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FUNCIONES DE LA VITAMINA C EN EL METABOLISMO DEL COLÁGENO
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RESUMEN La mayoría de los mamíferos son capaces de sintetizar vitamina C, pero algunas especies como el hombre son dependientes de fuentes exógenas de esta vitamina porque carecen de la última enzima en la biosíntesis del ácido ascórbico a partir de la glucosa. Su principal función es como agente reductor en diferentes reacciones en el metabolismo del colágeno. Su deficiencia se asocia fundamentalmente con una disminución en la síntesis de procolágeno y con una reducida hidroxilación de los residuos prolina y lisina, obteniéndose una molé-cula menos estable a la temperatura corporal. En animales de laboratorio con carencia de esta vitamina se observó una disminución en la formación de residuos hidroxilisina en hueso, y por tanto, una reducción en la proporción pyridinolina (Pyd)/deoxypyridinolina (Dpd) en hueso y orina. Recientemente se han encontrado afectaciones similares en humanos. Descriptores DeCS: COLAGENO/metabolismo;ACIDO ASCORBICO/fisiología. 1 Licenciada en Química. La vitamina C (ácido ascórbico) es un nutriente esencial de la dieta del hombre y otras pocas especies que carecen de la enzi-ma L-glucono-g lactanoa oxidasa (EC 1.1.3.8), que es la última enzima en la biosíntesis del ácido ascórbico a partir de la glucosa. 1 La deficiencia de esta vitamina está asociada fundamentalmente con la carencia de tejido conectivo. La síntesis de colágeno es un proceso complejo de síntesis de proteína, modifica-ciones postraduccionales, secreción de pro-teínas y formación de la matriz extracelular. Muchos de estos pasos se afectan con las va-riaciones de vitamina C en la dieta (fig. 1). 2
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... En el escorbuto el problema se produce en la síntesis del colágeno, ya que el AA es un cofactor esencial en este proceso (18). La deficiencia de AA se asocia con una disminución en la síntesis de pro-colágeno y con una reducida hidroxilación de los residuos prolina y lisina, obteniéndose una molécula menos estable a la temperatura corporal. ...
... El AA facilita la absorción del hierro en el tracto di-gestivo y regula la distribución y almacenamiento del mismo. El ascorbato (AH -), forma químicamente estable a pH fisiológico, es un gran agente reductor hidrosoluble debido a sus dos hidroxilos (OH -) ionizables capaces de "limpiar" a los tejidos de las ERO responsables del stress oxidativo (18) (20). A pesar de que en las vías degradativas del AA se producen EROs, no se ha demostrado que estas especies participen en procesos de oxidación ni peroxidación que sean perjudiciales (21). ...
Vitamin C or L-ascorbic acid (AA) is an essential vitamin and a water soluble important antioxidant agent, chemically synthesized from glucose, by enzymatic reactions, being the L-gulono -gamma-lactone oxidase (GLO) the last enzyme involved. The inability to synthesize AA by some species, due to the absence of GLO seems to have happened hundreds of millions years ago. The degradation of the AA is carried out by oxidative processes which involve the hydrolysis of the lactona ring to produce 2,3-diketogulonic acid (DCG) that is later degraded by decarboxilation, generating colored products, found in some ocular pathologies. Among the different properties of the AA, it is worth mentioning its capacity to absorb ultraviolet radiation (RUV) and to avoid the photochemical damage of exposed. tissues. In humans and in some animals (guinea pigs, primates, etc) the aqueous humor has bigger concentrations of AA than plasma. This responds to a mechanism of specialized active transport in the ciliary body that transfers AA from the blood towards the aqueous humor and from there to the corneal epithelium, transforming the cornea into the structure of the eye responsible for the biggest absorption of RUV.
... En el escorbuto el problema se produce en la síntesis del colágeno, ya que el AA es un cofactor esencial en este proceso (18). La deficiencia de AA se asocia con una disminución en la síntesis de pro-colágeno y con una reducida hidroxilación de los residuos prolina y lisina, obteniéndose una molécula menos estable a la temperatura corporal. ...
... El ascorbato (AH -), forma químicamente estable a pH fisiológico, es un gran agente reductor hidrosoluble debido a sus dos hidroxilos (OH -) ionizables capaces de "limpiar" a los tejidos de las especies reactivas del oxígeno (ERO) responsables del stress oxidativo (18) (20). A pesar de que en las vías degradativas del AA se producen EROs, no se ha demostrado que estas especies participen en procesos de oxidación ni peroxidación que sean perjudiciales (21). ...
