B-OXIDACION EN PEROXISOMAS: •. For peroxisomal β -oxidation, fatty acids are activated at different subcellular locations. Long-straight-chain and B-OXIDACION DE AG: Oxidación de un acil graso (16 C) For peroxisomal β – oxidation, fatty acids are activated at different subcellular. Omega oxidation (ω-oxidation) is a process of fatty acid metabolism in some species of animals. It is an alternative pathway to beta oxidation that, instead of.
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Donde campeones del alma muestran su luz con cada pisada. Tengo una vida tan espectacular y hay tanto que agradecer y es porque tu participaste en ella. Dime algo sobre que no me voy a vencer y yo Bienvenidos todos al protocolo Observacinal para gente en riesgo de Huntigton. El vive en Costa Rica y tiene una inmensa familia, ya es abuelo El es un hombre que le ha dicho que si a Dios, el siempre esta poniendo su mejor cara, siempre quiere sumar, siempre coopera, siempre dispuesto, siempre feliz a pesar de que la enfermedad lo tenga en silla de ruedas ya.
Y hoy por hoy el es impresindible para nuestra comunidad de HUntington, creo que te conocen en todo el mundo tan solo porque nos posteas TODO lo que publicamos nosotros y otras asociaciones. Profesionistas con sentido Humano” 9 de noviembre Profesionistas con sentido Humano” 9 de noviembre de 9 a 5 de la tarde en el Auditorio 1. Donde increibles profesionistas compartiran sus proyectos inovadores.
Abstract Redox homeostasis is crucial for proper cellular functions, including receptor tyrosine kinase signaling, protein folding, and xenobiotic detoxification. Under basal conditions, there is a balance between oxidants and antioxidants.
This balance facilitates the ability of oxidants, such as reactive oxygen species, to play critical regulatory functions through a direct modification of a small number of amino acids e.
These signaling functions leverage tight spatial, amplitude, and temporal control of oxidant concentrations. However, when oxidants overwhelm the antioxidant capacity, they lead to a harmful condition of oxidative stress. In this review, we will critically review this evidence, drawing some intermediate conclusions, and ultimately provide a framework for thinking about the role of oxidative stress in the pathophysiology of HD. The initial clinical manifestations include personality and mood changes which are sometimes followed by a cognitive decline, and then involuntary choreiform movements, bradykinesia, dystonia in some patientsrigidity, and dementia ultimately leading to death approximately 15—20 years from the age at onset [ 1, 2 ].
The genetic abnormality in HD involves an expansion of unstable CAG repeats in exon 1 of the huntingtin gene [ 3, 4 ]. The pathology of the disease has been attributed to toxic gain of functions for the mutant huntingtin protein, such as protein aggregation, transcriptional dysregulation, defective energy metabolism, oxidative stress, excitotoxicity, and inflammation [ 5—17 ], as well as to the loss of beneficial functions of wild type huntingtin protein Httwhich includes BDNF translation, vesicle transport and as scaffold for autophagic machinery [ 18—21 ].
Despite remarkable progress in our understanding of this disease, the molecular logic connecting mHtt aggregates with cell dysfunction and pathological symptoms remains unclear.
Transcriptionaldysregulation, mitochondrial dysfunction, oxidative stress and neuronal excitotoxicity are some of the key pathways consistently abnormal in cellular and mouse models of HD, as well as in autopsy tissue from HD patients. Herein, we will review the evidence regarding oxidative stress as a primary mediator of HD pathogenesis.
It is important to emphasize that while molecular events, such as transcriptional dysregulation, protein aggregation, and mitochondrial dysfunction, have been linked to HD pathogenesis, it is still not clear whether oxidative stress causes HD, or is a consequence of more primary events [ 7, 33—35 ].
This uncertainty provides a compelling reason to review the putative molecular regulatory connections between redox changes and the established early events, such as mHtt aggregate formation and transcriptional dysregulation. This review will also hopefully stimulate efforts to discover novel strategies for reducing oxidative stress not just through the use of non-specific antioxidants, but also by targeting redox modulatory agents to these established early and causal events.
Oxidants are short-lived molecules with an unpaired electron in one or more of their outer orbitals and, therefore, they have the theoretical capacity to steal electrons from any cellular constituent, including proteins, lipids, and DNA. Mitochondriause the electron transport chain to create a proton gradient and produce ATP. In this bioenergetic process, a small percentage of the electrons transferred down the electron transport chain for energy production inappropriately interact with oxygen molecules to produce superoxide free radicals O 2.
The resultant superoxide free radicals can readily react with other biomolecules to form other reactive molecules, including hydrogen peroxide, peroxyl ROO. Additionally, there are other sources of intracellular ROS production, such as cytochrome P enzymes of the endoplasmic reticulum, peroxisomal flavin oxidases, xanthine oxidase, and plasma membrane NADPH oxidases [ 38 ]. Other mediators of electrophilic stress are derived from lipids and are called RLS.
