RESUMEN
Methylglyoxal (MGO) is a reactive carbonyl species found at high levels in blood of diabetic patients. The anti-hyperglycemic drug metformin can scavenger MGO and reduce the formation of advanced glycation end products (AGEs). Here, we aimed to investigate if MGO-induced bladder dysfunction can be reversed by metformin. Male C57/BL6 mice received 0.5% MGO in drinking water for 12 weeks, and metformin (300 mg/kg, daily gavage) was given in the last two weeks. The bladder functions were evaluated by performing voiding behavior assays, cystometry and in vitro bladder contractions. MGO intake markedly elevated the levels of MGO and fluorescent AGEs in serum and reduced the mRNA expression and activity of glyoxalase (Glo1) in bladder tissues. Glucose levels were unaffected among groups. MGO intake also increased the urothelium thickness and collagen content of the bladder. Void spot assays in conscious mice revealed an increased void volume in MGO group. The cystometric assays in anesthetized mice revealed increases of basal pressure, non-voiding contractions frequency, bladder capacity, inter-micturition pressure and residual volume, which were accompanied by reduced voiding efficiency in MGO group. In vitro bladder contractions to carbachol, α,ß-methylene ATP and electrical-field stimulation were significantly greater in MGO group. Metformin normalized the changes of MGO and AGEs levels, Glo1 expression and activity, urothelium thickness and collagen content. The MGO-induced voiding dysfunction were all restored by metformin treatment. Our findings strongly suggest that the amelioration of MGO-induced voiding dysfunction by metformin relies on its ability to scavenger MGO, preventing its accumulation in blood.
Asunto(s)
Metformina/farmacología , Piruvaldehído/antagonistas & inhibidores , Enfermedades de la Vejiga Urinaria/tratamiento farmacológico , Micción/efectos de los fármacos , Administración Oral , Animales , Modelos Animales de Enfermedad , Productos Finales de Glicación Avanzada/metabolismo , Humanos , Masculino , Metformina/uso terapéutico , Ratones , Piruvaldehído/administración & dosificación , Piruvaldehído/sangre , Piruvaldehído/metabolismo , Vejiga Urinaria/efectos de los fármacos , Vejiga Urinaria/metabolismo , Vejiga Urinaria/patología , Enfermedades de la Vejiga Urinaria/sangre , Enfermedades de la Vejiga Urinaria/metabolismo , Enfermedades de la Vejiga Urinaria/patologíaRESUMEN
The present investigation entails the fabrication and characterization of nanometric emulsion of eugenol (Nm-eugenol) encompassed into chitosan for assessing bio-efficacy in terms of in vitro antifungal actions, antiaflatoxigenic potential, and in situ preservative efficacy against Aspergillus flavus infestation and aflatoxin B1 (AFB1) mediated loss of dietary minerals, lipid triglycerides and alterations in composition of important macronutrients in stored rice. Nm-eugenol characterized by SEM, XRD, and FTIR exhibited biphasic burst release of eugenol. Reduction in ergosterol and methylglyoxal (AFB1-inducer) content after Nm-eugenol fumigation depicted biochemical mechanism of antifungal and antiaflatoxigenic activities. In silico 3D homology docking of eugenol with Ver-1 gene validated molecular mechanism of AFB1 inhibition. Further, significant protection of rice seeds from fungi, AFB1 contamination and preservation against loss of rice minerals, macronutrients and lipids during storage suggested deployment of chitosan as a biocompatible wall material for eugenol encapsulation and application as novel green preservative for food protection.
Asunto(s)
Aflatoxina B1/antagonistas & inhibidores , Antiinfecciosos/farmacología , Aspergillus flavus/efectos de los fármacos , Quitosano/química , Eugenol/farmacología , Proteínas Fúngicas/antagonistas & inhibidores , Nanoestructuras/química , Aflatoxina B1/química , Aflatoxina B1/metabolismo , Aflatoxina B1/toxicidad , Antiinfecciosos/metabolismo , Aspergillus flavus/crecimiento & desarrollo , Aspergillus flavus/metabolismo , Sitios de Unión , Composición de Medicamentos/métodos , Liberación de Fármacos , Grano Comestible , Emulsiones , Ergosterol/antagonistas & inhibidores , Ergosterol/metabolismo , Eugenol/metabolismo , Conservación de Alimentos/métodos , Proteínas Fúngicas/química , Proteínas Fúngicas/metabolismo , Humanos , Cinética , Simulación del Acoplamiento Molecular , Nanoestructuras/ultraestructura , Nutrientes/análisis , Oryza/efectos de los fármacos , Oryza/microbiología , Unión Proteica , Conformación Proteica en Hélice alfa , Conformación Proteica en Lámina beta , Piruvaldehído/antagonistas & inhibidores , Piruvaldehído/metabolismo , Triglicéridos/análisisRESUMEN
The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and reduced glutathione (GSH), which perform an essential metabolic function in cells by detoxifying methylglyoxal (MG) and other endogenous harmful metabolites into non-toxic d-lactate. MG and MG-derived advanced glycation endproducts (AGEs) are associated with various diseases, such as diabetes, cardiovascular disease, neurodegenerative disorders and cancer, and GLO1 is a key rate-limiting enzyme in the anti-glycation defense. The abnormal activity and expression of GLO1 in various diseases make this enzyme a promising target for drug design and development. This review focuses on the regulatory mechanism of GLO1 in diverse pathogenic conditions with a thorough discussion of GLO1 regulators since their discovery, including GLO1 activators and inhibitors. The different classes, chemical structure and structure-activity relationship are embraced. Moreover, assays for the discovery of small molecule regulators of the glyoxalase system are also introduced in this article. Compared with spectrophotometer-based assay, microplate-based assay is a more simple, rapid and quantitative high-throughput method. This review will be useful to design novel and potent GLO1 regulators and hopefully provide a convenient reference for researchers.
