
Castilla-Cortázar I. Prieto J. Urdaneta E. Pascual M. Nuñez M. Zudaire E. García M. Quiroga J. Santidrian S. ”. Impaired intestinal sugar transport in cirrhotic rats: correction by low doses of insulin- like growth factor I 1997 Oct;113 4 1180 7 - 3.
Gastroenterology ”Hepatoprotective effects of insulin-like growth factor I in rats with carbon tetrachloride-induced cirrosis”.Castilla-Cortázar I. Garcia M. Muguerza B. Quiroga J. Perez R. Santidrian S. Prieto J. 1997 Nov;113 5 1682 91 - 4.
Ramalingam M. Kim S. J. . Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases 2012 - 5.
García-Fernández M. Delgado G. Puche J. E. González-Barón S. Castilla Cortázar. I. ”. Low doses of insulin-like growth factor I improve insulin resistance, lipid metabolism, and oxidative damage in aging rats 2008 May;149 5 2433 42 - 6.
Muguerza B. Castilla-Cortázar I. García M. Quiroga J. Santidrián S. Prieto J. “. Antifibrogenic effect in vivo of low doses of insulin-like growth factor-I in cirrhotic rats” Biochim Biophys Acta.2001 May 31; 1536(2-3):185 EOF 95 EOF - 7.
Am J Physiol.Castilla-Cortázar I. Picardi A. Ainzua J. Urdaneta E. Pascual M. García M. Pascual M. Quiroga J. Prieto “. Effect of. insulin-like growth. factor I. on in. vivo intestinal. absorption of. D-galactose in. cirrhotic rats.”. J. 1999 276 37 42 - 8.
York, NY.In “. Mitochondrial D. N. A. Mutations in. Aging Disease. Cancer” Singh. K. K. Ed Springer. New - 9.
Physiol. J.Ravagnan L. Roumier T. Kroemer G. “. Mitochondria the. killer organelles. their weapons.”. Cell 2002 192 131 137 - 10.
Sickmann A. Reinders J. Wagner Y. Joppich C. Zahedi R. Meyer H. E. Schonfisch B. Perschil I. Chacinska A. Guiard B. Rehling P. Pfanner N. Meisinger C. “. The proteome of Saccharomyces cerevisiae mitochondria Proc. Natl. Acad. Sci.2003 100 13207 13212 - 11.
Singh K. K. “. Mitochondrial me and the Mitochondrion”. Journ al.2000 1 1 2 - 12.
Andreyev A. Y. Kushnareva Y. E. Starkov A. A. “. Mitochondrial metabolism of reactive oxygen species Mosc.)2005 70 200 214 - 13.
Jezek P. lavata L. H. “. Mitochondria in homeostasis of reactive oxygen species in cell, tissues, and organism” Int. J. Biochem. Cell Biol.2005 37 2478 2503 - 14.
Biol. Chem.Muller F. L. Liu Y. Van Remmen H. Complex “. releases I. I. I. superoxide to. both sides. of the. inner mitochondrial. membrane” J. 2004 279 49064 49073 - 15.
Andreyev “Complex I-mediated reactive oxygen species generation: modulation by cytochrome c and NAD (P)+ oxidation- reduction state,, Biochem. J.Kushnareva Y. Murphy A. N. A. 2002 368 545 553 - 16.
Lesnefsky “Chen Q. Vazquez E. J. Moghaddas S. Hoppel C. L. E. J. Production of reactive oxygen species by mitochondria: central role of complex III, J. Biol. Chem.2003 278 36027 36031 - 17.
Williamson,D.“The curious history of yeast mitochondrial”. DNA. Nat. Rev. Genet.2002 3 475 481 - 18.
Proc. Natl Acad. Sci. USA.Sickmann A. Reinders J. Wagner Y. Joppich C. Zahedi R. Meyer H. E. Schonfisch B. Perschil I. Chacinska A. Guiard B. Rehling P. Pfanner N. Meisinger C. “. The proteome. of Saccharomyces. cerevisiae mitochondria.”. 2003 100 13207 13212 - 19.
Manipulations of the mitochondrial germ line must be openly debated and followed up”. Nature.Naviaux R. Singh K. K. “. 2001 - 20.
