RESUMO
Diabetes and its complications, Alzheimer's disease (AD), and Parkinson's disease (PD) are increasing gradually, reflecting a global threat vis-à-vis expressing the essentiality of a substantial paradigm shift in research and remedial actions. Protein glycation is influenced by several factors, like time, temperature, pH, metal ions, and the half-life of the protein. Surprisingly, most proteins associated with metabolic and neurodegenerative disorders are generally long-lived and hence susceptible to glycation. Remarkably, proteins linked with diabetes, AD, and PD share this characteristic. This modulates protein's structure, aggregation tendency, and toxicity, highlighting renovated attention. Gut microbes and microbial metabolites marked their importance in human health and diseases. Though many scientific shreds of evidence are proposed for possible change and dysbiosis in gut flora in these diseases, very little is known about the mechanisms. Screening and unfolding their functionality in metabolic and neurodegenerative disorders is essential in hunting the gut treasure. Therefore, it is imperative to evaluate the role of glycation as a common link in diabetes and neurodegenerative diseases, which helps to clarify if modulation of nonenzymatic glycation may act as a beneficial therapeutic strategy and gut microbes/metabolites may answer some of the crucial questions. This review briefly emphasizes the common functional attributes of glycation and gut microbes, the possible linkages, and discusses current treatment options and therapeutic challenges.
Assuntos
Doença de Alzheimer , Diabetes Mellitus , Microbioma Gastrointestinal , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Alzheimer/tratamento farmacológico , Reação de MaillardRESUMO
Diabetes mellitus, a metabolic disorder that is characterized by elevated blood glucose levels, is common throughout the world and its prevalence is steadily increasing. Early diagnosis and treatment are important to prevent acute complications and life-threatening long-term organ damage. Glycation sites in human serum albumin (HSA) are considered to be promising biomarkers of systemic glycemic status. This work aimed to develop a sensitive and clinically applicable ELISA for the quantification of glycation site Lys414 in HSA (HSAK414 ). The monoclonal antibodies (mAbs) were generated by immunizing mice with a glycated peptide. The established indirect ELISA based on mAb 50D8 (IgG1 isotype) yielded a limit of detection of 0.39â nmol/g HSA for HSAK414 with a linear dynamic range from 0.50 to 6.25â nmol/g glycated HSA. The inter- and intra-day assays with coefficients of variation less than 20 % indicated good assay performance and precision. Assay evaluation was based on plasma samples from diabetic and non-diabetic subjects with known HSAK414 glycation levels previously determined by LC-MS. Both data sets correlated very well. In conclusion, the generated mAb 50D8 and the established ELISA could be a valuable tool for the rapid quantitation of glycation site HSAK414 in plasma samples to evaluate its clinical relevance.
Assuntos
Diabetes Mellitus , Albumina Sérica , Humanos , Animais , Camundongos , Albumina Sérica/análise , Lisina , Anticorpos Monoclonais , Reação de Maillard , Albumina Sérica Humana/metabolismo , Ensaio de Imunoadsorção EnzimáticaRESUMO
The nonenzymatic protein glycation and the subsequent formation of advanced glycation end products is a process involved in the long-term complications of diabetes. In this context the collaboration, in the last 30 years, between my research group, operating in the DPT of Medicine of Padua University, and the mass spectrometric group, operating in CNR of Padua, are described and discussed. The development of new mass spectrometric techniques has allowed investigation more indepth, starting from the applications on small molecules responsible for the browning observed in the interactions between sugars and proteins, and growing up to intact proteins as albumin, immunoglobulin, hemoglobin, and so forth, with the determination of their glycation levels as well as their glycation sites. This study has helped to clarify the role of advanced glycation end products in the pathogenesis of the chronic complications of diabetes. In particular the results obtained in diabetic nephropathy, diabetic cardiovascular disease and in placenta samples of patients affected by gestational diabetes are described in this review.