Asunto(s)
Productos Biológicos/metabolismo , Productos Biológicos/uso terapéutico , Lactoilglutatión Liasa/metabolismo , Piruvaldehído/metabolismo , Animales , Productos Biológicos/farmacología , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Glicosilación/efectos de los fármacos , Humanos , Lactoilglutatión Liasa/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Piruvaldehído/antagonistas & inhibidoresRESUMEN
Reactive intermediate dicarbonyls, such as methylglyoxal (MGO) and glyoxal (GO), have received extensive attention recently due to their high reactivity and capability to form advanced glycation end products (AGEs) in foods, which have been implicated in the progression of age-related complaints. We aimed to investigate the effects of three structurally different phytosterols (PS), including stigmasterol (SS), ß-sitosterol (ßS), and γ-oryzanol (γO), on AGEs-formation by measuring their anti-GO/MGO activity. The glycoxidation-based products, SDS-PAGE intensity, free lysine, protein thiols, fluorescence microscopy clicks, scavenging of dicarbonyl activity, and protein aggregation in bovine serum albumin (BSA) models were therefore measured. The results showed that PS could strongly inhibit fluorescent-AGEs, lysine residues, intermediate di-carbonyls, beside their disaggregation effects in a dose and structure dependent manner. Additionally, γ-oryzanol strongly inhibited AGEs more than the other PS, mostly due to its distinctive structure. Our results will provide a new foundation for development of different structure of PS as natural AGEs-inhibitors.
Asunto(s)
Fitosteroles/farmacología , Piruvaldehído/antagonistas & inhibidores , Piruvaldehído/metabolismo , Albúmina Sérica Bovina/metabolismo , Albúmina Sérica/metabolismo , Animales , Bovinos , Productos Finales de Glicación Avanzada , Glicosilación/efectos de los fármacos , Lisina/metabolismo , Fitosteroles/química , Albúmina Sérica/química , Albúmina Sérica Bovina/química , Compuestos de Sulfhidrilo/metabolismo , Albúmina Sérica GlicadaRESUMEN
Methylglyoxal (MG), a highly reactive dicarbonyl derived from metabolic processes, is the most powerful precursor of advanced glycation end products (AGEs). Glycative stress has been recently associated with ovarian dysfunctions in aging and PCOS syndrome. We have investigated the role of the NAD+-dependent Class III deacetylase SIRT1 in the adaptive response to MG in mouse oocytes and ovary. In mouse oocytes, MG induced up-expression of glyoxalase 1 (Glo1) and glyoxalase 2 (Glo2) genes, components of the main MG detoxification system, whereas inhibition of SIRT1 by Ex527 or sirtinol reduced this response. In addition, the inhibition of SIRT1 worsened the effects of MG on oocyte maturation rates, while SIRT1 activation by resveratrol counteracted MG insult. Ovaries from female mice receiving 100â¯mg/kg MG by gastric administration for 28â¯days (MG mice) exhibited increased levels of SIRT1 along with over-expression of catalase, superoxide dismutase 2, SIRT3, PGC1α and mtTFA. Similar levels of MG-derived AGEs were observed in the ovaries from MG and control groups, along with enhanced protein expression of glyoxalase 1 in MG mice. Oocytes ovulated by MG mice exhibited atypical meiotic spindles, a condition predisposing to embryo aneuploidy. Our results from mouse oocytes revealed for the first time that SIRT1 could modulate MG scavenging by promoting expression of glyoxalases. The finding that up-regulation of glyoxalase 1 is associated with that of components of a SIRT1 functional network in the ovaries of MG mice provides strong evidence that SIRT1 participates in the response to methylglyoxal-dependent glycative stress in the female gonad.