Abd El-Gawad HM, Khalifa AE. “Quercetin, coenzyme Q10, and L-canavanine as protective agents against lipid peroxidation and nitric oxide generation in endotoxin-induced shock in rat brain”. Pharmacol Res.2001 43 3 257 63 - 21.
Natl Acad. Sci. USAYakes F. M. Van Houten B. Mitochondrial “. damage D. N. A. is more. extensive persists longer. than nuclear. D. N. A. damage in. human cells. following oxidative. stress Proc. 1997 94 514 519 - 22.
Lipid peroxidation in neurodegeneration: new insights into Alzheimer’s disease”. Curr Opin LipidolArlt S. Beisiegel U. Kontush A. “. 2002 13 3 289 94 - 23.
Vagal system impairment in human immunodeficiency virus-positive patients with chronic hepatitis C: does hepatic glutathione deficiency have a pathogenetic role?” Scand J Gastroenterol.Barbaro G. Di Lorenzo G. Soldini M. Bellomo G. Belloni G. Grisorio B. et al. “. 1997 32 12 1261 6 - 24.
Dihydroorotat-ubiquinone oxidoreductase links mitochondria in the biosynthesis of pyrimidine nucleotides.” Mol. Cell Biochem.Loffler M. Jockel J. Schuster G. Becker C. “. 1997 174 125 129 - 25.
Deoxyribonucleotide pool imbalance stimulates deletions in HeLa cell mitochondrial DNA”. J. Biol. Chem.Song S. Wheeler L. J. Mathews C. K. “. 2003 278 43893 43896 - 26.
Sister chromatid exchange formation in mammalian cells is modulated by deoxyribonucleotide pool imbalance” Somat. Cell Mol. Genet.Popescu N. C. “. 1999 - 27.
Long-term treatment with N(omega)-nitro-L-arginine methyl ester causes arteriosclerotic coronary lesions in endothelial nitric oxide synthase-deficient mice”. CirculationSuda O. Tsutsui M. Morishita T. Tanimoto A. Horiuchi M. Tasaki H. Huang P. L. Sasaguri Y. Yanagihara N. Nakashima Y. ”. 2002 106 1729 1735 - 28.
Beal MF. Mitochondrial dysfunction in neurodegenerative diseases”. Biochim Biophys Acta1998 1366 211 223 - 29.
The mitochondrial permeability transition in toxic, hypoxic and reperfusion injury”. Mol Cell BiochemLemasters J. J. Nieminen A. L. Qian T. Trost L. C. Herman B. “. 1997 174 159 165 - 30.
Biochem Biophys Res CommunLi Y. Wu H. Khardori R. Song Y. H. Lu Y. W. Geng Y. J. “. Insulin-like growth. factor receptor activation. prevents high. glucose-induced mitochondrial. dysfunction cytochrome-c. release apoptosis” 2009 384 259 264 - 31.
J Neurosci ResSatoh T. Enokido Y. Aoshima H. Uchiyama Y. Hatanaka H. “. Changes in. mitochondrial membrane. potential during. oxidative stress-induced. apoptosis in. P. C. cells” 1997 50 413 420 - 32.
Li Y. Meyer E. M. Walker D. W. Millard W. J. He Y. J. MA King “. Alpha nicotinic. receptor activation. inhibits ethanolinduced. mitochondrial dysfunction. cytochrome c. release neurotoxicity in. primary rat. hippocampal neuronal. cultures” 2002 J Neurochem81 853 858 - 33.
CellReed J. C. “. Cytochrome c. can’t live. with it-can’t. live without. it” 1997 91 559 562 - 34.
Deshmukh M. Johnson E. M. “. Evidence of. a. novel event. during neuronal. death development. of competence-to-die. in response. to cytoplasmic. cytochrome c”. 1998 Neuron21 695 705 - 35.
Exp Gerontol.Lopez-Lluch G. Irusta P. M. Navas P. de Cabo R. “. Mitochondrial biogenesis. healthy aging”. 2008 43 813 819 - 36.
Aging and dietary restriction effects on ubiquitination, sumoylation, and the proteasome in the heart”. Mech Ageing Dev.Li F. Zhang L. Craddock J. Bruce-Keller A. J. Dasuri K. Nguyen A. Keller J. N. “. 2008 129 515 521 - 37.