RLS are defined as the oxidized lipid products including aldehydes such as HNE, malondialdehyde and acrolein as well as the A- and J- series isoprostanes etc. Their electrophilic nature allows them to covalently modify nucleic acids, lipids, and proteins [ 39, 40 ].
RLS can be produced by enzymatic via the actions of lipoxygenase and cyclooxygenase enzymes as well as non-enzymatic oxidation of polyunsaturated fatty acids PUFAs [ 39 ].
In eukaryotes, ROS evolved with a variety of diversified signaling functions. Peroxisomzl acid residues such as cysteine and selenocysteine are particularly sensitive to the redox changes as they have the ability to not only donate electrons, but also to be reduced by cellular antioxidant enzymes.
It is important to note that not all cysteine residues within a protein are equally sensitive to redox changes. Within the physiological pH range, cysteine residues btea exist as either thiolate anion Cys-S – or protonated cysteine thiol Cys-SH depending upon the local redox environment.
Hydrogen peroxide is a key regulatory factor in dictating the redox state of cysteine residues within a protein [ 43 ]. Additionally, other molecules, such as NO and H oxidaion S, can also regulate the redox state of cysteine residues [ 44 ].
Under normal physiological conditions, for ROS to work as a signaling molecule, the ROS must generate reversible oxidation and exhibit substrate specificity [ 45 ].
The sulfenic form can be reduced back to a thiolate anion by different disulfide reductases, such as glutaredoxin and thioredoxin, and the sulfinic form can be reduced by sulfiredoxin, while the sulfonic forms are irreversible oxidation states. In addition, the cysteine residues can also be modified in other ways, including S-nitrosylation and S-glutathionylation, which are also reversiblemodifications. ROS as molecules also exhibit substrate specificity. PTPs regulate a cascade of signaling molecules involved in growth factor signaling bycatalyzing the dephosphorylation of tyrosine residues in target proteins.
PTPs, however, depend upon a redox sensitive cysteine for their enzymatic activity. ROS, by catalyzing the oxidavion of this reactive cysteine, lead to inactivation of the PTPs, which, in turn, results in increased tyrosine phosphorylation of proteins involved in growth factor signaling.
Moreover, the oxidative inactivation of PTPs is reversible[ 46, 47 ]. Spatially localized ROS production has been shown to be another important contributory factor in inducing effective redox signaling. For instance, ROS produced by NADPH oxidases present at the plasma membrane, which catalyzes redox changes mainly in membrane proteins, foster activation of kinase signaling and second messengers leading to modulation of nuclear proteins including transcription factors.
While many nuclear transcription factors TFs have been shown to be redox-modulated, surprisingly, little is peroxisomaal whether redox changes occur in the cytoplasm or within the nucleus. If they occur primarily in the nucleus, little is known about the factors in that subcellular compartment that govern its redox state, redox signaling, or redox related damage.
Beta oxidaciòn de A.G. y regulacion vìa mitocondrial y perox by Breen Santillan P’ on Prezi
Future studies that focus on the source of oxidants in the nuclear compartment may enhance our understanding of nuclear redox regulation. Rather, most of the information regarding the redox regulation of signaling is currentlyemerging from the cancer field. For instance, cell survival pathway, such as the Erk pathway, is regulated in a redox associated manner by mitogen activated protein kinase phosphatase-3 MKP MKP-3 has a reactive cysteine whose oxidation results in inactivation of the phosphatase activity, leading to activation of the ERK pathway [ 50, 51 ].
Besides this, caspases contain a reactive cysteine, which regulates their activity. Under physiological conditions, mitochondrial caspase 3 and 9 are nitrosylated and, therefore, inactive while in the presence of pro-apoptotic signals, caspases get activated through the denitrosylation of their reactive cysteines [ 52 ].
Likewise, the activity of chaperones involved in oxidwcion protein folding, such as Hsp70, Hsp90 oxidzcion PDI, are also redox-regulated through the reactive cysteine residues present in these proteins [ 53—55 ].
ROS also play important signaling functions in regulation of inflammatory responses. Immune cells express a number receptors, including Toll-like receptors TLRsNOD-like receptors NLRsand Rig-like receptors RLRswhich, when bound to either microorganism-derived pathogen-associated molecular patterns PAMPs or endogenous cell-derived damage-associated molecular patterns DAMPselicit the secretion of cytokines in order to fight pathogens or repair damaged tissue.
Now, it is a well-established notion that the amount of ROS production dictates the degree of pro-inflammatory response. However, it is important to emphasize here that macrophages differentiate into at least two different phenotypes, called Oxkdacion and M2 macrophages, which have different consequential fates [ 59, 60 ].
It is, therefore, very important to undertake studies focusing on understanding how ROS differentially regulate these two macrophage phenotypes or which of the ROS species are important for regulation of one phenotype, but not the other one. ROS as signaling molecules play important regulatory functions in a number of other pathways described in later sections of this review. Studies from our own lab have elucidated methods for spatially, temporally and quantitatively manipulating ROS such as peroxide.