Asunto(s)
Productos Finales de Glicación Avanzada/genética , Oocitos/efectos de los fármacos , Ovario/efectos de los fármacos , Piruvaldehído/farmacología , Sirtuina 1/genética , Animales , Benzamidas/farmacología , Carbazoles/farmacología , Catalasa/genética , Catalasa/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Inhibidores Enzimáticos/farmacología , Femenino , Regulación de la Expresión Génica , Productos Finales de Glicación Avanzada/metabolismo , Lactoilglutatión Liasa/antagonistas & inhibidores , Lactoilglutatión Liasa/genética , Lactoilglutatión Liasa/metabolismo , Ratones , Ratones Endogámicos , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Naftoles/farmacología , Oocitos/citología , Oocitos/metabolismo , Ovario/citología , Ovario/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Cultivo Primario de Células , Piruvaldehído/antagonistas & inhibidores , Resveratrol/farmacología , Transducción de Señal , Sirtuina 1/metabolismo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Tioléster Hidrolasas/antagonistas & inhibidores , Tioléster Hidrolasas/genética , Tioléster Hidrolasas/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
PURPOSE OF REVIEW: Chronic kidney disease (CKD) remains a serious diabetic complication despite the use of widely employed interventions such as angiotensin-converting enzyme inhibitors and glucose-lowering treatments. Accumulation of methylglyoxal, a highly reactive glucose metabolite and a major precursor in the formation of advanced glycation end products, may link the hemodynamic, inflammatory, metabolic, and structural changes that drive diabetic CKD. Therefore, methylglyoxal may serve as a potential therapeutic target to prevent diabetic CKD. RECENT FINDINGS: Higher plasma methylglyoxal levels were shown to be associated with a decline in the estimated glomerular filtration rate. Furthermore, interventions that lower methylglyoxal levels reduced albuminuria in rodent models of diabetes. In addition, the glyoxalase system, which detoxifies methylglyoxal into D-lactate, has been identified as a key protective enzymatic system against diabetic CKD in both human and rodent studies. Recently, several promising treatments to lower methylglyoxal directly or to boost the glyoxalase system have been identified. SUMMARY: The review highlights the mechanisms through which methylglyoxal is formed in diabetes, and how methylglyoxal contributes to the mechanisms that drive CKD in diabetes. Furthermore, we discuss the role of glyoxalase-1 in diabetic CKD. Finally, we discuss recent data about treatments that lower methylglyoxal stress.
Asunto(s)
Nefropatías Diabéticas/etiología , Lactoilglutatión Liasa/fisiología , Piruvaldehído/metabolismo , Insuficiencia Renal Crónica/etiología , Nefropatías Diabéticas/metabolismo , Humanos , Piruvaldehído/antagonistas & inhibidores , Insuficiencia Renal Crónica/metabolismoRESUMEN
The development of advanced glycation end-products (AGEs) inhibitors is considered to have therapeutic potential in diabetic complications inhibiting the loss of the biomolecular function. In the present study, zinc oxide nanoparticles (ZnO-NPs) were synthesized from aqueous leaf extract of Morus indica and were characterized by various techniques such as ultraviolet (UV)-Vis spectroscopy, Powder X-Ray Diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FT-IR), Scanning electron microscopy (SEM), and energy dispersive spectroscopy (EDS). Further, the inhibition of AGEs formation after exposure to ZnO-NPs was investigated by in-vitro, in-vivo, and molecular docking studies. Biochemical and histopathological changes after exposure to ZnO-NPs were also studied in streptozotocin-induced diabetic rats. ZnO-NPs showed an absorption peak at 359 nm with a purity of 92.62% and ~6-12 nm in size, which is characteristic of nanoparticles. The images of SEM showed agglomeration of smaller ZnO-NPs and EDS authenticating that the synthesized nanoparticles were without impurities. The biosynthesized ZnO-NPs showed significant inhibition in the formation of AGEs. The particles were effective against methylglyoxal (MGO) mediated glycation of bovine serum albumin (BSA) by inhibiting the formation of AGEs, which was dose-dependent. Further, the presence of MGO resulted in complete damage of biconcave red blood corpuscles (RBCs) to an irregular shape, whereas the morphological changes were prevented when they were treated with ZnO-NPs leading to the prevention of complications caused due to glycation. The administration of ZnO-NPs (100 mg Kg-1) in streptozotocin(STZ)-induced diabetic rats reversed hyperglycemia and significantly improved hepatic enzymes level and renal functionality, also the histopathological studies revealed restoration of kidney and liver damage nearer to normal conditions. Molecular docking of BSA with ZnO-NPs confirms that masking of lysine and arginine residues is one of the possible mechanisms responsible for the potent antiglycation activity of ZnO-NPs. The findings strongly suggest scope for exploring the therapeutic potential of diabetes-related complications.