Am J Physiol Heart Circ Physiol.Csiszar A. Labinskyy N. Perez V. Recchia F. A. Podlutsky A. Mukhopadhyay P. Losonczy G. Pacher P. Austad S. N. Bartke A. Ungvari Z. “. Endothelial function. vascular oxidative. stress in. long-lived gh/igfdeficient. ames dwarf. mice ”. 2008 H1882 H1894. - 38.
Arterioscler Thromb Vasc Biol.Delafontaine P. Song Y. H. Li Y. “. Expression regulation. function of. I. G. F- I. G. F. R. I. G. F. binding proteins. in blood. vessels” 2004 24 435 444 - 39.
JL “Fluorescence probes used for detection of reactive oxygen species”. J Biochem Biophys MethodsGomes A. Fernandes E. Lima J. L. “. Fluorescence probes. used for. detection of. reactive oxygen. species” 2005 65 45 80 - 40.
García- J Physiol Biochem.Fernández M. Castilla-Cortázar I. Díaz-Sánchez M. Díez Caballero. F. Castilla A. Díaz Casares. A. Varela-Nieto I. González-Barón S. “. Effect-I of. I. G. F. on total. serum antioxidant. status in. cirrhotic rats”. 2003 59 145 6 - 41.
Mitochondrial protection by low doses of insulin-like growth factor- I in experimental cirrosis”. I. World J Gastroenterol.Pérez R. García-Fernández M. Díaz-Sánchez M. Puche J. E. Delgado G. Conchillo M. Muntané J. Castilla-Cortázar “. 2008 14 2731 9 - 42.
Low doses of insulin-like growth factor-I induce mitochondrial protection in aging rats”. Endocrinology.Puche J. E. García-Fernández M. Muntané J. Rioja J. González-Barón S. Castilla Cortazar. I. “. 2008 May; 149. - 43.
New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose.” Neurochem ResNaziroglu M. “. 2007 32 1990 2001 - 44.
Oxidative and antioxidative potential of brain microglial cells.” Antioxid Redox SignalDringen R. “. 2005 7 1223 1233 - 45.
Role of superoxide dismutases (SODs) in controlling oxidative stress in plants”. J. Exp. BotAlscher R. G. Erturk N. Heath L. S. “. 2002 53 1331 1341 - 46.
Superoxide radical and superoxide dismutases. Annu. Rev. Biochem.Fridovich I. 1995 64 97 112 - 47.
Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and extracellular SOD (SOD3) gene structures, evolution, and expression”. Free Radic. Biol. Med.Zelko I. N. Mariani T. J. Folz R. J. “. 2002 33 337 349 - 48.
Amyotrophic-lateral-sclerosis and structural defects in Cu,Zn superoxide-dismutase”. ScienceDeng H. X. Hentati A. Tainer J. A. Iqbal Z. Cayabyab A. Hung W. Y. Getzoff E. D. Hu P. Herzfeldt B. Roos R. P. Warner C. Deng G. Soriano E. Smyth C. Parge H. E. Ahmed A. Roses A. D. Hallewell R. A. Pericakvance M. A. Siddique T. “. 1993 261 1047 1051 - 49.
Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis”. NatureRosen D. R. Siddique T. Patterson D. Figlewicz D. A. Sapp P. et al. “. 1993 362 59 62 - 50.
GenomicsHendrickson D. J. Fisher J. H. Jones C. Ho Y. S. “. Regional localization. of human. extracellular superoxide. dismutase gene. to 4pterq21”. 1990 8 736 738 - 51.
Biochem J.Karlsson K. Marklund S. L.” Heparin-induced. release of. extracellular superoxide. dismutase to. human blood. plasma” 1987 242 55 59 - 52.
Marklund S.”Extracellular superoxide dismutase in human tissues and human cell lines”. J Clin Invest1984 74 1398 1403 - 53.
Cell Mol Life Sci.Chelikani P. Fita I. Loewen P. . Diversity of. structures properties among. catalases 2004 61 2 192 208 - 54.
Understanding the structure and function of catalases: clues from molecular evolution and in vitro mutagenesis". Prog Biophys Mol Biol.Zámocký M. Koller F. . 1999 72 1 19 66 - 55.
