RESUMEN
BACKGROUND: Seaweed polysaccharides have been recommended as anticancer supplements and for boosting human health; however, their benefits in the treatment of triple-negative breast cancers (TNBCs) and improving immune surveillance remain unclear. Olaparib is a first-in-class poly (ADP-ribose) polymerase inhibitor. Oligo-Fucoidan, a low-molecular-weight sulfated polysaccharide purified from brown seaweed (Laminaria japonica), exhibits significant bioactivities that may aid in disease management. METHODS: Macrophage polarity, clonogenic assays, cancer stemness properties, cancer cell trajectory, glucose metabolism, the TNBC 4T1 cells and a 4T1 syngeneic mouse model were used to inspect the therapeutic effects of olaparib and Oligo-Fucoidan supplementation on TNBC aggressiveness and microenvironment. RESULTS: Olaparib treatment increased sub-G1 cell death and G2/M arrest in TNBC cells, and these effects were enhanced when Oligo-Fucoidan was added to treat the TNBC cells. The levels of Rad51 and programmed death-ligand 1 (PD-L1) and the activation of epidermal growth factor receptor (EGFR) and adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) facilitate drug resistance and TNBC metastasis. However, the combination of olaparib and Oligo-Fucoidan synergistically reduced Rad51 and PD-L1 levels, as well as the activity of EGFR and AMPK; consistently, TNBC cytotoxicity and stemness were inhibited. Oligo-Fucoidan plus olaparib better inhibited the formation of TNBC stem cell mammospheroids with decreased subpopulations of CD44high/CD24low and EpCAMhigh cells than monotherapy. Importantly, Oligo-Fucoidan plus olaparib repressed the oncogenic interleukin-6 (IL-6)/p-EGFR/PD-L1 pathway, glucose uptake and lactate production. Oligo-Fucoidan induced immunoactive and antitumoral M1 macrophages and attenuated the side effects of olaparib, such as the promotion on immunosuppressive and protumoral M2 macrophages. Furthermore, olaparib plus Oligo-Fucoidan dramatically suppressed M2 macrophage invasiveness and repolarized M2 to the M0-like (F4/80high) and M1-like (CD80high and CD86high) phenotypes. In addition, olaparib- and Oligo-Fucoidan-pretreated TNBC cells resulted in the polarization of M0 macrophages into CD80(+) M1 but not CD163(+) M2 macrophages. Importantly, olaparib supplemented with oral administration of Oligo-Fucoidan in mice inhibited postsurgical TNBC recurrence and metastasis with increased cytotoxic T cells in the lymphatic system and decreased regulatory T cells and M2 macrophages in tumors. CONCLUSION: Olaparib supplemented with natural compound Oligo-Fucoidan is a novel therapeutic strategy for reprogramming cancer stemness, metabolism and the microenvironment to prevent local postsurgical recurrence and distant metastasis. The combination therapy may advance therapeutic efficacy that prevent metastasis, chemoresistance and mortality in TNBC patients.
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Antineoplásicos , Neoplasias de la Mama Triple Negativas , Proteínas Quinasas Activadas por AMP , Adenosina/farmacología , Adenosina Difosfato/farmacología , Adenosina Difosfato/uso terapéutico , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis , Antígeno B7-H1 , Línea Celular Tumoral , Suplementos Dietéticos , Molécula de Adhesión Celular Epitelial , Receptores ErbB , Puntos de Control de la Fase G2 del Ciclo Celular , Glucosa , Humanos , Interleucina-6 , Lactatos/farmacología , Lactatos/uso terapéutico , Ratones , Ftalazinas , Piperazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Polisacáridos/uso terapéutico , Ribosa/farmacología , Ribosa/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Patients with heart failure with preserved ejection fraction (HFpEF) have few pharmacologic therapies, and it is not known if supplementing with ubiquinol and/or d-ribose could improve outcomes. The overall objective of this study was to determine if ubiquinol and/or d-ribose would reduce the symptoms and improve cardiac performance in patients with HFpEF. This was a phase 2 randomized, double-blind, placebo-controlled trial of 216 patients with HFpEF who were ≥ 50 years old with a left ventricular ejection fraction (EF) ≥ 50%. A total of 4 study groups received various supplements over 12 weeks: Group 1 received placebo ubiquinol capsules and d-ribose powder, Group 2 received ubiquinol capsules (600 mg/d) and placebo d-ribose powder, Group 3 received placebo ubiquinol capsules with d-ribose powder (15 g/d), and Group 4 received ubiquinol capsules and d-ribose powder. There were 7 outcome measures for this study: Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score, level of vigor using a subscale from the Profile of Mood States, EF, the ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (septal E/e' ratio), B-type natriuretic peptides, lactate/adenosine triphosphate ratio, and the 6-minute walk test. Treatment with ubiquinol and/or d-ribose significantly improved the KCCQ clinical summary score (17.30 to 25.82 points), vigor score (7.65 to 8.15 points), and EF (7.08% to 8.03%) and reduced B-type natriuretic peptides (-72.02 to -47.51) and lactate/adenosine triphosphate ratio (-4.32 to -3.35â¯×â¯10-4). There were no significant increases in the septal E/e' or the 6-minute walk test. In conclusion, ubiquinol and d-ribose reduced the symptoms of HFpEF and increased the EF. These findings support the use of these supplements in addition to standard therapeutic treatments for patients with HFpEF.