Asunto(s)
Eritrocitos/efectos de los fármacos , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Simulación del Acoplamiento Molecular , Morus/química , Nanopartículas/química , Piruvaldehído/antagonistas & inhibidores , Óxido de Zinc/farmacología , Animales , Bovinos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Eritrocitos/metabolismo , Productos Finales de Glicación Avanzada/metabolismo , Hiperglucemia/inducido químicamente , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Masculino , Morus/metabolismo , Nanopartículas/metabolismo , Piruvaldehído/farmacología , Ratas , Ratas Wistar , Albúmina Sérica Bovina/antagonistas & inhibidores , Albúmina Sérica Bovina/metabolismo , Estreptozocina , Óxido de Zinc/química , Óxido de Zinc/metabolismoRESUMEN
Methylglyoxal (MG) is a reactive α-oxoaldehyde that increases under diabetic conditions and subsequently contributes to the complications associated with this disease. Piceatannol is a naturally occurring analogue of resveratrol that possesses multiple biological functions. The present study investigated the effects of piceatannol on MG-induced cytotoxicity in MC3T3-E1 osteoblastic cells. Piceatannol significantly restored MG-induced reductions in cell viability and reduced lactate dehydrogenase release in MG-treated MC3T3-E1 osteoblastic cells, which suggests that it suppressed MG-induced cytotoxicity. Piceatannol also increased glyoxalase I activity and glutathione levels in MG-treated cells, which indicates that it enhanced the glyoxalase system and thus cellular protection. The present study also showed that piceatannol inhibited the generation of inflammatory cytokines and reactive oxygen species and ameliorated mitochondrial dysfunction induced by MG. Furthermore, piceatannol treatment significantly reduced the levels of endoplasmic reticulum stress and autophagy induced by MG. Therefore, piceatannol could be a potent option for the development of antiglycating agents for the treatment of diabetic osteopathy.
Asunto(s)
Osteoblastos/efectos de los fármacos , Sustancias Protectoras/farmacología , Piruvaldehído/antagonistas & inhibidores , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Estilbenos/farmacología , Animales , Autofagia/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Glutatión/agonistas , Glutatión/metabolismo , L-Lactato Deshidrogenasa/antagonistas & inhibidores , L-Lactato Deshidrogenasa/metabolismo , Lactoilglutatión Liasa/metabolismo , Ratones , Osteoblastos/citología , Osteoblastos/metabolismo , Piruvaldehído/toxicidad , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Glycation is associated with several neurodegenerative disorders, including Alzheimer's disease (AD), where it potentiates the aggregation and toxicity of proteins such as ß-amyloid (Aß). Published studies support the anti-glycation and neuroprotective effects of several polyphenol-rich fruits, including berries, which are rich in anthocyanins. Herein, blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts were evaluated for: (1) total phenolic and anthocyanins contents, (2) free radical (DPPH) scavenging and reactive carbonyl species (methylglyoxal; MGO) trapping, (3) anti-glycation (using BSA-fructose and BSA-MGO models), (4) anti-Aß aggregation (using thermal- and MGO-induced fibrillation models), and, (5) murine microglia (BV-2) neuroprotective properties. Berry crude extracts (CE) were fractionated to yield anthocyanins-free (ACF) and anthocyanins-enriched (ACE) extracts. The berry ACEs (at 100 µg/mL) showed superior free radical scavenging, reactive carbonyl species trapping, and anti-glycation effects compared to their respective ACFs. The berry ACEs (at 100 µg/mL) inhibited both thermal- and MGO-induced Aß fibrillation. In addition, the berry ACEs (at 20 µg/mL) reduced H2O2-induced reactive oxygen species production, and lipopolysaccharide-induced nitric oxide species in BV-2 microglia as well as decreased H2O2-induced cytotoxicity and caspase-3/7 activity in BV-2 microglia. The free radical scavenging, reactive carbonyl trapping, anti-glycation, anti-Aß fibrillation, and microglial neuroprotective effects of these berry extracts warrant further in vivo studies to evaluate their potential neuroprotective effects against AD.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Antocianinas/farmacología , Antioxidantes/farmacología , Frutas/química , Fármacos Neuroprotectores/farmacología , Polifenoles/farmacología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Animales , Antocianinas/aislamiento & purificación , Antioxidantes/aislamiento & purificación , Compuestos de Bifenilo/antagonistas & inhibidores , Arándanos Azules (Planta)/química , Caspasas/genética , Caspasas/metabolismo , Línea Celular , Fragaria/química , Regulación de la Expresión Génica , Glicosilación/efectos de los fármacos , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/farmacología , Ratones , Neuroglía/citología , Neuroglía/efectos de los fármacos , Neuroglía/fisiología , Fármacos Neuroprotectores/aislamiento & purificación , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Picratos/antagonistas & inhibidores , Extractos Vegetales/química , Polifenoles/aislamiento & purificación , Agregado de Proteínas/efectos de los fármacos , Piruvaldehído/antagonistas & inhibidores , Piruvaldehído/farmacología , Rubus/química , Vaccinium macrocarpon/químicaRESUMEN
Bergenin is the main chemical constituent of plants in the genus Bergenia, which are used in traditional medicines. Methylglyoxal (MG), a highly reactive dicarbonyl compound, is the major precursor for forming advanced glycation end products (AGEs). Pretreating MC3T3-E1 cells with bergenin prevented MG-induced protein adduct formation. Bergenin inhibited the MG-induced soluble receptor for AGE (sRAGE), interleukin, reactive oxygen species and mitochondrial superoxide production. Additionally bergenin increased glyoxalase I activity, glutathione, heme oxygenase-1 and nuclear factor erythroid 2-related factor 2 levels in the presence of MG. Pretreatment with bergenin before MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation, loss of adenosine triphosphate and reduced adenosine monophosphate-activated protein kinase. These results demonstrate that bergenin may prevent the development of diabetic osteopathy.