La Vitamina C o ácido L-ascórbico (AA), es una vitamina esencial y un importante agente antioxidante hidrosoluble, que se sintetiza químicamente a partir de la glucosa, mediante una serie de reacciones enzimáticas, siendo la L-gulono-g-lactona oxidasa (GLO) la última enzima involucrada. La incapacidad de sintetizar AA por ausencia de GLO ocurrió hace cientos de millones de años y se manifiesta sólo en algunas especies. La degradación del AA se lleva a cabo mediante procesos oxidativos que involucran la hidrólisis del anillo lactona para producir ácido 2,3-dicetogulónico (DCG), que posteriormente se degrada por decarboxilación, generando productos coloreados, encontrados en algunas patologías oculares. Entre las diferentes propiedades del AA cabe mencionar su capacidad de absorber radiación ultravioleta (RUV) y evitar el daño fotoquímico en órganos expuestos. En humanos, y en algunos animales (cobayos, ciertos primates, etc.) el humor acuoso tiene mayor concentración de AA que el plasma. Esto responde a un mecanismo de transporte activo especializado en el cuerpo ciliar que se encarga de transportar el AA desde la sangre hacia el humor acuoso y desde allí al epitelio corneal, transformando a la córnea en la estructura del ojo responsable de la mayor absorción de RUV.
... Among the vitamins, the most accumulated evidence in tendon repair processes corresponds to vitamins C and D. Vitamin C is instrumental due to its antioxidant properties and its action as a coenzyme in collagen synthesis through the hydroxyla-tion of proline and lysine to hydroxyproline and hydroxylysinerespectively. Both hy-droxylated amino acids are essential for collagen structure and tendon function [28,64,65]. Thus, vitamin C deficiency is associated with a decrease in the synthesis of procollagen, due to a lower hydroxylation of proline and lysine residues [66,67]. ...
Physical activity in general and sports in particular, is a mechanism that produces stress and generates great force in the tendon and in the muscle-tendon unit, which increases the risk of injury (tendinopathies). Eccentric and repetitive contraction of the muscle precipitates persistent microtraumatism in the tendon unit. In the development of tendinopathies, the cellular process includes inflammation, apoptosis, vascular, and neuronal changes. Currently, treatments with oral supplements are frequently used. Curcumin seems to preserve, and even repair, damaged tendons. In this systematic review, we focus more especially on the benefits of curcumin. The biological actions of curcumin are diverse, but act around three systems: (a) inflammatory, (b) nuclear factor B (NF-κB) related apoptosis pathways, and (c) oxidative stress systems. A bibliographic search is conducted under the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) as a basis for reporting reliable systematic reviews to perform a Scoping review. After analysing the manuscripts, we can conclude that curcumin is a product that demonstrates a significant biological antialgic, anti-inflammatory, and antioxidant power. Therefore, supplementation has a positive effect on the inflammatory and regenerative response in tendinopathies. In addition, curcumin decreases and modulates the cell infiltration, activation, and maturation of leukocytes, as well as the production of pro-inflammatory mediators at the site of inflammation.
... On the other hand, VC deficiency is associated with decreased procollagen synthesis and reduced hydroxylation of proline and lysine residues [63,64]. In studies in guinea pigs, proline hydroxylation in articular cartilage has been shown to be especially resistant to ascorbate deficiency [65]. ...
Tendinopathies represent 30–50% of all sports injuries. The tendon response is influenced by the load (volume, intensity, and frequency) that the tendon support, resulting in irritability and pain, among others. The main molecular component of tendons is collagen I (60–85%). The rest consist of glycosaminoglycans-proteoglycans, glycoproteins, and other collagen subtypes. This study's aim was to critically evaluate the efficacy of vitamin C supplementation in the treatment of tendinopathies. At the same time, the study aims to determine the optimal conditions (dose and time) for vitamin C supplementation. A structured search was carried out in the SCOPUS, Medline (PubMed), and Web of Science (WOS) databases. The inclusion criteria took into account studies describing optimal tendon recovery when using vitamin C alone or in combination with other compounds. The study design was considered, including randomized, double-blind controlled, and parallel designs in animal models or humans. The main outcome is that vitamin C supplementation is potentially useful as a therapeutic approach for tendinopathy recovery. Vitamin C supplementation, alone or in combination with other products, increases collagen synthesis with a consequent improvement in the patient’s condition. On the other hand, vitamin C deficiency is mainly associated with a decrease in procollagen synthesis and reduced hydroxylation of proline and lysine residues, hindering the tendon repair process.
