RESUMO
SCOPE: Activation of microglia, the resident immune cells of the central nervous system, has been related to the etiology and progression of neurodegenerative diseases; thus, finding novel approaches to suppress the neuroinflammatory process is of utmost relevance. METHODS AND RESULTS: The anti-inflammatory activity of whey Cu-, Fe-, and Zn-binding peptides and their possible underlying mechanism of action were evaluated in microglia. Whey metal-binding peptides decreased nitric oxide production and tumor necrosis factor α (TNF-α) at mRNA and protein levels by stimulated BV-2 microglia in comparison to the control with no peptide treatment. The hydrophobicity, specific sequences, and possible synergistic effects seem to play a role. Cu-binding peptides (Cu-bp) presented anti-inflammatory activity both in BV-2 and primary microglia cultures. These peptides exert their action by suppressing nuclear factor kappa B (NF-kB) pathway since nuclear translocation of NF-kB p65 is decreased by roughly 30% upon Cu-bp treatment. Specific sequences identified in Cu-bp showed high affinity to bind NF-kB p65 by molecular docking (up to -8.8 kcal mol-1 ), corroborating the immunofluorescence studies. CONCLUSION: Cu-bp represent food-derived peptides that may be useful for neuroprotective purposes. Chelation of copper excess in the CNS and the bioavailability of such peptides, as well as their behavior in in vivo models, deserve further research for future applications.
Assuntos
Microglia , NF-kappa B , Cobre/metabolismo , Cobre/farmacologia , Humanos , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Microglia/metabolismo , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-ß (Aß) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-ß protein precursor (AßPP) and Aß42 peptide, affecting Aß aggregation and increasing its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Quelantes/química , Quelantes/uso terapêutico , Polifenóis/química , Polifenóis/uso terapêutico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Quelantes/metabolismo , Quelantes/farmacologia , Cobre/metabolismo , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Polifenóis/metabolismo , Polifenóis/farmacologia , Zinco/metabolismoRESUMO
BACKGROUND: Melatonin is well known for its antioxidant capacity, which has been attributed to the combined protective effects of the parent molecule and its metabolites. However, the potential role of 2-hydroxymelatonin (2OHM) and 4-hydroxymelatonin (4OHM) in such protection has not been previously investigated. METHODS: The calculations were performed using the Density Functional Theory, with the M05-2X and M05 functionals, the 6-311+G(d,p) basis set and the solvation model based on density (SMD). RESULTS: 4OHM shows excellent antioxidant activity via radical-trapping, reacting with peroxyl radicals faster than Trolox and melatonin. 4OHM can be moderately efficient as a preventing antioxidant by inhibiting Cu(II). This effect would lower the Cu(I) availability, which is the redox state required for the OH to be formed, via Fenton-like reactions. 4OHM turns off the oxidant effects of copper-ascorbate mixtures. The presence of a phenolic group was identified as the key structural feature in the antioxidant activity of 4OHM. On the other hand, 2OHM does not present a phenolic group, despite its formal name. Its keto tautomer was identified as the most abundant one (~100%). This may explain the relative low antioxidant protection of 2OHM. CONCLUSIONS: 4OHM significantly contributes to the overall antioxidant activity exhibited by melatonin, while the effects of 2OHM in this context are predicted to be only minor. This low reactivity might justify the relatively large abundance of 2OHM in biological systems. GENERAL SIGNIFICANCE: Hydroxylated melatonin metabolites, such as 4OHM, may play an important role in the protective effects of melatonin against oxidative stress.
Assuntos
Antioxidantes/farmacologia , Sequestradores de Radicais Livres/farmacologia , Melatonina/análogos & derivados , Melatonina/farmacologia , Estresse Oxidativo , Melatonina/metabolismoRESUMO
Diabetes Mellitus (DM) is characterized by elevated blood glucose levels (hyperglycemia). It can occur due to impaired secretion or action of the hormone insulin, which is produced by pancreatic beta-cells to promote the entry of glucose into the cells. It is known that hyperglycemia has an important role in the production of reactive oxygen species in all types of DM and that an imbalance of transition metal as Cu and Fe plays a pivotal role in stimulating the oxidative stress. Different levels of some transition metals, as Cu, Fe, Mn, and Zn has been reported comparing diabetic animal models with the control group. An increased Cu status is also described in diabetic patients. Homeostasis of Cu depends on distinct proteins, where Cu(I)-ATPases are important transmembrane proteins for acquisition, active transport, distribution and elimination of Cu ions. In this review we first provide an overview of the literature about the relationship between diabetes and copper, the modulation of Cu(I)-ATPases activity and protein expression in DM, to next discuss the alternative treatments for diabetes using Cu chelation. © 2016 IUBMB Life, 69(4):255-262, 2017.
Assuntos
Adenosina Trifosfatases/metabolismo , Cobre/metabolismo , Diabetes Mellitus/metabolismo , Hiperglicemia/metabolismo , Adenosina Trifosfatases/genética , Animais , Diabetes Mellitus/patologia , Homeostase , Humanos , Hiperglicemia/patologia , Ferro/metabolismo , Manganês/metabolismo , Estresse Oxidativo , Zinco/metabolismoRESUMO
There is currently no doubt about the serious threat that oxidative stress (OS) poses to human health. Therefore, a crucial strategy to maintain a good health status is to identify molecules capable of offering protection against OS through chemical routes. Based on the known efficiency of the phenolic and melatonin (MLT) families of compounds as antioxidants, it is logical to assume that phenolic MLT-related compounds should be (at least) equally efficient. Unfortunately, they have been less investigated than phenols, MLT and its non-phenolic metabolites in this context. The evidence reviewed here strongly suggests that MLT phenolic derivatives can act as both primary and secondary antioxidants, exerting their protection through diverse chemical routes. They all seem to be better free radical scavengers than MLT and Trolox, while some of them also surpass ascorbic acid and resveratrol. However, there are still many aspects that deserve further investigations for this kind of compounds.