Detection of catalase in rat heart mitochondria”. J. Biol. Chem.Radi R. Turrens J. F. Chang L. Y. Bush K. M. Crapo J. D. Freeman B. A. “. 1991 266 22028 22034 - 56.
Isolation and characterization of the human catalase gene”. Nucleic Acids Res.Quan F. Korneluk R. G. Tropak M. B. Gravel R. A. “. 1986 14 5321 5335 - 57.
MA Khan Tania. M. Zhang D. Chen H. . Antioxidant enzymes. cancer 2010 Chin J Cancer Res22 2 87 92 - 58.
Levinson D. F. MM Mahtani Nancarrow. D. J. Brown D. M. Kruglyak L. Kirby A. et al. “. Genome scan. of schizophrenia”. Am J. Psychiatry 1998 155 741 750 - 59.
Catalase enzyme mutations and their association with Diseases”. Mol Diagn.Góth L. Rass P. Páy A. “. 2004 8 3 141 9 - 60.
Vitorica J. Machado A. Satrustegui J. “. Age-dependent variations. in peroxide-utilizing. enzymes from. rat brain. mitochondria cytoplasm” 1984 J Neurochem.42 351 357 - 61.
Glutathione peroxidases expression in the mammalian epididymis”. AndrologyDrevet J. R. Francavilla F. Francavilla S. Forti G. “. 2000 2000 427 461 - 62.
Drevet JR. The antioxidant glutathione peroxidase family and spermatozoa: a complex story”. Mol Cell Endocrinol.2006 250 70 79 - 63.
Expression and chromosomal mapping of mouse Gpx2 gene encoding the gastrointestinal form of glutathione peroxidase, GPX-GI”. Biomed. Environ.Chu F. F. Esworthy R. S. Ho Y. S. Bermeister M. Swiderek K. Elliott R. W. “. 1997 Sci.10 156 62 - 64.
Purification and characterization of human plasma glutathione peroxidase: a selenoglycoprotein distinct from the known cellular enzyme. Arch. Biochem. Biophys.Takahashi K. Avissar N. Whitin J. Cohen H. 1987 256 677 86 - 65.
Tissue specific expression of the plasma glutathione peroxidase gene in rat kidney”. J. Biochem.Yoshimura S. Watanabe K. Suemizu H. Onozawa T. Mizoguchi J. et al. “. 1991109 918 23 - 66.
Thomas J. P. Maiorino M. Ursini F. Girotti A. W. 1990 Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides”. J. Biol. Chem.265 454 61 - 67.
Mitochondrial phospholipid hydroperoxide glutathione peroxidase plays a major role in preventing oxidative injury to cells”. J. Biol. Chem.Arai M. Imai H. Koumura T. Yoshida M. Emoto K. et al. “. 1999 274 4924 33 - 68.
Mitochondrial phospholipid hydroperoxide glutathione peroxidase suppresses apoptosis mediated by a mitochondrial death pathway”. J. Biol. Chem.Nomura K. Imai H. Koumura T. Arai M. Nakagawa Y. “. 1999 274 29294 302 - 69.
Dual function of the selenoprotein PHGpx during sperm maturation. ScienceUrsini F. Heim S. Kiess M. Maiorino M. Roveri A. et al. 1999 285 1393 96 - 70.
Characterization of mammalian selenoproteomes”.Kryukov G. V. Castellano S. Novoselov S. V. Lobanov A. V. Zehtab O. et al. . 2003 Science300 1439 43 - 71.
In vitro expression of a mouse tissue specific glutathione-peroxidaselike protein lacking the selenocysteine can protect stably transfected mammalian cells against oxidative damage”. Biochem Cell Biol.Vernet P. Rigaudiere N. Ghyselinck N. B. Dufaure J. P. Drevet J. R. “. 1996 74 125 131 - 72.
Selenium-independent epididymis-restricted glutathione peroxidase5 protein (GPX5) can back up failing Se-dependent GPXs in mice subjected to selenium deficiency”. Mol Reprod Dev.Vernet P. Rock E. Mazur A. Rayssiguier Y. Dufaure J. P. Drevet J. R. “. 1999 54 362 370 - 73.
