br Conclusion br Acknowledgments br Introduction The gyloxal

Conclusion
Acknowledgments
Introduction The gyloxalase pathway is a well-conserved antioxidant defense system found in all cells of the body [1], [2], [3], [4]. The glyoxalase pathway facilitates the neutralization of highly reactive and oxidizing dicarbonyl molecules, with methylglyoxal (MG) being the most critical target [5]. Carbonyl molecules target the dilution equation due to its high rate of metabolism and low antioxidant defense capacity [6]. The brain also contains high concentrations of oxidizable substrates including polyunsaturated fats and metal ions [7]. Accumulation of MG damages and influences the cellular environment, leading to a state of chronic inflammation and oxidative stress [4], [5], [8], [9], [10], [11], [12]. The glyoxalase system is present in all cells in the body, but has especially important functions in the brain [3], [13] Oxidative stress (OS) results from an imbalance between electrophilic prooxidative molecules and the capacity of antioxidants to reduce and neutralize the free radicals [14]. It is a chronic state of inflammation that prevents the proper function of integral cellular processes, causing irreversible damage to cells [10], [14], [15]. Excessive oxidative stress in the brain leads to accelerated aging, and impacts the severity of neurodegenerative diseases [16], [17]. High levels of oxidative stress influence the onset and progression of aging, Alzheimer's disease (AD), Parkinson's disease (PD), and autism spectrum disorder (ASD) [18], [19]. Efficient and active function of the glyoxalase pathway is critical to reducing oxidative stress mediated damage to brain cells [20], [21], [22], [23], [24]. Flavonoid antioxidant compounds possess the capacity to enhance the glyoxalase pathway through several distinct mechanisms, including modulation of critical signaling pathways involved in cell proliferation [25], [26], [27] OS and inflammation gradually increase during aging [28], [29]. However, high levels of OS and inflammation can accrue over time and are contributing factors to aging and neurodegenerative diseases including AD, PD, ASD, dementia, and psychiatric disorders [1], [30]. Hallmarks of these diseases are also shared in glyoxalase pathway dysfunction: increased reactive oxygen species (ROS) production, apoptosis, and oxidation of molecules [2], [9], [31], [32]. The onset and progression of neurodegenerative disease can be influenced by substituents of the glyoxalase pathway. For example, inhibition of glo 1 reduces neuronal viability and increases accumulation of advanced glycation endproducts (AGEs), while overexpression of glo 1 reduces formation of ROS [4], [21], [33], [34]. Aging is correlated with a decrease in glo 1 concentration and activity [16], [35]. Depletion of GSH by MG can prevent astrocytic detoxification of reactive molecules and lead to an increase in oxidized proteins, lipids, and amino acids [21], [36]. Increasing the capacity and efficiency of the glyoxalase pathway appears to be an effective means of reducing the onset and severity of aging and neurodegenerative disease [37].
Diseases of glyoxalase pathway Impaired function of the glyoxalase pathway – especially in the brain - has very serious ramifications for cells and tissue. Aging, Alzheimer's, and Parkinson's, (Fig. 2) are neurodegenerative diseases that can be caused or influenced by elevated levels of oxidative stress [4], [48], [49]. These diseases are complex and multifactorial, and can be a cause and consequence of disrupted glyoxalase pathway function. Increased levels of oxidative stress can be a result of glyoxalase system impairment [19], [50], [51] Psychiatric disorders like ASD, schizophrenia, anxiety, bipolar disorder, and depression can also be a cause/effect of impaired glyoxalase function [52], [53], [54] The glyoxlase pathway exerts control over antioxidant defense mechanisms that are paramount for homeostasis of the redox environment of the cell [55], [56] Disrupted function of the glyoxalase pathway can lead to an inflammatory environment contributing to the pathogenesis of neurodegenerative disease [23], [40]. MG can cause mutations of DNA and nucleic acids, culminating in telomere shortening, loss of heterochromatin, altered gene expression patterns, and mitochondrial dysfunction [23], [57], [58]