Assuntos
Complicações do Diabetes , Diabetes Mellitus , Médicos , Humanos , Diabetes Mellitus/metabolismo , Produtos Finais de Glicação Avançada/análise , Espectrometria de Massas/métodosRESUMO
It is well-known that people suffering from hyperglycemia have a higher propensity to develop Parkinson's disease (PD). One of the most plausible mechanisms linking these two pathologies is the glycation of neuronal proteins and the pathological consequences of it. α-Synuclein, a key component in PD, can be glycated at its fifteen lysine. In fact, the end products of this process have been detected on aggregated α-synuclein isolated from inâ vivo. However, the consequences of glycation are not entirely clear, which are of crucial importance to understand the mechanism underlying the connection between diabetes and PD. To better clarify this, we have here examined how methylglyoxal (the most important carbonyl compound found in the cytoplasm) affects the conformation and aggregation propensity of α-synuclein, as well as its ability to cluster and fuse synaptic-like vesicles. The obtained data prove that methylglyoxal induces the Lys-Lys crosslinking through the formation of MOLD. However, this does not have a remarkable effect on the averaged conformational ensemble of α-synuclein, although it completely depletes its native propensity to form soluble oligomers and insoluble amyloid fibrils. Moreover, methylglyoxal has a disrupting effect on the ability of α-synuclein to bind, cluster and fusion synaptic-like vesicles.
Assuntos
Aldeído Pirúvico , alfa-Sinucleína , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Aldeído Pirúvico/química , Aldeído Pirúvico/metabolismo , Humanos , Doença de Parkinson/metabolismo , Agregados Proteicos/efeitos dos fármacos , Conformação Proteica , Glicosilação , Lisina/química , Amiloide/química , Amiloide/metabolismoRESUMO
BACKGROUND/AIMS: Trazodone is a selective serotonin reuptake inhibitor; however, other mechanisms of the drug's anti-depressive properties have also been postulated. Hence, the aim of the study was to perform a systematic review and assess antiglycoxidative properties of trazodone in in vitro models. METHODS: Trazodone's scavenging and chelating properties were measured with spectrophotometric method. The impact of the drug on carbonyl/oxidative stress was marked in the bovine serum albumin (BSA) model where sugars (glucose, fructose, galactose, ribose) and aldehydes (glyoxal and methylglyoxal) were used as glycation agents. Aminoguanidine and N-acetylcysteine (NAC) were applied as reference glycation/free radical inhibitors. Glycation biomarkers (kynurenine, N-formylkynurenine, dityrosine as well as advanced glycation end products contents) were assessed spectrofluorometrically. Concentrations of oxidation parameters (total thiols (TTs), protein carbonyls (PCs) and also advanced oxidation protein products (AOPPs) levels) were determined spectrophotometrically. RESULTS: We demonstrated that trazodone poorly scavenged radicals (hydroxyl radical, nitric oxide, hydrogen peroxide and 2,2-diphenyl-1-picrylhydrazyl radical) and showed low ferrous ion chelating, unlike aminoguanidine and NAC. Sugars/aldehydes caused enhancement of glycation parameters, as well as a decrease of TTs and an increase of PCs and AOPPs levels compared to BSA incubated alone. Trazodone did not reduce oxidation parameters to the baseline (BSA) and significantly exacerbated glycation markers in comparison with both BSA and BSA+glycators. The content of glycation products was markedly lower in aminoguanidine and NAC than in trazodone. The molecular docking of trazodone to BSA revealed its very low affinity, which may indicate non-specific binding of trazodone, facilitating the attachment of glycation factors. CONCLUSION: According to our findings, it may be concluded that trazodone poorly counteracts oxidation and intensifies glycation in vitro. A possible mechanism for antiglycoxidative effect of trazodone in vivo may be the enhancement of the body's adaptive response, as indicated by the results of our systematic review.
Assuntos
Antioxidantes , Trazodona , Antioxidantes/metabolismo , Trazodona/farmacologia , Glicosilação , Produtos da Oxidação Avançada de Proteínas/metabolismo , Simulação de Acoplamento Molecular , Produtos Finais de Glicação Avançada/metabolismo , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Glioxal/química , GlucoseRESUMO
An important drug used in the treatment of Parkinson's disease is amantadine. We are the first to perform a comprehensive study based on various glycation and oxidation factors, determining the impact of amantadine on protein glycoxidation. Sugars (glucose, fructose, galactose) and aldehydes (glyoxal, methylglyoxal) were used as glycation agents, and chloramine T was used as an oxidant. Glycoxidation biomarkers in albumin treated with amantadine were generally not different from the control group (glycation/oxidation factors), indicating that the drug did not affect oxidation and glycation processes. Molecular docking analysis did not reveal strong binding sites of amantadine on the bovine serum albumin structure. Although amantadine poorly scavenged hydroxyl radical and hydrogen peroxide, it had significantly lower antioxidant and antiglycation effect than all protein oxidation and glycation inhibitors. In some cases, amantadine even demonstrated glycoxidant, proglycation, and prooxidant properties. In summary, amantadine exhibited weak antioxidant properties and a lack of antiglycation activity.