More than simple antioxidant scavengers”. FEBS J.Herbette S. Roeckel-Drevet P. Drevet J. R. “. Seleno-independent glutathione. peroxidases 2007 274 2163 2180 - 74.
Epididymis selenoindependent glutathione peroxidase 5 (Gpx5) contributes to the maintenance of sperm DNA integrity. J Clin Invest.Chabory E. Damon C. Lenoir A. Kauselmann G. Kern H. Zevnik B. Garrel C. Saez F. Cadet R. Henry-Berger J. Schoor M. Gottwald U. Habenicht U. Drevet J. R. Vernet P. 2009 119 2074 2085 - 75.
Int J NeuropsychopharmacolBerk M. “. Neuroprogression pathways. to progressive. brain changes. in bipolar. disorder” 2009 12 4 441 5 - 76.
J. Biol. Chem.Meister A. . Glutathione metabolism. its selective. modification 1988 263 33 17205 8 - 77.
Biochem. Soc. Trans.Mannervik B. . The enzymes. of glutathione. metabolism an. overview 1987 15 4 717 8 - 78.
Kanzok S. M. Fechner A. Bauer H. Ulschmid J. K. Müller H. M. Botella-Munoz J. Schneuwly S. Schirmer R. Becker K. . Substitution of. the thioredoxin. system for. glutathione reductase. in Drosophila. melanogaster 2001 Science291 5504 643 6 - 79.
Krauth-Siegel RL, Comini MA "Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism". Biochim Biophys Acta2008 1780 11 1236 48 - 80.
Keen JH, Jakoby WB. “Glutathione transferases. Catalysis of nucleophilic reactions of glutathione”. J. Biol. Chem.1978 253 5654 57 - 81.
Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance”. Crit. Rev. Biochem. Mol. Biol.1995 30 445 600 - 82.
Armstrong RN. “Structure, catalytic mechanism, and evolution of the glutathione transferases”. Chem. Res. Toxicol.1997 10 2 18 - 83.
Hayes JD, McLellan LI. Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress” Free Radic. Res.1999 31 273 300 - 84.
Biochem. J.Sheehan D. Meade G. Foley V. M. CA Dowd “. Structure function. evolution of. glutathione transferases. implications for. classification of. nonmammalian members. of an. ancient enzyme. superfamily” 2001 360 1 16 - 85.
Ladner JE, Parsons JF, Rife CL, Gilliland GL, Armstrong RN. Parallel evolutionary pathways for glutathione transferases structure and mechanism of the mitochondrial class Kappa enzyme rGSTK1-1. Biochemistry2004 43 352 61 - 86.
Modelling and bioinformatics studies of the human Kappa class glutathione transferase predict a novel third transferase family with homology to prokaryotic 2-hydroxychromene-2-carboxylate isomerases”. Biochem J.Robinson A. Huttley G. A. Booth H. S. Board P. G. “. 2004 379 541 52 - 87.
Common structural features of MAPEG-a widespread superfamily of membrane associated proteins with highly divergent functions in eicosanoid and glutathione metabolism”. Protein SciJakobsson-J P. Morgenstern R. Mancini J. Ford-Hutchinson A. Persson B. “. 1999 8 689 92 - 88.
Crit. Rev. Biochem.Mannervik B. Danielson U. H. “. Glutathione-structure transferases. catalytic activity”. 1988 23 283 337 - 89.
Decreased glutathione transferase activity in brain and ventricular fluid in Alzheimer’s disease”. Neurology.Lovell M. A. Xie C. Markesbery W. R. “. 1998 51 1562 1566 - 90.
Identification of class-mu glutathione transferase genes GSTM1- GSTM5 on human chromosome 1Pearson W. R. Vorachek W. R. Xu S. J. Berger R. Hart I. Vannais D. et al. “. 13 Am J Hum Genet1993 - 91.
The human Hb (mu) class glutathione S-transferases are encoded by a dispersed gene family”. Biochem Biophys Res CommunDe Jong J. L. Mohandas T. CP Tu “. 1991 180 15 22 - 92.
Metabolic polymorphisms and cancer susceptibility.” Cancer SurvSmith G. Stanley L. A. Sim E. Strange R. C. Wolf C. R. “. 1995 25 27 65 - 93.