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Insuficiencia Cardíaca , Adenosina Trifosfato/farmacología , Adenosina Trifosfato/uso terapéutico , Cápsulas/farmacología , Cápsulas/uso terapéutico , Tolerancia al Ejercicio , Humanos , Lactatos/farmacología , Lactatos/uso terapéutico , Persona de Mediana Edad , Polvos/farmacología , Polvos/uso terapéutico , Ribosa/farmacología , Ribosa/uso terapéutico , Volumen Sistólico , Ubiquinona/análogos & derivados , Función Ventricular IzquierdaRESUMEN
Stenotrophomonas maltophilia has recently arisen as a prominent nosocomial pathogen because of its high antimicrobial resistance and ability to cause chronic respiratory infections. Often the infections are worsened by biofilm formation which enhances antibiotic tolerance. We have previously found that mutation of the gpmA gene, encoding the glycolytic enzyme phosphoglycerate mutase, impacts the formation of this biofilm on biotic and abiotic surfaces at early time points. This finding, indicating an association between carbon source and biofilm formation, led us to hypothesize that metabolism would influence S. maltophilia biofilm formation and planktonic growth. In the present study, we tested the impact of various growth substrates on biofilm levels and growth kinetics to determine metabolic requirements for these processes. We found that S. maltophilia wild type preferred amino acids versus glucose for planktonic and biofilm growth and that gpmA deletion inhibited growth in amino acids. Furthermore, supplementation of the ΔgpmA strain by glucose or ribose phenotypically complemented growth defects. These results suggest that S. maltophilia shuttles amino acid carbon through gluconeogenesis to an undefined metabolic pathway supporting planktonic and biofilm growth. Further evaluation of these metabolic pathways might reveal novel metabolic activities of this pathogen. IMPORTANCE Stenotrophomonas maltophilia is a prominent opportunistic pathogen that often forms biofilms during infection. However, the molecular mechanisms of virulence and biofilm formation are poorly understood. The glycolytic enzyme phosphoglycerate mutase appears to play a role in biofilm formation, and we used a mutant in its gene (gpmA) to probe the metabolic circuitry potentially involved in biofilm development. The results of our study indicate that S. maltophilia displays unique metabolic activities, which could be exploited for inhibiting growth and biofilm formation of this pathogen.
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Proteínas Bacterianas/metabolismo , Biopelículas/crecimiento & desarrollo , Regulación Bacteriana de la Expresión Génica/fisiología , Redes y Vías Metabólicas/fisiología , Stenotrophomonas maltophilia/fisiología , Aminoácidos/metabolismo , Aminoácidos/farmacología , Proteínas Bacterianas/genética , Medios de Cultivo , Ribosa/metabolismo , Ribosa/farmacología , Stenotrophomonas maltophilia/genéticaRESUMEN
BACKGROUND: Many muscular dystrophies currently remain untreatable. Recently, dietary ribitol has been suggested as a treatment for cytidine diphosphate (CDP)-l-ribitol pyrophosphorylase A (CRPPA, ISPD), fukutin (FKTN), and fukutin-related protein (FKRP) myopathy, by raising CDP-ribitol concentrations. Thus, to facilitate fast diagnosis, treatment development, and treatment monitoring, sensitive detection of CDP-ribitol is required. METHODS: An LC-MS method was optimized for CDP-ribitol in human and mice cells and tissues. RESULTS: CDP-ribitol, the product of CRPPA, was detected in all major human and mouse tissues. Moreover, CDP-ribitol concentrations were reduced in fibroblasts and skeletal muscle biopsies from patients with CRPPA myopathy, showing that CDP-ribitol could serve as a diagnostic marker to identify patients with CRPPA with severe Walker-Warburg syndrome and mild limb-girdle muscular dystrophy (LGMD) phenotypes. A screen for potentially therapeutic monosaccharides revealed that ribose, in addition to ribitol, restored CDP-ribitol concentrations and the associated O-glycosylation defect of α-dystroglycan. As the effect occurred in a mutation-dependent manner, we established a CDP-ribitol blood test to facilitate diagnosis and predict individualized treatment response. Ex vivo incubation of blood cells with ribose or ribitol restored CDP-ribitol concentrations in a patient with CRPPA LGMD. CONCLUSIONS: Sensitive detection of CDP-ribitol with LC-MS allows fast diagnosis of patients with severe and mild CRPPA myopathy. Ribose offers a readily testable dietary therapy for CRPPA myopathy, with possible applicability for patients with FKRP and FKTN myopathy. Evaluation of CDP-ribitol in blood is a promising tool for the evaluation and monitoring of dietary therapies for CRPPA myopathy in a patient-specific manner.