Assuntos
Antioxidantes , Produtos Finais de Glicação Avançada , Antioxidantes/química , Simulação de Acoplamento Molecular , Soroalbumina Bovina/química , Amantadina/farmacologiaRESUMO
This review focuses on the multiple and reciprocal relationships that exist between oxidative stress, hyperglycemia and diabetes and related metabolic disorders. Human metabolism uses most of the consumed glucose under aerobic conditions. Oxygen is needed in the mitochondria to obtain energy, as well as for the action of microsomal oxidases and cytosolic pro-oxidant enzymes. This relentlessly generates a certain amount of reactive oxygen species (ROS). Although ROS are intracellular signals necessary for some physiological processes, their accumulation leads to oxidative stress, hyperglycemia, and progressive resistance to insulin. A cellular pro-oxidant versus an antioxidant equilibrium would regulate ROS levels, but oxidative stress, hyperglycemia, and pro-inflammatory conditions feed back to each other and the relevance of the interconnections tends to increase those conditions. Hyperglycemia promotes collateral glucose metabolism through protein kinase C, polyols and hexosamine routes. In addition, it also facilitates spontaneous glucose auto-oxidation and the formation of advanced glycation end products (AGEs), which in turn interact with their receptors (RAGE). The mentioned processes undermine cellular structures, finally giving place to a progressively greater degree of oxidative stress with further hyperglycemia, metabolic alterations, and diabetes complications. NFκB is the major transcription factor involved in the expression of most of the pro-oxidant mediators, while Nrf2 is the major transcription factor regulating the antioxidant response. FoxO is also involved in the equilibrium, but its role is controversial. This review summarizes the key factors linking the diverse glucose metabolic routes enhanced in hyperglycemia with ROS formation and vice versa, emphasizing the role of the major transcription factors involved in the desirable balance between pro-oxidant and antioxidant proteins.
Assuntos
Antioxidantes , Hiperglicemia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Antioxidantes/metabolismo , Hiperglicemia/metabolismo , Estresse Oxidativo/fisiologia , Produtos Finais de Glicação Avançada/metabolismo , Glucose , Fatores de Transcrição/metabolismoRESUMO
Holarrhena pubescens is widely used in Indian and Chinese medicine in the treatment of diabetes. The current work determined the oral hypoglycemic and antidiabetic effects of seed extract in rats. The probable mechanism of action was evaluated in-vitro by α - glucosidase inhibition, glucose metabolism in insulinoma (INS-1) cells to reflect secretion of insulin, and protein glycation inhibition. Its potential for herb-drug interaction was evaluated in the cytochrome P450 3A4 (CYP3A4) inhibition assay. The seed extract increased serum insulin levels and reduced serum blood glucose levels in the oral glucose tolerance test. It also reduced the serum glucose levels in streptozocin-induced diabetes. The extract also inhibited α -glucosidase enzyme activity and demonstrated that it can increase the secretion of insulin from INS to 1-rat insulinoma cell line cells in-vitro in a concentration-dependent manner. However, it had a very weak inhibitory effect on protein glycation and it did not affect the activity of CYP3A4. The results of the study showed that H. pubescens seed extract increases insulin secretion and inhibits glucose absorption both in-vivo and in-vitro with a weak protein glycation inhibitory effect. The herb is devoid of CYP3A4 inhibitory effect indicating that it may not have pharmacokinetic interaction with the drug metabolized by this enzyme.
