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Protein and DNA-advanced glycation end-products (DNA-AGEs) are toxic by-products of metabolism and are also assimilated by high temperature processed foods. AGEs may be generated rapidly or over long times stimulated by distinct triggering mechanisms, thereby accounting for their roles in multiple settings and disease states. Neurodegenerative dise...
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TAR DNA-binding protein 43 (TDP-43) inclusions have been found in Amyotrophic lateral sclerosis (ALS) and several other neurodegenerative diseases. Many studies suggest the involvement of RNA recognition motifs (RRMs) in TDP-43 proteinopathy. To elucidate the structural stability and the unfolding dynamics of RRMs, we have carried out atomistic mol...
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... The pathophysiological consequences of AGEs are mediated by reactive oxygen species (ROS), especially superoxide and hydrogen peroxide production. These pathological actions have also been mediated by cascade events of inflammation (Akhter et al. , 2016(Akhter et al. , 2017aLi et al. 2018;Shahab et al. 2014), which induces lowered glucose consumption, lowered ATP levels and down regulated mitochondrial activity that leads to the neuronal cell death (Kuhla et al. 2004). AGEs have been reported to impair the neuronal cells by cross linking with the substrates, resulting an increased Aβ deposition in AD (Yan et al. 2008). ...
Alzheimer’s disease (AD) is the most common irreversible, progressive brain disorder which causes problems with memory, thinking and behavior with the age. Alzheimer's is the sixth leading cause of death in the United States. Combination of genetic, environmental factors like; chemical radiations, toxicants and mutagens are the main causes for neurodegeneration. Including with these factors some other events can produce early stages of AD, known as early stage AD, and lead to the same eventual distinctive final pathways in the late stages. Such stages could be characterized by neuroinflammation, oxidative stress and neurodegeneration. Furthermore, advanced glycation end products (AGEs) exacerbate amyloid beta (Aβ) has shown enhanced neurotoxicity. Considering these factors, we reinvestigated the role of AGE–RAGE interaction in AD pathology. Accumulation of AGEs is a normal feature of aging, but it becomes impaied in AD. AGEs are prominent in amyloid plaques and neurofibrillary tangles. Several lines of evidences demonstrate that AGE-RAGE interactions are critical for disease pathogenesis and it is at least partially responsible for extensive oxidative stress, inflammation, and neurodegeneration. Therefore many in vitro, in vivo and clinical studies have been focused on AGE–RAGE inhibitors, although their undesirable side effects and solubility issues may limits the usage. Therefore, it is needed to develop a potential, effective and multi-targeted inhibitors in order to prevent AGE induced neurological disorder.
... The pathophysiological consequences of AGEs are mediated by reactive oxygen species (ROS), especially superoxide and hydrogen peroxide production. These pathological actions have also been mediated by cascade events of inflammation (Akhter et al. , 2016(Akhter et al. , 2017aLi et al. 2018;Shahab et al. 2014), which induces lowered glucose consumption, lowered ATP levels and down regulated mitochondrial activity that leads to the neuronal cell death (Kuhla et al. 2004). AGEs have been reported to impair the neuronal cells by cross linking with the substrates, resulting an increased Aβ deposition in AD . ...
Nanotechnology, a science dealing with particles at nano scale, is currently used in many fields including environmental management and medicine for welfare of human being. The economic development and quality of life have been improved through nanotechnology. The Polycyclic aromatic hydrocarbons (PAHs) and other toxicants have higher affinity to scaveng by nanopartilces. The structural properties and surface chemistry of nanoparticles are the players, further, extremely high surface area to volume ratio results in multiple enhancement of many beneficial properties. Hence, we have followed a methodology to compare the binding efficiency of nanoparticles and cigarette smoke carcinogens with selected enzymes involved in DNA repair pathways. The molecular interactions have been accomplished using PatchDock server and interestingly got significant interacting results for our hypothesis. PatchDock results showed nanoparticles could be able to trap cigarette smoke carcinogens efficiently in the cellular system. The highest obtained binding efficiency between 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) versus Single wall carbon nanotube (SWcNT) is 2632 score in contrast with NNK versus Human MDC1 BRCT T2067D in complex (PDB ID: 3K05) shows 2454 score, which means NNK could interact with SWcNT more efficiently than 3K05. Another part of the study shows that the highest binding efficiency 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) versus SWcNT = 2746 score and NNAL versus Titanium dioxide (TiO2) Rutile = 2110 score in contract with NNAL versus Human Thymine DNA Glycosylase(PDB ID: 2RBA) shows 1696 score. It is also signified that NNAL interact with SWcNT and TiO2 rutile more efficiently than 2RBA. The results clearly signifying that SWcNT/TiO2 are binding with NNK/NNAL more efficiently than biomolecules.
... The induced level of stress from AGEs, ROS, and dicarbonyl overproductions results in prolonged inflammation, which offers an appropriate microenvironment for tumor growth. Additionally, it endorses cancer inception in regular tissues such as liver, pancreas, prostate, and colon through stress dependent DNA damage and a surplus of inflammatory response and various cytokines generations [105]. ...