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Monitoreo de Drogas/métodos , Distrofias Musculares/sangre , Distrofias Musculares/tratamiento farmacológico , Azúcares de Nucleósido Difosfato/sangre , Animales , Cromatografía Liquida , Suplementos Dietéticos , Distroglicanos , Femenino , Glicosilación , Células HEK293 , Humanos , Masculino , Espectrometría de Masas , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Músculo Esquelético/patología , Distrofias Musculares/patología , Mutación , Azúcares de Nucleósido Difosfato/análisis , Nucleotidiltransferasas/genética , Ribitol/farmacología , Ribosa/farmacologíaRESUMEN
Diabetes patients associated with liver disease carry a significant risk of morbidity and mortality. Cinnamon has been reported to reduce fructose-induced oxidative stress in the rat liver. However, the mechanism by which cinnamon protects the liver in a high-saccharide environment remains to be investigated. HepG2 cells were cultured with 30 mM D-ribose to mimic the high-oxidative-stress environment, typical of a liver in a diabetic patient. Three different chemical types of C. osmophloeum ethanol extracts (CEEs) were added in HepG2 culture media and the administration of all three CEEs protected HepG2 cells from D-ribose damage and increased cell survival by approximately 20 percent. Exclusively, the transcript variant 1 of the ghrelin gene, but not variant 3, was 2-3 times induced by the addition of these CEEs. Moreover, the mRNAs of ghrelin processing enzyme, furin, and mboat4 were detected in HepG2 cells. The ghrelin hormones in the culture media were increased 4-9 times by the addition of CEEs. The protective effects of ghrelin on HepG2 cells in D-ribose environment were further confirmed by recombinant ghrelin transfection. We conclude that the CEEs induce ghrelin gene expression and protect HepG2 cells from D-ribose-induced oxidative damage through ghrelin signalling.
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Antioxidantes/farmacología , Cinnamomum/química , Ghrelina/agonistas , Extractos Vegetales/farmacología , ARN Mensajero/agonistas , Aciltransferasas/genética , Aciltransferasas/metabolismo , Antioxidantes/química , Supervivencia Celular/efectos de los fármacos , Etanol/química , Furina/genética , Furina/metabolismo , Regulación de la Expresión Génica , Ghrelina/genética , Ghrelina/metabolismo , Células Hep G2 , Humanos , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/química , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribosa/antagonistas & inhibidores , Ribosa/farmacología , Transducción de Señal , Solventes/químicaRESUMEN
BACKGROUND: Skeletal muscle adenosine triphosphate (ATP) levels are severely depleted during and following prolonged high intensity exercise. Recovery from these lower ATP levels can take days, which can affect performance on subsequent days of exercise. Untrained individuals often suffer the stress and consequences of acute, repeated bouts of exercise by not having the ability to perform or recovery sufficiently to exercise on subsequent days. Conversely, trained individuals may be able to recover more quickly due to their enhanced metabolic systems. D-Ribose (DR) has been shown to enhance the recovery in ATP; however, it is not known if recovery and performance can be benefitted with DR ingestion. Therefore, this study was designed to determine what influence DR might have on muscular performance, recovery, and metabolism during and following a multi-day exercise regimen. METHODS: The study was a double blind, crossover study in 26 healthy subjects compared 10 g/day of DR to 10 g/day of dextrose (DEX, control). All subjects completed 2 days of loading with either DR or DEX, followed by 3 additional days of supplementation and during these 3 days of supplementation, each subject underwent 60 min of high intensity interval exercise in separate daily sessions, which involved cycling (8 min of exercise at 60% and 2 min at 80% VO2max), followed by a 2 min power output (PO) test. Subjects were divided into two groups based on peak VO2 results, lower VO2 (LVO2) and higher peak VO2 (HVO2). RESULTS: Mean and peak PO increased significantly from day 1 to day 3 for the DR trial compared to DEX in the LVO2 group. Rate of perceived exertion (RPE) and creatine kinase (CK) were significantly lower for DR than DEX in the LVO2 group. No differences in PO, RPE, heart rate, CK, blood urea nitrogen, or glucose were found between either supplement for the HVO2 group. CONCLUSION: DR supplementation in the lower VO2 max group resulted in maintenance in exercise performance, as well as lower levels of RPE and CK. Unlike no observed benefits with DEX supplementation.