Glutathione transferases catalyse the detoxication of oxidized metabolites (o-quinones) of catecholamines and may serve as an antioxidant system preventing degenerative cellular processes”. Biochem JBaez S. Segura-Aguilar J. Widersten M. AS Johansson Mannervik. B. “. 1997 Pt 1):25-8. - 94.
Strange RC, Fryer AA. “The glutathione S-transferases: influence of polymorphism on cancer susceptibility”. IARC Sci Publ1999 1999 231 49 - 95.
CarcinogenesisChenevix-Trench G. Young J. Coggan M. Board P. “. Glutathione S-transferase. M. polymorphisms T. susceptibility to. colon cancer. age of. onset” 1995 16 1655 7 - 96.
Lippincott Williams and Wilkins.Champe et. al Biochemistry. Fourth Edition. 2008 - 97.
Influence of Coenzyme Q_{10} on release of pro-inflammatory chemokines in the human monocytic cell line THP-1”. BiofactorsSchmelzer C. Lorenz G. Rimbach G. Döring F. “. 2007 - 98.
Effects of Coenzyme Q10 on TNF-alpha secretion in human and murine monocytic cell lines”. BiofactorsSchmelzer C. Lorenz G. Lindner I. Rimbach G. Niklowitz P. Menke T. et al. “. 2007 31 1 35 41 - 99.
Functions of coenzyme Q10 in inflammation and gene expression”. BiofactorsSchmelzer C. Lindner I. Rimbach G. Niklowitz P. Menke T. Döring F. “. 2008 - 100.
Abd El-Gawad HM, Khalifa AE. “Quercetin, coenzyme Q10, and L-canavanine as protective agents against lipid peroxidation and nitric oxide generation in endotoxin-induced shock in rat brain”.Pharmacol.Res 2001 43 257 63 - 101.
Chaturvedi RK, Beal MF. Mitochondrial approaches for neuroprotection Ann N Y Acad Sci2008 1147 395 412 - 102.
Barbato J. C. “. Have no. fear Mito. Q. is here”. Hypertension 2009 54 222 223 - 103.
Smith R. A. Murphy M. P. Animal and human studies with the mitochondria-targeted antioxidant MitoQ Ann. N.Y.2010 Acad. Sci.1201 96 10386 - 104.
The mitochondria targeted antioxidant MitoQ decreases features of the metabolic syndrome in ATM+ /− /ApoE− /− mice” Radical Biol. Med.Mercer J. R. Yu E. Figg N. Cheng K. K. Prime T. A. Griffin J. L. Masoodi M. Vidal-Puig A. Murphy M. P. Bennett M. R. “. 2012 52 841 849 - 105.
Mitochondria-targeted antioxidants protect pancreatic β-cells against oxidative stress and improve insulin secretion in glucotoxicity and glucolipotoxicity”. Cell. Physiol.Biochem.Lim S. Rashid M. A. Jang M. Kim Y. Won H. Lee J. Woo J. T. Kim Y. S. Murphy M. P. Ali L. “. 2011 28 873 886 - 106.
Wani W. Y. Gudup S. Sunkaria A. Bal A. Singh P. P. Kandimalla R. J. Sharma D. R. Gill K. D. “. Protective efficacy of mitochondrial targeted antioxidant MitoQ against dichlorvos induced oxidative stress and cell death in rat brain 2011 61 1193 1201 - 107.
Gane E. J. Weilert F. Orr D. W. Keogh G. F. Gibson M. Lockhart M. M. Frampton C. M. Taylor K. M. Smith R. A. Murphy M. P. “. The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients 2010 Liver Int.30 1019 1026 - 108.
Gane E. J. Weilert F. Orr D. W. Keogh G. F. Gibson M. Lockhart M. M. Frampton C. M. Taylor K. M. Smith R. A. Murphy M. P. “. The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients 2010 Liver Int.30 1019 1026 - 109.
Zhao K. Zhao G. M. Wu D. Soong Y. Birk A. V. Schiller P. W. Szeto H. H. “. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury” J Biol Chem.2004 279 34682 34690 - 110.