... Además, Rojas y su equipo encontraron una cantidad significativa de ácido ascórbico en el extracto hidroalcohólico (136,63 mg/100 g extracto) siendo esto uno de los posibles factores que influyeron en la actividad promotora de colágeno, ya que se ha encontrado que la vitamina C produce un incremento en la transcripción, traducción y estabilidad del ARNm del procolágeno (Basabe, 2000). ...
In the last few decades, numerous illnesses have been documented due to the loss of collagen in the human body, therefore, a sector of the scientific community has been given the task to search for new sources of collagen in vitro models, allowing to model their behavior in vivo. Plants have evidenced being one of the most promising sources, demonstrating the presence of compounds with collagen promoter activity without significant cytotoxic effects. In this investigation, the ability of 3 extracts of Bixa orellana in collagen I promotion was evaluated in NIH/3T3 fibroblasts. Extracts were elaborated in ethanol, water, and hexane, the latest showed high cytotoxicity with dose and time dependency, while the aqueous and ethanolic extracts showed medium and low cytotoxicity respectively. Procollagen I induced by the extracts was quantified, evidencing hexanic extract was the most effective treatment, with higher levels than the positive control, while the aqueous extract showed medium synthesis of procollagen level and the ethanolic extract low activity. It is recommended to perform tests of recognition of secondary metabolites in order to find the compounds responsible for the biological activity.
... El mango de hilacha es uno de los frutos de más amplio cultivo en la costa norte colombiana, con un contenido promedio de 35 mg/100g de vitamina C (Mendoza-Corvis, 2014). La mayoría de los mamíferos son capaces de sintetizarla, pero algunas especies como el hombre son dependientes de fuentes exógenas de ésta, porque carecen de la última enzima en la biosíntesis del ácido ascórbico a partir de la glucosa (Babase, 2000), la L-gulonalactona oxidasa (Leong & Oey, 2012). La vitamina C ayuda a prevenir el cáncer, escorbuto, enfermedades cardiovasculares y mejora la absorción de hierro para prevenir la anemia (Leong & Oey, 2012;Amer et al., 2002). ...
The objective of this research was to determine the degradation kinetics of vitamin C and the effect of blanching in the color of mango of hilacha pulp sweetened with 20% sucrose. The determination of vitamin C was performed using 2.6 Dichlorophenol indophenol method and color using a colorimeter Color Flex EZ mark HunterLab. The kinetic parameters were determined by the least square method and the statistical analysis with the software Desing expert 6.0. Vitamin C followed degradation kinetics of first order in all treatments. The degradation rate constant k1 increased with the process temperature elevation, with a maximum value of 0.061 min-1 for the treatment at 85°C for 10 min. The value of the half life time t1/2 and the reduction time D decreased to half of their values with the elevation of the temperature from 65°C to 85°C with values of 11.23 min and 37.30 min, respectively. The activation energy Ea was 8.57 Kcal/mol.
This study examines 102 news items related to collagen as a dietary supplement, written in Spanish and published over a period of 2 years, in both digital and print media. The objective of this study is to evaluate the scientific rigor and consistency of the news information included in the sample. Errors and incorrect uses relative to the current scientific knowledge were identified in the analyzed information, and these errors were classified according to the criteria extracted from previous research. The evidence gathered shows a relevant frequency of errors in the information examined. The results are discussed in light of the role that the media plays in the transmission of beliefs regarding the value of collagen supplements.
Binding proteins for the insulin-like growth factors (IGF-I and IGF-II) are increasingly being recognized as modulators of IGF actions in both inhibitory and stimulatory ways. At least three distinct classes of binding protein are thought to exist, differing in their primary structures and binding characteristics, although all are able to bind both IGF-I and IGF-II. This review outlines the purification and characterization of the binding proteins that have been identified to date, and describes the regulation of their production and of their levels in the circulation. Current views on their potential biological roles are also discussed.
1. The synthesis of collagen in several tissues, including the C1q component of complement in serum, was measured in vitamin C-deficient and control guinea pigs by incorporating labelled proline into hydroxyproline in vivo. 2. Of the tissues examined, by far the greatest specific effect of vitamin C deficiency was observed in skin. Bone was second in order of sensitivity; skeletal muscle, lung, heart and kidney exhibited only small effects, which were difficult to distinguish from those of inanition, while liver, C1q, and the ethanol-soluble components of serum were virtually insensitive. The effect on urinary hydroxyproline was also extremely small. 3. The lack of sensitivity of C1q confirms previous conclusions (BATES, LEVENE, OLDROYD and LACHMANN 1978), based on total protein bound hydroxyproline levels and total C1 activity in plasma. Since C1q, which turns over rapidly, is insensitive, the high sensitivity of "repair" tissues to vitamin C deficiency is unlikely to be connected with their high turnover rate. Differential concentration of vitamin C by different tissues seems more likely to be the critical factor.