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Adenosina Trifosfato/metabolismo , Umbral Anaerobio/efectos de los fármacos , Rendimiento Atlético/fisiología , Suplementos Dietéticos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Aptitud Física/fisiología , Ribosa/farmacología , Adulto , Umbral Anaerobio/fisiología , Estudios Cruzados , Método Doble Ciego , Metabolismo Energético/efectos de los fármacos , Femenino , Humanos , Masculino , Fenómenos Fisiológicos en la Nutrición DeportivaAsunto(s)
Antioxidantes/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Obesidad/metabolismo , Ribosa/análogos & derivados , Taurina/análogos & derivados , Taurina/deficiencia , Animales , Aspartato Aminotransferasa Citoplasmática/sangre , Dieta , Suplementos Dietéticos , Crecimiento/efectos de los fármacos , Hígado/patología , Masculino , Obesidad/complicaciones , Obesidad/patología , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Ribosa/farmacología , Taurina/farmacologíaRESUMEN
Microglia are main immune cells to exacerbate neural disorders in persistent overactivating. Therefore, it is a good strategy to regulate microglia for the treatment of neural disorders. In the present study, we isolated and characterized a novel compound, 5-O-isoferuloyl-2-deoxy-D-ribono-γ-lacton (5-DRL) from Clematis mandshurica, and evaluated its anti-inflammatory effect in lipopolysaccharide (LPS)-treated BV2 microglial cells. 5-DRL inhibited the expression of LPS-stimulated proinflammatory mediators such as nitric oxide (NO) and prostaglandin E2 (PGE2), as well as their regulatory genes inducible NO syntheses (iNOS) and cyclooxygenase-2 (COX-2). 5-DRL also downregulated the LPS-induced DNA-binding activity of nuclear factor-κB (NF-κB) through suppression of the nuclear translocation of the NF-κB subunits, p65 and p50. Consistent with the inhibition of iNOS and COX-2 via NF-κB activity with 5-DRL, an inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC), also led to the suppression of LPS-induced iNOS and COX-2 expression. Additionally, 5-DRL corresponding with antioxidants, N-acetylcysteine (NAC) and glutathione (GSH), remarkably inhibited reactive oxygen species (ROS) generation. Both NAC and GSH, thus attenuated the expression of iNOS and COX-2 by suppressing NF-κB activation, indicating that 5-DRL suppresses LPS-induced iNOS and COX-2 expression through downregulation of the ROS-dependent NF-κB signaling pathway. The present study also indicated that 5-DRL suppresses NO and PGE2 production by inducing heme oxygenase-1 (HO-1) via nuclear factor erythroid 2-related factor 2 (Nrf2). Taken together, the present data indicate that 5-DRL attenuates the production of proinflammatory mediators such as NO and PGE2 as well as their regulatory genes in LPS-stimulated BV2 microglial cells by inhibiting ROS-dependent NF-κB activation and stimulating the Nrf2/HO-1 signal pathway. These data may be implicated in the application of 5-DRL in LPS-stimulated inflammatory disease.