Asunto(s)
Benzopiranos/farmacología , Osteoblastos/efectos de los fármacos , Piruvaldehído/farmacología , Animales , Línea Celular , Productos Finales de Glicación Avanzada/metabolismo , Hemo-Oxigenasa 1/metabolismo , Interleucinas/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Piruvaldehído/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Superóxidos/metabolismoRESUMEN
Cancer is a disease characterised by uncontrolled growth and proliferation of cells. Tumours primarily show a higher rate of glucose uptake for lactate production even in the presence of functional mitochondria. An important metabolic consequence is intracellular formation of glucose-derived carbonyl reactive species such as methylglyoxal (MG). It has become clear that MG is the most potent glycation agent in our body, leading to alterations of proteins and DNA, and cellular dysfunction. In recent years, emerging evidence indicates that MG plays a role in the development of cancer. This review will examine studies regarding the effects of MG on cancer onset and progression and discuss their controversies. Finally, the utilisation of inhibitors and MG scavengers will be addressed in the context of MG-mediated stress blockade for cancer therapy.
Asunto(s)
Transformación Celular Neoplásica/metabolismo , Lactoilglutatión Liasa/metabolismo , Piruvaldehído/metabolismo , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/farmacología , Transformación Celular Neoplásica/efectos de los fármacos , Resistencia a Antineoplásicos , Silenciador del Gen , Glucólisis/efectos de los fármacos , Glicosilación/efectos de los fármacos , Humanos , Lactoilglutatión Liasa/genética , Piruvaldehído/antagonistas & inhibidores , Piruvaldehído/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Methylglyoxal (MG) is generated from glycolytic metabolites, lipid peroxidation, glucose autooxidation and protein glycation. It is a prooxidant inducing oxidative stress and formation of advanced glycation end products (AGE). Effect of carnosine (CAR) as an antioxidant on toxicity due to MG has generated interest. In this study, rats were given incrementally increased doses (100-300 mg/kg) of MG in drinking water for ten weeks. CAR (250 mg/kg i.p.) was administered with MG. Plasma thiobarbituric reactive substances (TBARS), protein carbonyl (PC), advanced oxidation protein products (AOPP) and AGE levels were elevated by MG, and CAR decreased PC, AOPP and AGE levels. MG increased liver reactive oxygen species (ROS), TBARS, PC and AOPP levels, which were decreased by CAR. Thus, in vivo role of CAR on chronic MG administration was observed to suppress the generated hepatic and plasma oxidative stress.
Asunto(s)
Productos Avanzados de Oxidación de Proteínas/antagonistas & inhibidores , Antioxidantes/farmacología , Carnosina/farmacología , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Hígado/efectos de los fármacos , Piruvaldehído/antagonistas & inhibidores , Productos Avanzados de Oxidación de Proteínas/agonistas , Productos Avanzados de Oxidación de Proteínas/metabolismo , Animales , Productos Finales de Glicación Avanzada/agonistas , Productos Finales de Glicación Avanzada/metabolismo , Inyecciones Intraperitoneales , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Carbonilación Proteica , Piruvaldehído/toxicidad , Ratas , Ratas Sprague-Dawley , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
BACKGROUND: Methylglyoxal (MG) is an endogenous product of glucose metabolism known to be toxic to cells and to be present in elevated concentrations under certain pathophysiological conditions. In the present study the effect of actein isolated from black cohosh on MG-induced cytotoxicity was investigated in MC3T3-E1 osteoblastic cells. RESULTS: Treatment of MC3T3-E1 osteoblastic cells with actein prevented MG-induced cell death and the production of intracellular reactive oxygen species (ROS), mitochondrial superoxide, inflammatory cytokines and soluble receptor for advanced glycation end-products (sRAGE). In addition, actein increased the activity of glyoxalase I and levels of reduced glutathione (GSH) and the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2). These findings suggest that actein protects against MG-induced cell damage by reducing oxidative stress and increasing MG detoxification. Treatment with actein prior to MG exposure reduced MG-induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation and adenosine triphosphate (ATP) loss. Additionally, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and nitric oxide (NO) levels were significantly increased by actein, suggesting that actein may induce mitochondrial biogenesis. CONCLUSION: This study demonstrates that actein reduces MG-induced damage in osteoblastic MC3T3-E1 cells by enhancing antioxidant defenses, the glyoxalase system and mitochondrial biogenesis. © 2016 Society of Chemical Industry.