RESUMO
Cotoneaster species have gained significant importance in traditional Asian medicine for their ability to prevent and treat hyperglycemia and diabetes. Therefore, in this study, some aspects of the beneficial health effects of hydromethanolic extracts of C. bullatus, C. zabelii, and C. integerrimus leaves and fruits were evaluated, including their influence on α-glucosidase, α-amylase, and nonenzymatic protein glycation. The activity was investigated in relation to the polyphenolic profile of the extracts determined by UV-spectrophotometric and HPLC-PDA-fingerprint methods. It was revealed that all leaf and fruit extracts are a promising source of biological components (caffeic acid pseudodepsides, proanthocyanidins, and flavonols), and the leaf extracts of C. bullatus and C. zabelii contain the highest levels of polyphenols (316.3 and 337.6 mg/g in total, respectively). The leaf extracts were also the most effective inhibitors of digestive enzymes and nonenzymatic protein glycation. IC50 values of 8.6, 41.8, and 32.6 µg/mL were obtained for the most active leaf extract of C. bullatus (MBL) in the α-glucosidase, α-amylase, and glycation inhibition tests, respectively. In the kinetic study, MBL was displayed as a mixed-type inhibitor of both enzymes. The correlations between the polyphenol profiles and activity parameters (|r| > 0.72, p < 0.05) indicate a significant contribution of proanthocyanidins to the tested activity. These results support the traditional use of Cotoneaster leaves and fruits in diabetes and suggest their hydrophilic extracts be promising in functional applications.
Assuntos
Diabetes Mellitus , Proantocianidinas , Rosaceae , alfa-Amilases , alfa-Glucosidases/metabolismo , Frutas/metabolismo , Polifenóis/farmacologia , Antioxidantes/farmacologia , Extratos Vegetais/farmacologia , Rosaceae/metabolismo , Fenóis/farmacologia , Hipoglicemiantes/farmacologia , Flavonóis , Inibidores de Glicosídeo Hidrolases/farmacologiaRESUMO
Endophytes, microorganisms that live in the internal tissues and organs of the plants, are known to produce numerous bioactive compounds, including, at times, some phytochemicals of their host plant. For such reason, endophytes have been quoted as a potential source for discovering bioactive compounds, particularly, of medical interest. Currently, many non-communicable diseases are threatening global human health, noticeably: diabetes, neurodegenerative diseases, cancer, and other ailment related to chronic inflammation and ageing. Intriguingly, the pathogenesis and development of these diseases have been linked to an excessive formation and accumulation of advanced glycation end products (AGEs). AGEs are a heterogeneous group of compounds that can alter the conformation, function, and lifetime of proteins. Therefore, compounds that prevent the formation and consequent accumulation of AGEs (AntiAGEs compounds) could be useful to delay the progress of some chronic diseases, and/or harmful effects of undue AGEs accumulation. Despite the remarkable ability of endophytes to produce bioactive compounds, most of the natural antiAGEs compounds reported in the literature are derived from plants. Accordingly, this work covers 26 plant antiAGEs compounds and some derivatives that have been reported as endophytic metabolites, and discusses the importance, possible advantages, and challenges of using endophytes as a potential source of antiAGEs compounds.
Assuntos
Endófitos , Produtos Finais de Glicação Avançada , Endófitos/química , Fungos/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Humanos , Compostos Fitoquímicos/metabolismo , Plantas/químicaRESUMO
Ginseng (Panax ginseng and red ginseng) extract has been reported to inhibit the formation of advanced glycation end-products (AGEs); however, the potential inhibitory activity of its major constituents (ginsenosides) against AGE formation is still unknown. In the present study, we investigated the inhibitory effect of ginsenoside derivatives on AGE formation. Herein, we assessed the activity of 22 ginsenosides, most of which significantly inhibited fluorescent AGE formation. Notably, ginsenoside Rh2, ginsenoside Rh1, and compound K exhibited the most potent AGE inhibitory potential with IC50 values of 3.38, 8.42, and 10.85 µM, respectively. The structure- activity relationship revealed that the presence of sugar moieties, hydroxyl groups, and their linkages, and the stereostructure of the ginsenoside skeleton played an important role in the inhibition of AGE formation. Furthermore, the inhibitory activity of the most active ginsenoside Rh2 on fructose-glucose-mediated protein glycation and oxidation of bovine serum albumin (BSA) was explored. Rh2 (0.1-12.5 µM) inhibited the formation of fluorescent AGE and non-fluorescent AGE, as well as the level of fructosamine and prevented protein oxidation by decreasing protein carbonyl formation and protein thiol group modification. Rh2 also suppressed the formation of the ß-cross amyloid structure of BSA. Ginsenosides might be promising new anti-glycation agents for the prevention of diabetic complications via inhibition of AGE formation and oxidation-dependent protein damage.