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Antiinflamatorios no Esteroideos/farmacología , Clematis , Microglía/efectos de los fármacos , FN-kappa B/metabolismo , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Fitoterapia , Acetilcisteína/farmacología , Animales , Línea Celular Transformada , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Lactonas/química , Lactonas/farmacología , Lipopolisacáridos/inmunología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Microglía/inmunología , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Raíces de Plantas , Prolina/análogos & derivados , Prolina/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ribosa/análogos & derivados , Ribosa/química , Ribosa/farmacología , Transducción de Señal/efectos de los fármacos , Tiocarbamatos/farmacologíaRESUMEN
Chitin synthases polymerize UDP-GlcNAC to form chitin polymer, a key component of fungal cell wall biosynthesis. Furthermore, chitin synthases are desirable targets for fungicides since chitin is absent in plants and mammals. Two potent Botrytis cinerea chitin synthase inhibitors, 2,3,5-tri-O-benzyl-d-ribose (compound 1) and a 2,5-functionalized imidazole (compound 2) were identified by screening a chemical library. We adapted the wheat germ agglutinin (WGA) test for chitin synthase activity detection to allow miniaturization and robotization of the screen. Both identified compounds inhibited chitin synthases in vitro with IC50 values of 1.8 and 10µM, respectively. Compounds 1 and 2 were evaluated for their antifungal activity and were found to be active against B. cinerea BD90 strain with MIC values of 190 and 100µM, respectively. Finally, we discovered that both compounds confer resistance to plant leaves against the attack of the fungus by reducing the propagation of lesions by 37% and 23%, respectively. Based on the inhibitory properties found in different assays, compounds 1 and 2 can be considered as antifungal hit inhibitors of chitin synthase, allowing further optimization of their pharmacological profile to improve their antifungal properties.
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Antifúngicos/química , Botrytis/enzimología , Quitina Sintasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Imidazoles/química , Ribosa/análogos & derivados , Bibliotecas de Moléculas Pequeñas/química , Antifúngicos/farmacología , Arabidopsis/microbiología , Botrytis/efectos de los fármacos , Botrytis/patogenicidad , Quitina Sintasa/metabolismo , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento , Imidazoles/farmacología , Cinética , Pruebas de Sensibilidad Microbiana , Miniaturización , Enfermedades de las Plantas/microbiología , Ribosa/química , Ribosa/farmacología , Robótica , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
BACKGROUND: Current treatments for idiopathic inflammatory myopathies (collectively called myositis) focus on the suppression of an autoimmune inflammatory response within the skeletal muscle. However, it has been observed that there is a poor correlation between the successful suppression of muscle inflammation and an improvement in muscle function. Some evidence in the literature suggests that metabolic abnormalities in the skeletal muscle underlie the weakness that continues despite successful immunosuppression. We have previously shown that decreased expression of a purine nucleotide cycle enzyme, adenosine monophosphate deaminase (AMPD1), leads to muscle weakness in a mouse model of myositis and may provide a mechanistic basis for muscle weakness. One of the downstream metabolites of this pathway, D-ribose, has been reported to alleviate symptoms of myalgia in patients with a congenital loss of AMPD1. Therefore, we hypothesized that supplementing exogenous D-ribose would improve muscle function in the mouse model of myositis. We treated normal and myositis mice with daily doses of D-ribose (4 mg/kg) over a 6-week time period and assessed its effects using a battery of behavioral, functional, histological and molecular measures. RESULTS: Treatment with D-ribose was found to have no statistically significant effects on body weight, grip strength, open field behavioral activity, maximal and specific forces of EDL, soleus muscles, or histological features. Histological and gene expression analysis indicated that muscle tissues remained inflamed despite treatment. Gene expression analysis also suggested that low levels of the ribokinase enzyme in the skeletal muscle might prevent skeletal muscle tissue from effectively utilizing D-ribose. CONCLUSIONS: Treatment with daily oral doses of D-ribose showed no significant effect on either disease progression or muscle function in the mouse model of myositis.
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Suplementos Dietéticos , Antígenos de Histocompatibilidad Clase I/genética , Miositis/genética , Ribosa/farmacología , AMP Desaminasa/metabolismo , Adenosina Monofosfato/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Masculino , Redes y Vías Metabólicas , Ratones , Ratones Transgénicos , Contracción Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Miositis/tratamiento farmacológico , Ribosa/administración & dosificación , Ribosa/metabolismoRESUMEN
A healthy cellular system involves the maintenance of an intracellular metabolic balance. Reactive oxygen species (ROS) are constantly produced as a normal product of cellular metabolism; however, during situations of cellular stress, these levels can increase dramatically with the potential to cause deleterious cellular structural and/or functional consequences. There is a significant elevation in these ROS following stressful situations, such as ischemia, hypoxia, high-intensity exercise, and in many diseases. To combat these ROS, neutralizing endogenous enzymes, as well as exogenous antioxidants, can aid in minimizing their potential untoward cellular effects. Exogenous reducing antioxidant agents, such as vitamin C and/or E, play a role in addressing these formed species; however, recent research has suggested that fruit seed extracts may provide additional cellular benefits beyond their antioxidant features. Furthermore, supplemental D-ribose enhances the recovery of high-energy phosphates following stress and appears to potentially offer additional benefits by reducing radical formation. Specifically, during periods of hypoxia/ischemia, supplemental D-ribose may play an inhibitory role in the breakdown of adenine nucleotides, influencing the subsequent formation of xanthine and uric acid compounds; and thereby affecting the release of superoxide anion radicals. The combination of D-ribose with reducing antioxidants may provide a more optimal state of cellular protection during and following times of oxidative stress.