Asunto(s)
Osteoblastos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Piruvaldehído/antagonistas & inhibidores , Piruvaldehído/toxicidad , Saponinas/farmacología , Triterpenos/farmacología , Antioxidantes/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Cimicifuga/química , Citocinas/metabolismo , Glutatión/metabolismo , Lactoilglutatión Liasa/metabolismo , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Óxido Nítrico/metabolismo , Osteoblastos/metabolismo , Osteoblastos/fisiología , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Superóxidos/metabolismoRESUMEN
The antiglycative activity of hydroxytyrosol (HT) and olive leaf extract (OLE) was investigated in wheat-flour biscuits. Quercetin (QE) and gallic acid (GA) were used as reference of antiglycative activity of phenolic compounds. HT, OLE, QE and GA were added in the range of 0.25-0.75% (w/w). Samples were compared against a control recipe baked at 180°C/20min. HT biscuit was able to inhibit efficiently the formation of hydroxymethylfurfural (HMF) and 3-deoxyglucosone (3-DG), as well as reduced the formation of overall free fluorescent AGEs and pentosidine. The inhibition of the 3-DG and HMF formation was directly and significantly correlated under controlled baking conditions. However, samples formulated with OLE exerted similar antiglycative capacity against pentosidine and Nε-carboxyethyl-lysine, although the amount of HT in the biscuit was 100-fold lower than the biscuit formulated with HT. Methylglyoxal, 3-DG, and glyoxal were the predominant 1,2-dicarbonyl compounds after baking but only 3-DG was significantly reduced by HT.
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Alcohol Feniletílico/análogos & derivados , Extractos Vegetales/farmacología , Hojas de la Planta/química , Arginina/análogos & derivados , Arginina/análisis , Arginina/antagonistas & inhibidores , Cromatografía Liquida , Desoxiglucosa/análogos & derivados , Desoxiglucosa/análisis , Desoxiglucosa/antagonistas & inhibidores , Harina/análisis , Manipulación de Alimentos , Furaldehído/análogos & derivados , Furaldehído/análisis , Furaldehído/antagonistas & inhibidores , Ácido Gálico/farmacología , Productos Finales de Glicación Avanzada/análisis , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Lisina/análogos & derivados , Lisina/análisis , Lisina/antagonistas & inhibidores , Reacción de Maillard/efectos de los fármacos , Olea/química , Alcohol Feniletílico/farmacología , Piruvaldehído/análisis , Piruvaldehído/antagonistas & inhibidores , Quercetina/farmacología , Espectrometría de Masas en Tándem , Triticum/químicaRESUMEN
Methylglyoxal (MG) can react with amino acids of proteins to induce protein glycation and consequently the formation of advanced glycation end-products (AGEs). Previous studies reported that ferulic acid (FA) prevented glucose-, fructose-, and ribose-induced protein glycation. In this study, FA (0.1-1 mM) inhibited MG-induced protein glycation and oxidative protein damage in bovine serum albumin (BSA). Furthermore, FA (0.0125-0.2 mM) protected against lysine/MG-mediated oxidative DNA damage, thereby inhibiting superoxide anion and hydroxyl radical generation during lysine and MG reaction. In addition, FA did not have the ability to trap MG. Finally, FA (0.1 mM) pretreatment attenuated MG-induced decrease in cell viability and prevented MG-induced cell apoptosis in pancreatic ß-cells. The results suggest that FA is capable of protecting ß-cells from MG-induced cell damage during diabetes.