Assuntos
Descoberta de Drogas , Ginsenosídeos/farmacologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Panax/química , Soroalbumina Bovina/antagonistas & inibidores , Animais , Bovinos , Relação Dose-Resposta a Droga , Frutose/metabolismo , Ginsenosídeos/química , Ginsenosídeos/isolamento & purificação , Glucose/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Glicosilação/efeitos dos fármacos , Estrutura Molecular , Soroalbumina Bovina/metabolismo , Relação Estrutura-AtividadeRESUMO
Technical failures lead to deviations in process parameters that can exceed studied process boundaries. The impact on cell and target protein is often unknown. However, investigations on common technical failures might yield interesting insights into process and protein robustness. Recently, we published a study on the impact of technical failures on an inclusion body process that showed high robustness due to the inherent stability of IBs. In this follow-up study, we investigated the influence of technical failures during production of two soluble, cytosolic proteins in E. coli BL21(DE3). Cell physiology, productivity and protein quality were analyzed, after technical failures in aeration, substrate supply, temperature and pH control had been triggered. In most cases, cell physiology and productivity recovered during a subsequent regeneration phase. However, our results highlight that some technical failures lead to persistent deviations and affect the quality of purified protein.
Assuntos
Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , SolubilidadeRESUMO
Protein function and flexibility is directly related to the native distribution of its structural elements and any alteration in protein architecture leads to several abnormalities and accumulation of misfolded proteins. This phenomenon is associated with a range of increasingly common human disorders, including Alzheimer and Parkinson diseases, type II diabetes, and a number of systemic amyloidosis characterized by the accumulation of amyloid aggregates both in the extracellular space of tissues and as intracellular deposits. Post-translational modifications are known to have an active role in the in vivo amyloid aggregation as able to affect protein structure and dynamics. Among them, a key role seems to be played by non-enzymatic glycation, the most unwanted irreversible modification of the protein structure, which strongly affects long-living proteins throughout the body. This study provided an overview of the molecular effects induced by glycation on the amyloid aggregation process of several protein models associated with misfolding diseases. In particular, we analyzed the role of glycation on protein folding, kinetics of amyloid formation, and amyloid cytotoxicity in order to shed light on the role of this post-translational modification in the in vivo amyloid aggregation process.
Assuntos
Amiloide/metabolismo , Metabolismo dos Carboidratos , Agregados Proteicos , Agregação Patológica de Proteínas , Animais , HumanosRESUMO
Protein glycation is an important protein post-translational modification and is one of the main pathogenesis of diabetic angiopathy. Other than glycated hemoglobin, the protein glycation of other globins such as myoglobin (Mb) is less studied. The protein glycation of human Mb with ribose has not been reported, and the glycation sites in the Mb remain unknown. This article reports that d-ribose undergoes rapid protein glycation of human myoglobin (HMb) at lysine residues (K34, K87, K56, and K147) on the protein surface, as identified by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) and electrospray ionization tandem mass spectrometry (ESI-MS/MS). Moreover, glycation by d-ribose at these sites slightly decreased the rate of the met heme (FeIII) in reaction with H2O2 to form a ferryl heme (FeIV=O). This study provides valuable insight into the protein glycation by d-ribose and provides a foundation for studying the structure and function of glycated heme proteins.