Specifically, we have utilized a cDNA of D-amino acid oxidase from red yeast as a strategy to tune the levels of peroxide in a cells. These studies have confirmed prior notions that low levels of peroxide can act as a second messenger, while higher levels can induce non cell-autonomous toxicity [ 61 ]. Their chemical nature enables peroxismal transitional metals eg.
Fe, Cu, Zn to take part in a number of physiological redox reactions [ 62 ]. A growing number of studies suggest metal dyshomeostasis may be a part of HD pathogenesis [ 63 ]. In particular, iron Fe and copper Cu have been implicated as mediators of pathology. A recent MRI study showed enhanced accumulation of iron in basal ganglia and cortex of peroxosomal HD patients and found its correlation with the CAG repeat number and severity of the disease pathogenesis [ 65 ].
Interestingly, few groups have attempted to understand the molecular basis of metal dyshomeostasis. Specifically, changes in expression of specific receptors and transporters of these metals such as transferrin receptors, ferroportin and metallothioneins have not been systematically examined in HD [ 67, 68 ]. Iron is classically believed to mediate oxidative damage via Fenton chemistry bta 62 ], although more recent studies suggest that iron may permit toxicity via its oxidaciom to activate iron containing proteins such as the hypoxia inducible factor prolyl hydroxylases HIF PHDs [ 69 ].
By contrast, copper has been shown to directly interact with N-terminal end of huntingtin to catalyze cysteine oxidation, cross-linking at itsN-terminal end and consequent mHtt oligomerization. Incomplete autophagic clearance of mHtt leads to increases in huntingtin aggregates [ 70—72 ]. Besides this, the excessive copper can also increase ROS production because of its capability to participate in a number of electron-transfer reactions.
In order to deal with the metal overload, a host of metal chelators have been tried as therapeutic options in HD. In order to overcome the problem of CNS penetration, moderate affinity hydrophobic metal chelators such as 8-hydroxyquinoline 8-HQ and its derivatives such as clioquinol and PBT2 have been developed and examined not only in AD but HD. Very recently, PBT2 was found to be safe and well tolerable in early-stage to mid-stage HD patients [ 76 ].
Although peroxisimal sample size was smaller and the clinical benefits were not very clear in this study, the outcome looks promising. Non-selective metal chelation thus looks promising, but may risk the unintended consequence of stealing metals from physiological metalloenzymes. This may necessitate an alternative approach of identifying the key molecular players perturbed by the excessive accumulation or altered distribution of these redox active metals and focusing on these players as therapeutic targets.
In this context, inhibiting Hif-PHDs provides neuroprotection independent of global iron chelation and suppression of Fenton chemistry [ 69, 77 ].
Blog · Fundación Verónica Ruiz · Huntington:
The model advanced in these studies is that metal chelators, including oxyquinolines optimally abrogate cell death by inhibiting the activity of pro-death transcription factors such as ATF4, thus leading to repression of death gene expression.
This model has yet to be explored in the contextof HD. A holy grail for the oxidative stress field has been identification of biomarkers for redox dyshomeostasis that suggest that this damage will or has occurred.
Importantly, an oxidative stress product must be sensitive to oxidative stress changes, show specificity towards a particular oxidative pathway and must also be chemically stable in order to qualify as a good oxidative stress biomarker [ 78 ].
Practical and non-invasive methods of sample collection and detection are important criteria for identification of a good oxidative stress biomarker [ 78 ]. Unfortunately, none of the currently available tools appropriately meet criteria for an ideal oxidative biomarker, in part because increases in many currently used biomarkers could occur because of increased production or decreased turnover.
While this may reflect something about disease presence or course, it is unclear whether it reflects increased oxidative stress, or diminished turnover or repair of oxidized bases in HD. The amino acids, cysteine and methionine, which are present in proteins, are very sensitive to oxidation [ 45 ].
Oxidation of beya side beat leads to carbonylation, which is viewed as an important biomarker of protein oxidation [ 82 ].
The oxidative attack on proteins can also lead to the formation of nitrated products such as 3-nitrotyrosine 3-NO 2 -Tyr or halogenated products such as 3-chlorotyrosine Cl-Tyr and 3-bromotyrosine [ 83 ].
These oxidation products are also some of the commonly used markers of protein oxidation.
Oxidative Stress and Huntington’s Disease: The Good, The Bad, and The Ugly
Recently, other redox dependent post-translational modifications of proteins such as S-nitosylation, S-sulfenylation, S-glutathionylation, and S-sulfhydration have also been used as markers of protein oxidation [ 84 ]. Lipid peroxidation is a potential consequence of a specific type of oxidative stress.
Oxidative damage to membrane lipids leads to changes in properties of cell membranes such as the fluidity, and inactivation of membrane associated enzymes or receptors.