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Nucleótidos de Adenina/metabolismo , Antioxidantes/uso terapéutico , Citoprotección/efectos de los fármacos , Suplementos Dietéticos , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Ribosa/uso terapéutico , Antioxidantes/farmacología , Hipoxia de la Célula/efectos de los fármacos , Humanos , Ribosa/farmacología , Semillas , Superóxidos/metabolismo , Ácido Úrico/metabolismo , Xantina/metabolismoAsunto(s)
Suplementos Dietéticos , Testosterona/farmacología , Suplementos Dietéticos/normas , Doping en los Deportes , Ácidos Grasos/farmacología , Ácidos Grasos/uso terapéutico , Hormonas/uso terapéutico , Humanos , Ribosa/farmacología , Ribosa/uso terapéutico , Smilax/química , Deportes , Testosterona/químicaRESUMEN
The importance of supporting energy production in heart cells and the preservation of the mitochondria in these cells will be the focus of a new frontier in cardiovascular prevention, treatment, and management. Many physicians are not trained to look at heart disease in terms of cellular biochemistry; therefore, the challenge in any metabolic cardiology discussion is in taking the conversation from the "bench to the bedside." An understanding of the vital role that adenosine triphosphate (ATP) plays in the heart is critical for any physician or clinician considering therapeutic options that support ATP production and turnover in jeopardized cardiac muscle cells. Metabolic therapies that help cardiomyocytes meet their absolute need for ATP fulfill a major clinical challenge of preserving pulsatile cardiac function while maintaining cell and tissue viability. D-ribose, L-carnitine, and coenzyme Q10 work in synergy to help the ischemic or hypoxic heart preserve its energy charge. This article introduces how ATP, diastolic heart function, and metabolic support help maintain cardiac energy by preserving ATP substrates. Part 2 will investigate an in-depth biochemical discussion of congestive heart failure with physiologic, pathophysiologic, and treatment considerations.
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Adenosina Trifosfato/metabolismo , Antioxidantes/farmacología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/prevención & control , Miocardio/metabolismo , Carnitina/farmacología , Metabolismo Energético , Humanos , Ribosa/farmacología , Ubiquinona/análogos & derivados , Ubiquinona/farmacologíaRESUMEN
Ribose, a critical building block for nucleotides, plays an important role in energy metabolism, transcription, translation, and second messenger systems. This 5-carbon sugar, synthesized from glucose via the pentose phosphate pathway, has a rate-limiting step at glucose-6-phosphate dehydrogenase. Therefore, we hypothesized that when cells are required to proliferate or differentiate, as in an immune response, the requirement for D-ribose may be greater than what could be supplied by the synthetic pathway. We hypothesized that providing an exogenous source of D-ribose during cell differentiation will enhance the process of differentiation. We used a retinoic acid-induced HL-60 cell differentiation culture as a model of neutrophil maturation. The addition of 10 to 25 mmol/L D-ribose was shown to reduce cell proliferation and move the cell population toward apoptosis in a dose-dependent manner. The expression of a cell surface marker representing maturity (CD11b) significantly increased and a cell surface marker indicative of immaturity (CD117) significantly decreased. Functionally, the cells had a greater oxidative burst function dependent on time and dose. The mechanism by which ribose enhances HL-60 cell differentiation is not known; however, as adenosine triphosphate levels did not change, adenosine triphosphate is not thought to be involved. We conclude that in this cell culture model, ribose supplementation enhanced cellular differentiation and function. Thus, ribose might be conditionally essential during time of higher need as in an immune response.