Assuntos
Compostos Férricos/química , Heme/química , Peróxido de Hidrogênio/química , Mioglobina/química , Ribose/química , Cromatografia Líquida , Glicosilação , Humanos , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Methanolic leaf extracts of four Lauraceae species endemic to Laurisilva forest (Apollonias barbujana, Laurus novocanariensis, Ocotea foetens and Persea indica) were investigated for the first time for their potential to inhibit key enzymes linked to type-2 diabetes (α-amylase, α-glucosidase, aldose reductase) and obesity (pancreatic lipase), and protein glycation. Lauraceae extracts revealed significant inhibitory activities in all assays, altough with different ability between species. In general, P. indica showed the most promissing results. In the protein glycation assay, all analysed extracts displayed a stronger effect than a reference compound: aminoguanidine (AMG). The in vitro anti-diabetic, anti-obesity and anti-glycation activities of analysed extracts showed correlation with their flavonols and flavan-3-ols (in particular, proanthocyanins) contents. These Lauraceae species have the capacity to assist in adjuvant therapy of type-2 diabetes and associated complications, through modulation of the activity of key metabolic enzymes and prevention of advanced glycation end-products (AGEs) formation.
Assuntos
Biomarcadores , Diabetes Mellitus Tipo 2/metabolismo , Glicoproteínas/metabolismo , Hipoglicemiantes/farmacologia , Lauraceae/química , Obesidade/metabolismo , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Aldeído Redutase/antagonistas & inibidores , Aldeído Redutase/química , Animais , Diabetes Mellitus Tipo 2/enzimologia , Diabetes Mellitus Tipo 2/etiologia , Florestas , Glicosilação , Hipoglicemiantes/química , Redes e Vias Metabólicas , Estrutura Molecular , Obesidade/enzimologia , Obesidade/etiologia , Fenóis/química , Extratos Vegetais/química , RatosRESUMO
The interaction of reducing sugars with proteins leads to the formation of advanced glycation end products (AGE) and reactive oxidative species (ROS). ROS peroxidise free or membrane included unsaturated fatty acids, leading to generate reactive aldehydes as advanced lipid peroxidation end products (ALE). Aldehydes from lipid peroxidation (LPO) react with proteins to cause alteration of protein structure to exacerbate complication of diseases. Here we studied serum albumin glycation in the presence and absence of liposomes as a bio-membrane model to investigate protein structural changes using various techniques including intrinsic and extrinsic fluorescence spectroscopies and electron microscopy analysis. Accordingly, serum albumin glycation and fibrillation were accelerated and intensified in the presence of liposomes through a hypothesized glycation-peroxidation loop (GPL). Together, our results shed light on the necessity of reconsidering diabetic protein glycation to make it close to physiological conditions mimicry, more importantly, proteins structural change due to diabetic glycation is intensified in the proximity of cell membranes which probably potentiates programmed cell death distinct from apoptosis.
Assuntos
Proteínas Amiloidogênicas/metabolismo , Produtos Finais de Glicação Avançada/metabolismo , Multimerização Proteica , Soroalbumina Bovina/metabolismo , 1,2-Dipalmitoilfosfatidilcolina/química , Proteínas Amiloidogênicas/química , Animais , Bovinos , Frutose/química , Produtos Finais de Glicação Avançada/química , Peróxido de Hidrogênio/química , Peroxidação de Lipídeos , Lipossomos/química , Oxirredução , Fosfatidilcolinas/química , Soroalbumina Bovina/químicaRESUMO
Hyperglycemia in diabetes causes protein glycation that leads to oxidative stress, release of cytokines, and establishment of secondary complications such as neuropathy, retinopathy, and nephropathy. Several other metabolic disorders, stress, and inflammation generate free radicals and oxidative stress. It is essential to study whether oxidative stress independently enhances protein glycation leading to rapid establishment of secondary complications. Oxidative stress was experimentally induced using rotenone and Fenton reagent for in vivo and in vitro studies, respectively. Results showed significant increase in the rate of modification of BSA in the form of fructosamine and protein-bound carbonyls in the presence of fenton reagent. Circular dichroism studies revealed gross structural changes in the reduction of alpha helix structure and decreased protein surface charge was confirmed by zeta potential studies. Use of rotenone demonstrated enhanced AGE formation, ROS generation, and liver and kidney tissue glycation through fluorescence measurement. Similar findings were also observed in cell culture studies. Use of aminoguanidine, a protein glycation inhibitor, demonstrated reduction in these changes; however, a combination of aminoguanidine along with vitamin E demonstrated better amelioration. Thus, oxidative stress accelerates the process of protein glycation causing gross structural changes and tissue glycation in insulin-independent tissues. Use of antioxidants and protein glycation inhibitors in combination are more effective in preventing such changes and could be an effective therapeutic option for preventing establishment of secondary complications of diabetes.
