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  • br Conclusions Both NAD and AcCoA are cellular metabolic int


    Conclusions Both NAD+ and AcCoA are cellular metabolic intermediates that are essential for amino acids, fatty-acids, and bioenergetic metabolism. Furthermore, they influence gene expression by serving as cofactors for epigenetic modifiers mediating post-translational alterations of histone and non-histone proteins. Thus, the concentrations of AcCoA and NAD+ affect the acetylation levels of proteins controlling transcriptional regulation and metabolic status. As we discussed both NAD+ and AcCoA metabolism is disturbed following ischemic stress and there is a complex interplay between downstream effects due to imbalance in NAD+ and AcCoA homeostasis. The majority of AcCoA is generated via NAD+ dependent processes from pyruvate resulting in an intimate relationship between the mechanisms involved in NAD+, AcCoA metabolism, and mitochondrial function and dynamics. Due to the complexity of post-ischemic pathology that involves changes in almost every metabolic pathway, a successful treatment strategy will need to comprise of a multi-targeted approach, using KRN7000 that affects multiple pathways. Administration of intermediates that can modulate the post-insult NAD+ and AcCoA levels represents a promising way to manipulate several pathways since these metabolites are involved in many enzymatic reactions and also play a significant role in regulating enzymes activity and gene expression via post-translational modifications.
    Conflict of interests
    Transparency document
    Acknowledgements This work was supported by U.S. Department of Veterans Affairs Merit award BX000917 to TK.
    Introduction Mercury (Hg) exposure remains a major public health concern as the metal is present in the environment due to both natural and anthropogenic sources. Within the environment, Hg occurs as both inorganic (elemental or Hg0, Hg+ or Hg2+) and organic compounds, such as methylmercury (MeHg) [1]. Organic mercurials, such as MeHg, have received extensive attention due to their ability to cause congenital effects, leading to the development of characteristic neurological symptoms, including mental retardation, cerebellar ataxia and cerebral palsy, commonly characterized as Fetal Minamata disease (FMD) [2,3]. In adults, toxic effects of environmental level of MeHg are characterized by a long latency period before the appearance of neurotoxic symptoms, which include weight loss, blurred vision and paresthesia, followed by visual field constriction and ataxia [4]. MeHg is produced by biomethylation of inorganic mercury present in aquatic sediments, a reaction catalyzed primarily by aquatic microorganisms [5]. It accumulates up the aquatic food chain, and reaches maximal concentrations in long-lived, predatory fish such as tuna, swordfish, shark and whale [5]. As a consequence, MeHg toxicity represents an ongoing environmental problem to human health, especially in susceptible populations whose diet consists largely of fish and other seafood products [1,6]. As mentioned previously, seafood is the main source of MeHg in the human diet, and about 95% of that ingested is absorbed in the gastrointestinal tract [7]. After absorption, MeHg is ubiquitously distributed, and readily penetrates the central nervous system (CNS) [8]. It can distribute to all brain regions by crossing the blood–brain barrier via the neutral amino acid transport system l as a complex with l‑cysteine [9]. The brain has high affinity for MeHg, and concentrations can be 3–6 times greater than those found in blood [10]. In fact, it is well documented that the brain is particularly vulnerable to MeHg, especially the developing CNS [[11], [12], [13]]. In this regard, the most susceptible brain regions to MeHg-mediated injury are the brain cortex and the cerebellum, with particular susceptibility exhibited by cerebellar granule cells (CGC) [2]. The neurotoxic effects of MeHg are largely related to its pro-oxidative properties. MeHg is a soft electrophile that has extremely high affinity for nucleophilic thiol (SH) and selenol (SeH) groups, which plays a fundamental role in MeHg-induced toxicity. Indeed, the high affinity of MeHg for SH and SeH groups on amino acids such as cysteine and selenocysteine may block critical (catalytic) functional groups and/or alter the structure of a large number of proteins [14], leading to disruption of various intracellular functions, including elevations of reactive oxygen species (ROS) [[15], [16], [17]].