Oxidative, carbonyl, and glycative stress have gained substantial attention recently for their alleged influence on cancer progression. Oxidative stress can trigger variable transcription factors, such as nuclear factor erythroid-2-related factor (Nrf2), nuclear factor kappa B (NF-κB), protein-53 (p-53), activating protein-1 (AP-1), hypoxia-inducible factor-1α (HIF-1α), β-catenin/Wnt and peroxisome proliferator-activated receptor-γ (PPAR-γ). Activated transcription factors can lead to approximately 500 different alterations in gene expression, and can alter expression patterns of inflammatory cytokines, growth factors, regulatory cell cycle molecules, and anti-inflammatory molecules. These alterations of gene expression can induce a normal cell to become a tumor cell.
Glycative stress resulting from advanced glycation end products (AGEs) and reactive dicarbonyls can significantly affect cancer progression. AGEs are fashioned from the multifaceted chemical reaction of reducing sugars with a compound containing an amino group. AGEs bind to and trigger the receptor for AGEs (RAGE) through AGE-RAGE interaction, which is a major modulator of inflammation allied tumors. Dicarbonyls like, GO (glyoxal), MG (methylglyoxal) and 3-DG (3-deoxyglucosone) fashioned throughout lipid peroxidation, glycolysis, and protein degradation are viewed as key precursors of AGEs. These dicarbonyls lead to the carbonyl stress in living organisms, possibly resulting in carbonyl impairment of proteins, carbohydrates, DNA, and lipoproteins. The damage caused by carbonyls results in numerous lesions, some of which are involved in cancer pathogenesis. In this review, the effects of oxidative, carbonyl and glycative stress on cancer initiation and progression are thoroughly discussed, including probable signaling pathways and the effects on tumorigenesis.
Alzheimer’s disease (AD) is the most common and important reason for dementia in the elderly. Amyloid-β (Aβ) is reported to play an important role in the genesis of AD. It has been confirmed that Aβ is a suitable substrate for glycation, while glycative stress induced by Aβ is also confirmed in AD patients’ brains. Glycation-induced reactive oxygen species (ROS) generation, neuronal inflammation, and apoptosis are the key pathological points of this disorder, but the main signaling pathways are not well understood. Although Nelumbo nucifera contains many bioactive compounds such as rutin, isoorientin, orientin, isoquercitrin, and hyperoside, ascorbic acid (vitamin C) is a potential compound due to its water-soluble, highly antioxidant property and is a commonly consumed dietary supplement. Here we elucidate the antiglycative and oxidative stress (antiadvanced glycation end product, anti-ROS) role of ascorbic acid in the promotion of healthy brain aging. To develop antidementia drugs with potential therapeutic value, ascorbic acid has already been examined as a depleting agent of Aβ peptide (Aβ1−42, A1−40) and an antiinflammatory agent (inhibition of interleukin [IL]-1 and IL-6, and tumor necrosis factor-α). This chapter discusses the beneficial effect of N. nucifera and its constituents in the pathogenesis of AD and highlights its therapeutic potential against glycoxidative and Aβ stress-induced AD pathology.
Glycation refers to the covalent binding of sugar molecules to macromolecules, such as DNA, proteins, and lipids in a non-enzymatic reaction, resulting in the formation of irreversibly bound products known as advanced glycation end products (AGEs). AGEs are synthesized in high amounts both in pathological conditions, such as diabetes and under physiological conditions resulting in aging. The body’s anti-glycation defense mechanisms play a critical role in removing glycated products. However, if this defense system fails, AGEs start accumulating, which results in pathological conditions. Studies have shown that increased accumulation of AGEs acts as key mediators in multiple diseases, such as diabetes, obesity, arthritis, cancer, atherosclerosis, decreased skin elasticity, male erectile dysfunction, pulmonary fibrosis, aging, and Alzheimer’s disease. Further, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), cause potential damage to the genome, proteome, and lipidome. Glyoxalase-1 (GLO-1) acts as a part of the anti-glycation defense system by carrying out detoxification of GO and MGO. It has been demonstrated that GLO-1 protects dicarbonyl modifications of the proteome and lipidome, thereby impeding the cell signaling and affecting age-related diseases. Its relationship with detoxification and antiglycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide the evidence for the rationale that the functional modulation of GLO pathway could be used as a potential therapeutic target. In the present review, we summarize the newly emerged literature on GLO pathway including enzymes regulating the process. In addition, we describe small bioactive molecules with the potential to modulate the GLO pathway, thereby providing a basis for the development of new treatment strategies against age-related complications.
Advanced glycation end-products (AGEs) have been implicated in chronic hyperglycemia and age-related diseases. Endogenous AGEs produced by humans generate oxidative stress and activation of inflammatory signaling pathways via AGE-specific receptors. The present review summarizes current knowledge on the pathogenic role of AGEs in chronic noncommunicable diseases. Although correlations exist between glycation and the pathogenesis of these diseases, uncertainties remain in light of recurrent intervention failures of apparently promising animal models to be translated into clinically useful anti-AGE strategies. Future intervention of AGEs or their receptors should embrace more carefully executed clinical trials. Nevertheless, suppressing symptoms via lifetime drug application is unlikely to eliminate the burden of chronic diseases unless deep-rooted lifestyle issues that cause these diseases are simultaneously addressed.