Doughan AK, Dikalov SI. Mitochondrial redox cycling of mitoquinone leads to superoxide production and cellular apoptosis Antioxid Redox Signal.2007 9 1825 1836 - 111.
Bakeeva LE, Barskov IV, Egorov MV, et al. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program: 2. Treatment of some ros- and age-related diseases (heart arrhythmia, heart infarctions, kidney ischemia, and stroke) 2008 73 1288 1299 - 112.
Zhao K. Zhao G. M. Wu D. Soong Y. Birk A. V. Schiller P. W. Szeto H. H. “. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury” 2004 J. Biol. Chem.279 34682 34690 - 113.
Cho J. Won K. Wu D. Soong Y. Liu S. Szeto H. H. Hong M. K. Potent mitochondria-targeted peptides reduce myocardial infarction in rats. 2007 Coron. Artery Dis.18 215 220 - 114.
Anderson E. J. Lustig M. E. Boyle K. E. Woodlief T. L. Kane D. A. Lin C. T. Price I. I. I. J. W. Kang L. Rabinovitch P. S. Szeto H. H. et al. Mitochondrial H. O. emission cellular redox. state link. excess fat. intake to. insulin resistance. in both. rodents humans 2009 J. Clin. Invest.119 573 58 - 115.
Rocha M. Hernandez-Mijares A. Garcia-Malpartida K. Banuls C. Bellod L. Victor V. M. . Mitochondria-targeted antioxidant. peptides” 2010 Curr. Pharm. Des16 3124 3131 - 116.
Circ ResYamawaki H. Haendeler J. Berk B. C. “. Thioredoxin a. key regulator. of cardiovascular. homeostasis” 2003 93 1029 1033 - 117.
Cho C. G. Kim H. J. Chung S. W. Jung K. J. Shim K. H. Yu B. P. Yodoi J. Chung H. Y. “. Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process Exp Gerontol2003 38 539 548 - 118.
Arn é. r. E. S. Holmgren A. “. Physiological functions of thioredoxin and thioredoxin reductase Eur J Biochem2000 267 6102 6109 - 119.
Kim Y. C. Yamaguchi Y. Kondo N. Masutani H. Yodoi J. “. Thioredoxin-dependent redox regulation of the antioxidant responsive element (ARE) in electrophile response” 2003 22 1860 1865 - 120.
Perry J. J. Shin D. S. Getzoff E. D. Tainer J. A. The structural biochemistry of the superoxide dismutases. Biochim Biophys Acta2010 1804 245 262 - 121.
Controlled elimination of intracellular H2O2: regulation of peroxiredoxin, catalase, and glutathione peroxidase via post-translational modification” Antioxid. Redox SignalingRhee S. G. Yang K. S. Kang S. W. Woo H. A. Chang T. S. “. 2005 7 619 626 - 122.
Ungvari Z. Bailey-Downs L. Gautam T. Sosnowska D. Wang M. Monticone R. E. Telljohann R. Pinto J. T. de Cabo R. Sonntag W. E. Lakatta E. Csiszar A. Age-associated vascular oxidative stress, nrf2 dysfunction and nf-kb activation in the non-human primate macaca mulatta J Gerontol Biol Med Sci.2011 66 866 875 - 123.
Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of nrfUngvari Z. Bailey-Downs L. Sosnowska D. Gautam T. Koncz P. Losonczy G. Ballabh P. de Cabo R. Sonntag W. E. Csiszar A. 2 mediated antioxidant response Am J Physiol.2011 H363-H372. - 124.
Cell Sci.Cantrell D. A. Phosphoinositide “. 3-kinase signalling. pathways” J. 2001 114 1439 1445 - 125.
Leslie N.R., Downes C.P., “PTEN: The down side of PI 3-kinase signaling”. Cell. Signal.2002 14 285 295 - 126.
Kwon J., Lee S.R., Yang K.S., Ahn Y., Kim Y.J., Stadtman E.R., Rhee S.G., “Peroxiredoxin as a Peroxidase for as well as a Regulator and Sensor of Local Peroxides”. Proc. Natl. Acad. Sci. U.S.A.2004 101 16419 16424 - 127.
