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Advanced Glycation and Aging
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
There are several lines of evidence indicating that aging is accompanied by epigenetic changes, and that epigenetic changes can provoke progeroid syndromes. Additionally, sirtuin 6 is an epigenetically relevant enzyme whose loss-of-function reduces longevity and whose gain-of-function extends longevity in mice. It appears that understanding and manipulating the epigenome may result in improvement of age-related pathologies and extending healthy lifespan. Epigenetic changes include modifications in DNA methylation patterns, post-translational modification of histones and chromatin remodeling. The evidence of the role of glycation in epigenetics is indirect and based on cell culture or animal studies. Indeed, histones are target for glycation based on their chemistry, they are basic proteins very rich in lysine and arginine. Amadori glycation of individual histones was demonstrated very early in vitro (Lakatos and Jobst 1991, De Bellis and Horowitz 1987). Thereafter, the author’s group was the first to show that intact nucleosomes were easily glycated in vitro and accumulated AGE (Gugliucci 1994). Others showed ADP ribosylation of histones (Cervantes-Laurean et al. 1993) and we later on demonstrated dramatically increased AGE on histones from diabetic rats (Gugliucci and Bendayan 1995). Histones from the liver of diabetic rats showed AGE levels three-fold higher than those of their age-matched controls. Histone AGE increased with the duration of diabetes and tended to increase with the age as well, even when this was a short-term study (Gugliucci and Bendayan 1995). Histones are then an easy target for glycation as they protect DNA from it. The author’s group suggested a possible role for intracellular glycation in the increased theratogeny associated with diabetes mellitus due to this epigenetic change. Regulatory survival information may be encoded epigenetically by levels of histone lysine acetylation/acylation and lysine is a key target for glycation. Is that epigenetic change repaired? Does it interfere with the critical regulation pathways enunciated above? Is the continuous onslaught of electrophils on histones a player in aging through disrupted epigenetic changes? We believe these questions deserve exploration in future studies.
α-Hederin inhibits the growth of lung cancer A549 cells in vitro and in vivo by decreasing SIRT6 dependent glycolysis
Published in Pharmaceutical Biology, 2021
Cong Fang, Yahui Liu, Lanying Chen, Yingying Luo, Yaru Cui, Ni Zhang, Peng Liu, Mengjing Zhou, Yongyan Xie
Reprogramming energy metabolism is a hallmark of cancer. Energy metabolism is the process in which energy is generated from nutrients, released, stored, and consumed by organisms or living cells. Energy metabolism is divided into glucose metabolism, protein metabolism, and fat metabolism. Under normal conditions, cells generate energy primarily via aerobic respiration. When the oxygen content is insufficient, cells perform glycolysis to generate energy. This process is called anaerobic respiration. Unlike normal cells, tumour cells generate energy primarily via glycolysis, even under aerobic conditions, a phenomenon known as the Warburg effect. Glycolytic capacity is characterized by rapid productivity and low efficiency. The rapid proliferation of tumour cells requires rapid energy consumption. Meanwhile, the lactic acid generated by glycolysis creates an acidic environment for tumour cells, which is conducive to their growth and leads to their rapid proliferation (Zhao et al. 2014; Potter et al. 2016). Sirtuin 6 (SIRT6) protein is a chromatin binding factor that was initially described as an inhibitor of gene instability (Mostoslavsky et al. 2006). During energy metabolism, SIRT6 regulates the fat and glucose metabolism, which is a key regulator of energy stress and is closely related to the process of tumour growth (Sebastián and Mostoslavsky 2015). With the metabolic profile used for energy production is elucidated, regulating tumour metabolism is a new therapeutic strategy to inhibit tumour growth (Zhang and Yang 2013).
Sirtuins: potential therapeutic targets for regulating acute inflammatory response?
Published in Expert Opinion on Therapeutic Targets, 2020
Vidula Vachharajani, Charles E. McCall
Taken together, many studies support that both shifts in redox and activation of sirtuins by NAD direct immuno-metabolic and bioenergy shifts during sepsis. Excessive induction of ROS and NOS breaks down mitochondria and nuclear DNA, which within and without cells further activates hyper-inflammatory injury [55]. Nuclear sirtuin 6 promotes nuclear DNA repair [56]. Summary: Sirtuins play a critical role in controlling immuno-metabolic and energy reprogramming at multiple levels during sepsis, including epigenetics, transcription, post translational modifications, and shifts in the redox code. Importantly, sirtuin 1 and 2 are emerging as potential druggable targets for promoting homeostasis during the acute inflammatory responses of sepsis in lean and obese mice, respectively.
Hidden allosteric sites and De-Novo drug design
Published in Expert Opinion on Drug Discovery, 2022
Ashfaq Ur Rehman, Shaoyong Lu, Abdul Aziz Khan, Beenish Khurshid, Salman Rasheed, Abdul Wadood, Jian Zhang
Sirtuin 6 (Sirt6) is a histone deacetylase, transferring the acetyl group to NAD+ from the side-chain of residue lysine of a protein [97]. Several biological processes, i.e. DNA repairs, organ metabolism, aging and tumor progression, have been directly connected with the regulation of SIRT6 protein [98]. Therefore, a promising new strategy in the treatment of cancer and age could be given by pharmacodynamic stimulation of a SIRT6 protein by a small-molecule [99]. The development of molecules to directly compete with natural NAD+ is inefficient to boost SIRT6 catalytic activity because NAD+ is the SIRT6 co-factor participating in the reaction mechanism. Therefore, targeting hidden allosteric sites just outside of the orthosteric NAD+ site is recommended and effective. To address these concerns, we used our previously developed structure-based algorithm; Allosite (http://mdl.shsmu.edu.cn/AST) [72] which predict the potential hidden allosteric sites (see in Figure 3). Promptly, we discovered that the hidden site was composed of the residues, i.e. Phe86 and Phe862. We also conducted site-based virtual screening of 07 commercial chemical databases based on these assessments. Following the theory that allosteric modulators are rigid and much more aromatic than orthosteric ligands, 20 rigid and aromatic compounds were selected and purchased from the top-ranked compounds determined by our established Alloscore approach [100] to evaluate allosteric interactions. Dosage-dependent compounds 2 and 3 (from SPECS) activate the SIRT6 deacetylation with half-maximum effective concentration values of 173.8 ± 1.3 μM and 217.6 ± 1.1 μM, respectively, were identified in the experimental studies.