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Apoptosis/efectos de los fármacos , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Neutrófilos/metabolismo , Ribosa/farmacología , Adenosina Trifosfato/biosíntesis , Antígeno CD11b/metabolismo , Relación Dosis-Respuesta a Droga , Células HL-60/citología , Células HL-60/inmunología , Humanos , Neutrófilos/citología , Proteínas Proto-Oncogénicas c-kit/metabolismo , Estallido Respiratorio/efectos de los fármacos , Tretinoina/farmacologíaRESUMEN
Glycation is a slow chemical reaction which takes place between amino residues in protein and a reducing sugar. In skin this reaction creates new residues or induces the formation of cross-links (advanced glycation end products or AGEs) in the extracellular matrix of the dermis. Formation of such cross-links between macromolecules may be responsible for loss of elasticity or modification of other properties of the dermis observed during aging. We had previously developed a reconstructed skin model which enabled us to study the consequences of matrix alteration by preglycation of the collagen and have reported several modifications of interest induced by glycation in the dermal and epidermal compartments of reconstructed skin as well as at the level of the dermal-epidermal junction. For example we showed that collagen IV and laminin were increased in the basement membrane zone and that alpha6 and beta1 integrins in epidermis were expanded to suprabasal layers. The aim of this new study was to look at the biological effects of glycation inhibitors like aminoguanidine in the skin model. Aminoguanidine was mixed with collagen in the presence of ribose as reducing sugar, and immunostaining was used to visualize its effects on AGE Products and biological markers. After aminoguanidine treatment, we found a low amount of AGE products and a possible return to the normal pattern of distribution of markers in skin constructs as compared to those treated with ribose only. Interestingly similar results were also obtained, although to a lesser extent, with a blueberry extract. In conclusion the glycation inhibitory effect has been functionally demonstrated in the reconstructed skin model and it is shown that this model can be used to assess anti-glycation agents.
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Dermis/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Envejecimiento de la Piel/fisiología , Biomarcadores/análisis , Arándanos Azules (Planta) , Colágeno/metabolismo , Dermis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Productos Finales de Glicación Avanzada/análisis , Guanidinas/farmacología , Humanos , Inmunohistoquímica , Integrina beta1/análisis , Metaloproteinasa 1 de la Matriz/análisis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Técnicas de Cultivo de Órganos , Oxidación-Reducción , Extractos Vegetales/farmacología , Ribosa/farmacología , Envejecimiento de la Piel/efectos de los fármacos , Piel ArtificialRESUMEN
Every cell needs energy, i.e., adenosine triphosphate (ATP), to carry out its function. Decreased oxygen levels, decreased blood flow, and other stressful conditions can drastically effect the intracellular concentrations of these energy compounds. Skeletal muscle, unlike the heart, can address this drop in ATP by employing the myokinase reaction, ultimately producing ATP with a subsequent elevation in adenosine monophosphate (AMP). Ribose, a naturally occurring 5-carbon monosaccharide, is a key component of RNA, DNA (which has deoxyribose), acetyl coenzyme A, and ATP. Each cell produces its own ribose, involved in the pentose phosphate pathway (PPP), to aid in ATP production. States of ischemia and/or hypoxia can severely lower levels of cellular energy compounds in the heart, with an associated compromise in cellular processes, ultimately reflected in altered function. Ribose appears to provide a solution to the problem in replenishing the depressed ATP levels and improving functional status of patients afflicted with cardiovascular diseases.
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Adenosina Trifosfato/biosíntesis , Enfermedades Cardiovasculares/tratamiento farmacológico , Suplementos Dietéticos , Metabolismo Energético , Corazón/efectos de los fármacos , Miocardio/metabolismo , Ribosa/uso terapéutico , Fármacos Cardiovasculares/farmacología , Fármacos Cardiovasculares/uso terapéutico , Enfermedades Cardiovasculares/metabolismo , Humanos , Hipoxia/tratamiento farmacológico , Hipoxia/metabolismo , Isquemia/tratamiento farmacológico , Isquemia/metabolismo , Miocardio/citología , Ribosa/metabolismo , Ribosa/farmacologíaRESUMEN
This article reviews the current literature regarding the use of ribose as an ergogenic aid. Ribose manufacturers claim that it provides ergogenic benefit, but this has not been substantiated through scientific investigations. Data have shown promise that ribose supplementation leads to enhanced restoration of ATP levels following exercise, but this has seldom translated into increased athletic performance. However, as with many ergogenic aids, additional research is needed to clarify its value as a supplement.