Lee S. R. Yang K. S. Kwon J. Lee C. Jeong W. Rhee S. G. J. “. Reversible Inactivation of the Tumor Suppressor PTEN by H2O2” Biol. Chem.2002 277 20336 20342 - 128.
Seo J.H., Ahn Y., Lee S.R., Yeol Yeo C., Chung Hur K., “The major target of the endogenously generated reactive oxygen species in response to insulin stimulation is phosphatase and tensin homolog and not phosphoinositide-3 kinase (PI-3 kinase) in the PI-3 kinase/Akt pathway”. Mol. Biol. Cell2005 16 348 357 - 129.
Kops G. J. Dansen T. B. Polderman P. E. Saarloos I. Wirtz K. W. Coffer P. J. Huang T. T. Bos J. L. Medema R. H. BM Burgering Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress” 2002 419 316 321 - 130.
Sakamoto K., Iwasaki K., Sugiyama H., Tsuji Y., Role of the tumor suppressor PTEN in antioxidant responsive element-mediated transcription and associated histone modifications. Mol. Biol. Cell2009 20 1606 1617 - 131.
Sara VR, Hall K.,“Insulin-like growth factors and their binding proteins”. Physiol Rev1990 70 591 613 - 132.
JD Veldhuis Liem. A. Y. South S. Weltman A. Weltman J. Clemmons D. A. Abbott R. Mulligan T. Johnson M. L. Pincus S. Straume M. Iranmanesh A. “. Differential impact of age, sex steroid hormones, and obesity on basal versus pulsatile growth hormone secretion in men as assessed in an ultrasensitive chemiluminescence assay” J Clin Endocrinol Metab1995 80 3209 3222 - 133.
J Endocrinol InvestCeda G. P. Dall’Aglio E. Maggio M. Lauretani F. Bandinelli S. Falzoi C. Grimaldi W. Ceresini G. Corradi F. Ferrucci L. Valenti G. Hoffman A. R. Clinical implications. of the. reduced activity. of-I the. G. H. -I G. F. axis in. older men. 2005 28 96 100 - 134.
N Engl JLaron Z. Short stature. due to. genetic defects. affecting growth. hormone activity. 1996 Med334 463 465 - 135.
Wu A. Grant D. B. Hambley J. Levi A. J. . Reduced serum somatomedin activity in patients with chronic liver disease" Clin Sci Mol Med1974 47 359 366 - 136.
elegans mutant that lives twice as long as wild type.”Kenyon C. Chang J. Gensch E. A. “. C. 1993 366 461 464 - 137.
Int J Biochem Cell Biol.Mirpuri E. García-Trevijano E. R. Castilla-Cortazar I. Berasain C. Quiroga J. Rodriguez-Ortigosa C. Mato J. M. Prieto J. MA Avila “. Altered liver. gene expression. in C. Cl4-cirrhotic rats. is partially. normalized by. insulin-like growth. factor-I” 2002 34 242 52 - 138.
Antioxidant effects of insulin-like growth factor-I (IGF-I) in rats with advanced liver cirrosis”. BMC Gastroenterol.García-Fernández M. Castilla-Cortázar I. Díaz-Sanchez M. Navarro I. Puche J. E. Castilla A. Casares A. D. Clavijo E. González-Barón S. “. 2005 - 139.
Conchillo M. de Knegt R. J. Payeras M. Quiroga J. Sangro B. Herrero J. I. Castilla-Cortazar I. Frystyk J. Flyvbjerg A. Yoshizawa C. Jansen P. L. Scharschmidt B. Prieto J. “. Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial” J Hepatol.2005 43 630 6 - 140.
JE, Sierra I, Barhoum R, González-Barón S “Castilla-Cortázar I. García-Fernández M. Delgado G. Puche J. E. Sierra I. Barhoum R. González-Barón S. “. Hepatoprotection neuroprotection induced. by low. doses-I of. I. G. F. in I. aging rats”. Hepatoprotection and neuroprotection induced by low doses of IGF-II in aging rats” J Transl Med.2011 103 EOF - 141.
Garcia-Fernandez M. Sierra I. Puche J. E. Guerra L. Castilla-Cortazar I. “. Liver mitochondrial dysfunction is reverted by insulin-like growth factor II (IGF-II) in aging rats” J Transl Med.2011 123 EOF