Collagen secretion by chick embryo fibroblasts was measured by incorporating [14C]proline into proteins and then analyzing the amount of collagen in the cell and medium separately by using purified bacterial collagenase. In order to produce varying levels of hydroxylation, cells were incubated with varying concentrations of ascorbate or with varying concentrations of α,α′-dipyridyl in the presence of saturating ascorbate. Ascorbate stimulated both the hydroxylation of proline in collagen and the secretion of collagen; the concentration of ascorbate required for half-maximal stimulation of both proesses was approximately 4.5 × 10−7, m. Since the cells could concentrate ascorbate 10-fold, this KM for proline hydroxylation is 100-fold lower than values reported for purified prolyl hydroxylase (Abbot, M. T., and Udenfriend, S. (1974) in Molecular Mechanisms of Oxygen Activation (Hayaishi, O., ed.), p. 173, Academic Press New York; Kivirikko K. I., et al. (1968) Biochim. Biophys. Acta, 151, 558–567). Conversely, α,ga′-dipyridyl inhibited both proline hydroxylation and collagen secretion; half-maximal inhibition of both processes was observed at 7 × 10−5, m. The results of the two types of experiments show that the secretion of collagen becomes directly proportional to proline hydroxylation when approximately 30% of the proline residues in collagen have been hydroxylated compared to maximal hydroxylation of 50%. Since the stability of triple-helical collagen at 37 °C has been shown to be dependent on the hydroxyproline content of the molecule (Rosenbloom, J., et al. (1973) Arch. Biochem. Biophys., 158, 478–484), we suggest that the observed proportionality between secretion and hydroxylation is a reflection of the increased amount of stable triple helical collagen at 37 °C. When the cells were incubated with a concentration of ascorbate that was saturating for secretion and hydroxylation, there was no significant activation of prolyl hydroxylase as measured in a cell-free extract. These experiments suggest that ascorbate effects collagen secretion by acting at the site of proline hydroxylation but not by increasing the activity of prolyl hydroxylase.
We have previously reported that scorbutic and fasted guinea pig sera contain an insulin-like growth factor-I (IGF-I)-reversible inhibitor of collagen, proteoglycan, and DNA synthesis in cultured cells. Here we report that IGF-binding protein (IGFBP) activity is increased in serum containing the inhibitor [125I]IGF-I or -II bound to these sera was eluted in the 30- to 50-kDa region of an S200 gel column. [125I]IGF-I affinity cross-linking analysis revealed that a 38-kDa cross-linked species increased markedly in fasted and scorbutic sera, with a lesser increase in a 34-kDa species, while scorbutic sera also yielded a 44-kDa species. Gel filtration of unlabeled sera showed a 10-fold increase in the activity of two proteins in the 30- to 50-kDa region from the experimental sera. Their activity correlated with their ability to inhibit binding of [125I]IGF-I to its cellular receptor, suggesting that they have the potential to inhibit IGF-I-dependent functions. Ligand blotting showed that 29 and 35-kDa IGFBPs were almost undetectable in normal serum, but were dramatically induced by scurvy and fasting, so that they accounted for close to 40% of the total circulating BPs. Total IGFBP-3 in the experimental sera was increased about 30%, while there was little effect of scurvy or fasting on the level of BP-3 activity isolated by acid extraction of the high mol wt region of the S200 column. An IGF-I analog with normal affinity for the 30- to 50-kDa BPs from fasted and scorbutic sera, but with reduced affinity for the cell receptor, was equivalent to IGF-I in reversing the inhibition of collagen synthesis by scorbutic guinea pig serum in human fibroblasts. Thus, reversal of inhibition appears to require initial saturation of IGFBPs. The overall results suggest that two circulating IGFBPs with unoccupied binding sites are induced in vitamin C-deficient or fasted guinea pigs and may be responsible for inhibition of IGF-I-dependent functions by sera from these animals.