Asunto(s)
Suplementos Dietéticos , Ejercicio Físico/fisiología , Resistencia Física/efectos de los fármacos , Ribosa/farmacología , Humanos , Fuerza Muscular/efectos de los fármacos , Ribosa/administración & dosificaciónRESUMEN
In this study, we investigated the immunomodulatory activity of coffee and Maillard reaction products on macrophages in vitro. Stimulation of macrophages with coffee, but not with raw coffee extract in PBS, led to a 13-fold increased nuclear NF-kappaB translocation. A Maillard reaction mixture (25 mM D-ribose/L-lysine, 30 min at 120 degrees C) increased NF-kappaB translocation 18-fold (in PBS) or six-fold (in medium). MRPs also induced a two-fold increased NF-kappaB translocation in untransfected human embryonic kidney (HEK) cells as well as in HEK cells stably transfected with the receptor for advanced glycation endproducts (RAGE), indicating that the effect was not RAGE mediated. On the other hand, catalase totally abolished coffee- and MRP-induced NF-kappaB translocation. Consequently, up to 366 microM hydrogen peroxide was measured in the coffee preparation and Maillard mixtures used for cell stimulation. Stimulation of macrophages with MRPs did not lead to significantly increased IL-6 or NO release. Thus, it can be concluded that coffee and MRPs induce NF-kappaB translocation in macrophages via the generation of hydrogen peroxide.
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Café/química , Peróxido de Hidrógeno/metabolismo , Macrófagos/química , Reacción de Maillard , FN-kappa B/metabolismo , Animales , Línea Celular , Embrión de Mamíferos , Humanos , Interleucina-6/metabolismo , Riñón , Lisina/farmacología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Óxido Nítrico/metabolismo , Ratas , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada , Receptores Inmunológicos/genética , Receptores Inmunológicos/fisiología , Ribosa/farmacología , TransfecciónRESUMEN
The amount of adenosine triphosphate (ATP) stored in the muscle available for immediate use is limited, and once used, must be resynthesized in the muscle. Ribose, a naturally occurring pentose sugar, helps resynthesize ATP for use in muscles. There have been claims that ribose supplements increase ATP levels and improve performance. Other studies have provided mixed results on the effectiveness of ribose as an ergogenic aid at high doses. None of these studies have compared the impact of the recommended dose of ribose on athletes and nonathletes under exercise conditions that are most conducive for effectiveness. The purpose of this study was to evaluate the effectiveness of ribose as an ergogenic aid at the dose recommended for supplements currently on the market during an exercise trial to maximize its efficacy. Male subjects (n = 11) performed 2 trials 1 week apart. Each trial consisted of three 30-second Wingate tests with a 2-minute recovery between each test. Trials were counterbalanced, with 1 trial being performed with 625 mg of ribose and the other with a placebo. Peak power, mean power, and percent decrease in power were recorded during each Wingate test. Repeated-measures analysis of variance (p > 0.05) found no significant differences between ribose and placebo. These results suggest that ribose had no effect on performance when taken orally, at the dose suggested by the distributor.
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Ciclismo/fisiología , Suplementos Dietéticos , Resistencia Física/efectos de los fármacos , Ribosa/farmacología , Análisis de Varianza , Estudios Cruzados , Método Doble Ciego , Prueba de Esfuerzo , Humanos , Masculino , Resistencia Física/fisiología , Aptitud Física/fisiología , Levantamiento de Peso/fisiologíaRESUMEN
BACKGROUND: Free radical injury contributes to cardiac dysfunction during ischemia-reperfusion. Detoxification of free radicals requires maintenance of reduced glutathione (GSH) by NADPH. The principal mechanism responsible for generating NADPH and maintaining GSH during periods of myocardial ischemia-reperfusion remains unknown. Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway, generates NADPH in a reaction linked to the de novo production of ribose. We therefore hypothesized that G6PD is essential for maintaining GSH levels and protecting the heart during ischemia-reperfusion injury. METHODS AND RESULTS: Susceptibility to myocardial ischemia-reperfusion injury was determined in Langendorff-perfused hearts isolated from wild-type mice (WT) and mice lacking G6PD (G6PD(def)) (20% of WT myocardial G6PD activity). During global zero-flow ischemia, cardiac function was similar between WT and G6PD(def) hearts. On reperfusion, however, cardiac relaxation and contractile performance were greatly impaired in G6PD(def) myocardium, as demonstrated by elevated end-diastolic pressures and decreased percent recovery of developed pressure relative to WT hearts. Contractile dysfunction in G6PD(def) hearts was associated with depletion of total glutathione stores and impaired generation of GSH from its oxidized form. Increased ischemia-reperfusion injury in G6PD(def) hearts was reversed by treatment with the antioxidant MnTMPyP but unaffected by supplementation of ribose stores. CONCLUSIONS: These results demonstrate that G6PD is an essential myocardial antioxidant enzyme, required for maintaining cellular glutathione levels and protecting against oxidative stress-induced cardiac dysfunction during ischemia-reperfusion.