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Apoptosis/efectos de los fármacos , Ácidos Cumáricos/farmacología , Daño del ADN/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Células Secretoras de Insulina/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Roturas del ADN/efectos de los fármacos , Productos Finales de Glicación Avanzada/antagonistas & inhibidores , Productos Finales de Glicación Avanzada/metabolismo , Glicosilación/efectos de los fármacos , Células Secretoras de Insulina/metabolismo , Concentración Osmolar , Oxidantes/antagonistas & inhibidores , Oxidantes/toxicidad , Estrés Oxidativo/efectos de los fármacos , Carbonilación Proteica/efectos de los fármacos , Piruvaldehído/antagonistas & inhibidores , Piruvaldehído/toxicidad , Ratas , Albúmina Sérica Bovina/antagonistas & inhibidores , Albúmina Sérica Bovina/metabolismo , Sustancias Reactivas al Ácido Tiobarbitúrico/química , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
BACKGROUND: Advanced glycation end-products (AGEs) play a significant role in the development and progression of vascular complication in diabetes. Anthocyanin has been recently reported to possess antiglycating activity. This study aimed to determine whether a naturally occurring anthocyanin, cyanidin-3-rutinoside (C3R) inhibits methylglyoxal (MG) induced protein glycation and oxidative protein and DNA damage. METHODS: C3R (0.125-1 mM) was incubated with bovine serum albumin and MG (1 mM) for 2 weeks. The formation of fluorescent AGEs was measured by using spectrofluorometer and thiol group content were used to detect protein oxidative damage. Gel electrophoresis was used to determine whether C3R (0.125-1 mM) reduced DNA strand breakage in a glycation model comprising lysine, MG and/or Cu(2+). The generation of superoxide anions and hydroxyl radicals were detected by the cytochrome c reduction assay and the thiobarbituric acid reactive substances assay. MG-trapping capacity was assessed by high performance liquid chromatography (HPLC). RESULTS: C3R (0.25-1 mM) reduced the formation of fluorescent AGEs and depleted protein thiol groups in bovine serum albumin mediated by MG. At 1 mM C3R inhibited oxidative DNA damage in the glycation model (p < 0.05) and at 0.5-1 mM prevented Cu(2+) induced DNA strand breakage in the presence of lysine and MG. The findings showed that C3R reduced the formation of superoxide anion and hydroxyl radicals during the glycation reaction of MG with lysine. C3R directly trapped MG in a concentration and time dependent manner (both p < 0.001). CONCLUSIONS: These findings suggest that C3R protects against MG-induced protein glycation and oxidative damage to protein and DNA by scavenging free radicals and trapping MG.
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Antocianinas/farmacología , Daño del ADN/efectos de los fármacos , Productos Finales de Glicación Avanzada/metabolismo , Piruvaldehído/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Animales , Bovinos , Radicales Libres/metabolismo , Técnicas In Vitro , Oxidación-Reducción , Albúmina Sérica Bovina , Compuestos de Sulfhidrilo/metabolismoRESUMEN
Reactive carbonyl species (RCS) are endogenous or exogenous byproducts involved in the pathogenic mechanisms of different oxidative-based disorders. Detoxification of RCS by carbonyl quenchers is a promising therapeutic strategy. Among the most studied quenchers are aminoguanidine, hydralazine, pyridoxamine, and carnosine; their quenching activity towards four RCS (4-hydroxy-trans-2-nonenal, methylglyoxal, glyoxal, and malondialdehyde) was herein analyzed and compared. Their ability to prevent protein carbonylation was evaluated inâ vitro by using an innovative method based on high-resolution mass spectrometry (HRMS). The reactivity of the compounds was RCS dependent: carnosine efficiently quenched 4-hydroxy-trans-2-nonenal, pyridoxamine was particularly active towards malondialdehyde, aminoguanidine was active towards methylglyoxal and glyoxal, and hydralazine efficiently quenched all RCS. Reaction products were generated inâ vitro and were characterized by HRMS. Molecular modeling studies revealed that the reactivity was controlled by specific stereoelectronic parameters that could be used for the rational design of improved carbonyl quenchers.
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Aldehídos/antagonistas & inhibidores , Glioxal/antagonistas & inhibidores , Malondialdehído/antagonistas & inhibidores , Piruvaldehído/antagonistas & inhibidores , Secuestrantes/farmacología , Carnosina/química , Carnosina/farmacología , Relación Dosis-Respuesta a Droga , Guanidinas/química , Guanidinas/farmacología , Humanos , Hidralazina/química , Hidralazina/farmacología , Estructura Molecular , Piridoxamina/química , Piridoxamina/farmacología , Secuestrantes/química , Relación Estructura-ActividadRESUMEN
AIM: Diabetes mellitus associated cardiovascular complications are a leading cause of morbidity and mortality worldwide. Methylglyoxal (MG) is a reactive ketoaldehyde and a byproduct of glucose metabolism and an inducer of advanced glycation endproducts (AGEs). Alagebrium (ALA) is an AGEs crosslink breaker, however, the effects of ALA on MG levels and its consequences in cultured rat cardiomyocytes are not known. The aim of the present study was to examine the effect of high glucose and MG on cultured rat cardiomyocytes and to investigate whether ALA could prevent any deleterious effects of high glucose and MG in these cells. MAIN METHODS: MG levels were determined by HPLC. The expression of different genes was measured by RT-PCR. Oxidative stress and AGEs formation was determined by DCF probe and immunocytochemistry respectively. KEY FINDINGS: High glucose- and MG treated- cardiomyocytes developed a significant increase in MG, and the expression for caspase-3, Bax, RAGE and NF-KB, which were all attenuated after pretreatment with ALA. A significant increase in reactive oxygen species generation and AGEs formation in high glucose- and MG treated- cultured cardiomyocytes was also observed, which was attenuated after pretreatment with ALA. SIGNIFICANCE: ALA may have a preventive role against the deleterious effects of high glucose and MG in the heart. Prevention of dicarbonyl-induced AGEs, by safer and specific scavengers of MG is an attractive therapeutic option.