Vitamin C deficiency is associated with defective connective tissue, particularly in wound healing. Ascorbate is required for hydroxylation of proline residues in procollagen and hydroxyproline stabilizes the collagen triple helical structure. Consequently, ascorbate stimulates procollagen secretion. However, collagen synthesis in ascorbate-deficient guinea pigs is decreased with only moderate effects on proline hydroxylation. Proteoglycan synthesis, which does not require ascorbate, also is decreased and both effects are correlated with the extent of weight loss during scurvy. Fasting, with ascorbate supplementation, produces similar effects. Both functions are inhibited in cells cultured in sera from either scorbutic or starved guinea pigs and inhibition is reversed with insulin-like growth factor (IGF)-I. The inhibitor appears to consist of two IGF-binding proteins induced during vitamin C deficiency and starving and may be responsible for in vivo inhibition of collagen and proteoglycan synthesis.
Ascorbic acid stimulates collagen gene expression in cultured fibroblasts but mechanisms responsible for this effect are poorly understood. In the presence of the transitional metal iron, ascorbic acid could induce lipid peroxidation with the formation of reactive aldehydes. Because another aldehyde, acetaldehyde, the first metabolite of ethanol, also stimulates collagen transcription in cultured fibroblasts, we investigated whether ascorbic acid induces lipid peroxidation in cultured cells and if this is the mechanism by which ascorbic acid stimulates collagen gene expression. Ascorbic acid (0.2 mmol/L) induced lipid peroxidation and stimulated collagen alpha 1(I) gene transcription in cultured human fibroblasts. Inhibition of the ascorbic acid-induced lipid peroxidation in cultured human fibroblasts with alpha-tocopherol (50 mumol/L) or methylene blue (10 mumol/L) prevented the stimulation of collagen gene expression. Addition of malondialdehyde (200 mumol/L), a product of lipid peroxidation, to cultured human fibroblasts also increased two- to threefold collagen production and procollagen alpha 1(I) mRNA levels. Thus, ascorbic acid induces lipid peroxidation and reactive aldehydes, and this step may be necessary for stimulation of collagen gene expression by ascorbic acid in cultured human fibroblasts.
Ever since the discovery of vitamin C (ascorbic acid), scientists have been intrigued as to how ascorbic acid deficiency can lead to the diverse symptoms exhibited in scurvy. Only in recent years has it been appreciated that ascorbic acid has important functions in many cellular reactions and processes in addition to its role in collagen synthesis. The few such reactions that are understood at the molecular level make it apparent that ascorbic acid does not directly participate in enzyme-catalyzed conversion of substrate to product. Instead, the vitamin regenerates prosthetic metal ions in these enzymes in their required reduced forms. This is in agreement with other antioxidant functions of vitamin C, e.g., scavenging of free radicals. Ascorbate and other antioxidant nutrients are presumed to play a pivotal role in minimizing the damage from oxidative products, including free radicals. This protective function is twofold: the already-oxidized groups in prosthetic centers of enzymes are reduced and the oxidants and free radicals are removed.
Chick embryo chondrocytes cultured in sera from scorbutic and fasted guinea pigs exhibited decreases in collagen and proteoglycan production to about 30-50% of control values (I. Oyamada et al., 1988, Biochem. Biophys. Res. Commun. 152, 1490-1496). Here we show by pulse-chase labeling experiments that in the chondrocyte system, as in the cartilage of scorbutic and fasted guinea pigs, decreased incorporation of precursor into collagen was due to decreased synthesis rather than to increased degradation. There was a concomitant decrease in type II procollagen mRNA to about 32% of the control level. As in scorbutic cartilage, proteoglycan synthesis by chondrocytes in scorbutic serum was blocked at the stage of glycosaminoglycan chain initiation. Scorbutic and fasted guinea pig sera also caused a 50-60% decrease in the rates of collagen and proteoglycan synthesis in adult human skin fibroblasts, which synthesize mainly type I collagen. Decreased matrix synthesis in both cell types resulted from the presence of an inhibitor in scorbutic and fasted sera. Elevated cortisol levels in these sera were not responsible for inhibition, as determined by the addition of dexamethasone to chondrocytes cultured in normal serum. Insulin-like growth factor I (IGF-I, 300-350 ng/ml) reversed the inhibition of extracellular matrix synthesis by scorbutic and fasted guinea pig sera in both cell types and prevented the decrease in type II procollagen mRNA in chondrocytes. Therefore, in addition to its established role in proteoglycan metabolism, IGF-I also regulates the synthesis of several collagen types. An increase in the circulating inhibitor of IGF-I action thus could lead to the negative regulation of collagen and cartilage proteoglycan synthesis that occurs in ascorbate-deficient and fasted guinea pigs.