Assuntos
Antioxidantes/farmacologia , Produtos Finais de Glicação Avançada/antagonistas & inibidores , Guanidinas/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Rotenona/farmacologia , Animais , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Complicações do Diabetes/prevenção & controle , Produtos Finais de Glicação Avançada/metabolismo , Masculino , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoRESUMO
The reaction of free amino groups in proteins with reactive carbonyl species, known as glycation, leads to the formation of mixtures of products, collectively referred to as advanced glycation endproducts (AGEs). These compounds have been implicated in several important diseases, but their role in pathogenesis and clinical symptoms' development is still debated. Particularly, AGEs are often associated to the formation of amyloid deposits in conformational diseases, such as Alzheimer's and Parkinson's disease, and it has been suggested that they might influence the mechanisms and kinetics of protein aggregation. We here present the characterization of the products of glycation of the model protein MNEI with methylglyoxal and their effect on the protein structure. We demonstrate that, despite being an uncontrolled process, glycation occurs only at specific residues of the protein. Moreover, while not affecting the protein fold, it alters its shape and hydrodynamic properties and increases its tendency to fibrillar aggregation. Our study opens the way to in deep structural investigations to shed light on the complex link between protein post-translational modifications, structure, and stability.
Assuntos
Amiloide/química , Proteínas de Plantas/química , Agregados Proteicos , Processamento de Proteína Pós-Traducional , Aldeído Pirúvico/química , Glicosilação , Proteínas de Plantas/metabolismo , Aldeído Pirúvico/metabolismoRESUMO
Prolonged exposure to ultraviolet (UV) radiation causes photoaging of the skin and induces a number of disorders, including sunburn, fine and coarse wrinkles, and skin cancer risk. Therefore, the application of sunscreen has gained much attention to reduce the harmful effects of UV irradiation on our skin. Recently, there has been a growing demand for the replacement of chemical sunscreens with natural UV-absorbing compounds. Mycosporine-like amino acids (MAAs), promising alternative natural UV-absorbing compounds, are a group of widely distributed, low molecular-weight, water-soluble molecules that can absorb UV radiation and disperse the absorbed energy as heat, without generating reactive oxygen species (ROS). More than 30 MAAs have been characterized, from a variety of organisms. In addition to their UV-absorbing properties, there is substantial evidence that MAAs have the potential to protect against skin aging, including antioxidative activity, anti-inflammatory activity, inhibition of protein-glycation, and inhibition of collagenase activity. This review will provide an overview of MAAs, as potential anti-aging ingredients, beginning with their structure, before moving on to discuss the most recent experimental observations, including the molecular and cellular mechanisms through which MAAs might protect the skin. In particular, we focus on the potential anti-aging activity of mycosporine-2-glycine (M2G).
Assuntos
Aminoácidos/farmacologia , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Cicloexanóis/farmacologia , Glicina/análogos & derivados , Envelhecimento da Pele/efeitos dos fármacos , Pele/efeitos dos fármacos , Animais , Glicina/farmacologia , HumanosRESUMO
Glycation can be defined as an array of non-enzymatic post-translational modifications of proteins formed by their interaction with reducing carbohydrates and carbonyl products of their degradation. Initial steps of this process rely on reducing sugars and result in the formation of early glycation products-Amadori and Heyns compounds via Schiff base intermediates, whereas their oxidative degradation or reactions of proteins with α-dicarbonyl compounds yield a heterogeneous group of advanced glycation end products (AGEs). These compounds accompany thermal processing of protein-containing foods and are known to impact on ageing, pathogenesis of diabetes mellitus and Alzheimer's disease in mammals. Surprisingly, despite high tissue carbohydrate contents, glycation of plant proteins was addressed only recently and its physiological role in plants is still not understood. Therefore, here we summarize and critically discuss the first steps done in the field of plant protein glycation during the last decade. We consider the main features of plant glycated proteome and discuss them in the context of characteristic metabolic background. Further, we address the possible role of protein glycation in plants and consider its probable contribution to protein degradation, methylglyoxal and sugar signalling, as well as interplay with antioxidant defense.