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Depuradores de Radicales Libres/farmacología , Productos Finales de Glicación Avanzada/metabolismo , Miocitos Cardíacos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Piruvaldehído/antagonistas & inhibidores , Piruvaldehído/farmacología , Tiazoles/farmacología , Animales , Caspasa 3/biosíntesis , Línea Celular , Células Cultivadas , Glucosa/farmacología , Miocitos Cardíacos/efectos de los fármacos , FN-kappa B/biosíntesis , Ratas , Especies Reactivas de Oxígeno/metabolismo , Receptor para Productos Finales de Glicación Avanzada/biosíntesis , Proteína X Asociada a bcl-2/biosíntesisRESUMEN
In this study we have tested an idea on the important role of amine oxidases (semicarbazide-sensitive amine oxidase, diamine oxidase, polyamine oxidase) as an additional source of oxidative/carbonyl stress under glycerol-induced rhabdomyolysis, since the enhanced formation of reactive oxygen species and reactive carbonyl species in a variety of tissues is linked to various diseases. In our experiments we used the sensitive fluorescent method devised for estimation of amine oxidases activity in the rat kidney and thymus as targeted organs under rhabdomyolysis. We have found in vivo the multiple rises in activity of semicarbazide-sensitive amine oxidase, diamine oxidase, polyamine oxidase (2-4.5 times) in the corresponding cell fractions, whole cells or their lysates at the 3-6th day after glycerol injection. Aberrant antioxidant activities depended on rhabdomyolysis stage and had organ specificity. Additional treatment of animals with metal chelator 'Unithiol' adjusted only the activity of antioxidant enzymes but not amine oxidases in both organs. Furthermore the in vitro experiment showed that Fenton reaction (hydrogen peroxide in the presence of iron) products alone had no effect on semicarbazide-sensitive amine oxidase activity in rat liver cell fraction whereas supplementation with methylglyoxal resulted in its significant 2.5-fold enhancement. Combined action of the both agents had additive effect on semicarbazide-sensitive amine oxidase activity. We can assume that biogenic amine and polyamine catabolism by amine oxidases is upregulated by oxidative and carbonyl stress factors directly under rhabdomyolysis progression, and the increase in catabolic products concentration contributes to tissue damage in glycerol-induced acute renal failure and apoptosis stimulation in thymus.
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Amina Oxidasa (conteniendo Cobre)/metabolismo , Monoaminooxidasa/metabolismo , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Rabdomiólisis/enzimología , Animales , Quelantes/farmacología , Glicerol , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Hepatocitos/patología , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/farmacología , Riñón/efectos de los fármacos , Riñón/enzimología , Riñón/patología , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/patología , Masculino , Especificidad de Órganos , Oxidación-Reducción , Carbonilación Proteica , Piruvaldehído/antagonistas & inhibidores , Piruvaldehído/farmacología , Ratas , Ratas Wistar , Rabdomiólisis/inducido químicamente , Rabdomiólisis/tratamiento farmacológico , Rabdomiólisis/patología , Semicarbacidas/antagonistas & inhibidores , Semicarbacidas/farmacología , Timo/efectos de los fármacos , Timo/enzimología , Timo/patología , Unitiol/farmacología , Poliamino OxidasaRESUMEN
In this study, we examined the possible mechanisms of trehalose (Tre) in improving copper-stress (Cu-stress) tolerance in rice seedlings. Our findings indicated that pretreatment of rice seedlings with Tre enhanced the endogenous Tre level and significantly mitigated the toxic effects of excessive Cu on photosynthesis- and plant growth-related parameters. The improved tolerance induced by Tre could be attributed to its ability to reduce Cu uptake and decrease Cu-induced oxidative damage by lowering the accumulation of reactive oxygen species (ROS) and malondialdehyde in Cu-stressed plants. Tre counteracted the Cu-induced increase in proline and glutathione content, but significantly improved ascorbic acid content and redox status. The activities of major antioxidant enzymes were largely stimulated by Tre pretreatment in rice plants exposed to excessive Cu. Additionally, increased activities of glyoxalases I and II correlated with reduced levels of methylglyoxal in Tre-pretreated Cu-stressed rice plants. These results indicate that modifying the endogenous Tre content by Tre pretreatment improved Cu tolerance in rice plants by inhibiting Cu uptake and regulating the antioxidant and glyoxalase systems, and thereby demonstrated the important role of Tre in mitigating heavy metal toxicity. Our findings provide a solid foundation for developing metal toxicity-tolerant crops by genetic engineering of Tre biosynthesis.