Methylglyoxal Metabolism and Aging-Related Disease: Moving from Correlation toward Causation

Kold-Christensen, Rasmus; Johannsen, Mogens

doi:10.1016/j.tem.2019.10.003

Cited by 89 publications

(65 citation statements)

References 102 publications

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“…An important consequence of the accumulation of MGO is that it covalently binds to biopolymers, and the adducts further rearrange into stable modifications known as AGEs, which in turn damage cell lipids and proteins [ 31 , 32 ]. Therefore, we tested E. coli Δ tim cells complemented with the mentioned genes to corroborate the apparition rates of AGEs.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, the cells complemented with N16D HsTIM showed 1506 nmol/mL MGO in the absence of omeprazole (2.6-fold) and reached 2617 nmol/mL MGO when this drug was present, which corresponded to a 4.5-fold increase in MGO in N16 HsTIM compared to the WT HsTIM control (Table 3). An important consequence of the accumulation of MGO is that it covalently binds to biopolymers, and the adducts further rearrange into stable modifications known as AGEs, which in turn damage cell lipids and proteins [31,32]. Therefore, we tested E. coli ∆tim cells complemented with the mentioned genes to corroborate the apparition rates of AGEs.…”

Section: Omeprazole Induces Increasing Levels Of Mgo and Ages In E Cmentioning

confidence: 99%

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Deamidated Human Triosephosphate Isomerase is a Promising Druggable Target

et al. 2020

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Therapeutic strategies for the treatment of any severe disease are based on the discovery and validation of druggable targets. The human genome encodes only 600–1500 targets for small-molecule drugs, but posttranslational modifications lead to a considerably larger druggable proteome. The spontaneous conversion of asparagine (Asn) residues to aspartic acid or isoaspartic acid is a frequent modification in proteins as part of the process called deamidation. Triosephosphate isomerase (TIM) is a glycolytic enzyme whose deamidation has been thoroughly studied, but the prospects of exploiting this phenomenon for drug design remain poorly understood. The purpose of this study is to demonstrate the properties of deamidated human TIM (HsTIM) as a selective molecular target. Using in silico prediction, in vitro analyses, and a bacterial model lacking the tim gene, this study analyzed the structural and functional differences between deamidated and nondeamidated HsTIM, which account for the efficacy of this protein as a druggable target. The highly increased permeability and loss of noncovalent interactions of deamidated TIM were found to play a central role in the process of selective enzyme inactivation and methylglyoxal production. This study elucidates the properties of deamidated HsTIM regarding its selective inhibition by thiol-reactive drugs and how these drugs can contribute to the development of cell-specific therapeutic strategies for a variety of diseases, such as COVID-19 and cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Omeprazole Induces Increasing Levels Of Mgo and Ages In E Cmentioning

confidence: 99%

Deamidated Human Triosephosphate Isomerase is a Promising Druggable Target

et al. 2020

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“…Alzheimer's disease (AD) is an insidious progressive neurodegenerative disease, which is affected by many factors, including environmental factors and genetic and epigenetic variations (Toledo et al, 2015), but there is no doubt that aging is the biggest risk factor (Kold-Christensen and Johannsen, 2019). As the global population ages, there will be two billion people aged 60 years or over in the world by 2050 (Harper, 2014), and two new patients will be diagnosed with AD every minute, resulting in one million new patients who will be diagnosed every year (Alzheimer's Association, 2015).…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Analyses for Identification and Prioritization of Genes Associated With Alzheimer’s Disease in Humans

Shi

Liu

Yang

et al. 2020

Front. Bioeng. Biotechnol.

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Long non-coding RNAs (lncRNAs), as important ncRNA regulators, play crucial roles in the regulation of various biological processes, and their aberrant expression is related to the occurrence and development of diseases, which is gradually validated by more and more studies. Alzheimer's disease (AD) is a chronic neurodegenerative disease that often develops slowly and gradually deteriorates over time. However, which functions the lncRNAs perform in AD are almost unknown. In this study, we performed transcriptome analysis in AD, containing 12,892 known lncRNAs and 19,053 protein-coding genes (PCGs). Further, 14 down-regulated and 39 up-regulated lncRNAs were identified, compared with normal brain samples, which indicated that these lncRNAs might play critical roles in the pathogenesis of AD. In addition, 19 down-regulated and 28 upregulated PCGs were also detected. Using the differentially expressed lncRNAs and PCGs through the WGCNA method, an lncRNA-mRNA co-expressed network was constructed. The results showed that lncRNAs RP3-522J7, MIR3180-2, and MIR3180-3 were frequently co-expressed with known AD risk PCGs. Interestingly, PCGs in the network are significantly enriched in brain-or AD-related biological functions, including the brain renin-angiotensin system, cell adhesion, neuroprotective role of THOP1 in AD, and so on. Furthermore, it was shown that 18 lncRNAs and 7 PCGs were highly expressed in normal brain tissue relative to other normal tissue types, suggesting their potential as diagnostic markers of AD, especially RP3-522J7, MIR3180-2, MIR3180-3, and CTA-929C8. In total, our study identified a compendium of AD-related dysregulated lncRNAs and characterized the corresponding biological functions of these lncRNAs in AD, which will be helpful to understand the molecular basis and pathogenesis of AD.

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“…Advanced glycation end products (AGEs), a complex group of oxidant compounds synthesized from slowly occurring non-enzymatic glycation between reducing sugars, such as glucose or fructose, and proteins or lipids, play an important role in the pathogenesis of diabetic vascular disease [7][8][9]. Methylglyoxal (MG), a highly reactive carbonyl species formed as a by-product of glycolysis, is a strong precursor of AGEs [10], whereas N-carboxymethyl lysine (CML) is a well-characterized AGE present in long-lived proteins that has been used as an indicator of oxidative stress in biological systems [11]. Small amounts of AGEs are generated in vivo as a normal consequence of metabolism, and they gradually accumulate during aging, especially in the context of associated chronic diseases [12].…”

Section: Introductionmentioning

confidence: 99%

Endothelial Dysfunction and Advanced Glycation End Products in Patients with Newly Diagnosed Versus Established Diabetes: From the CORDIOPREV Study

et al. 2020

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Endothelial dysfunction and intima-media thickness of common carotid arteries (IMT-CC) are considered subclinical markers of atherosclerotic cardiovascular disease (ASCVD). Advanced glycation end products (AGEs) are increased in type 2 diabetes mellitus (T2DM) patients, compared with non-diabetics, being implicated in micro- and macrovascular complications. Our aim was to compare serum AGEs levels and subclinical atherosclerotic markers between patients with established and newly diagnosed T2DM. Among 540 patients with T2DM and coronary heart disease from the CORDIOPREV study, 350 patients had established T2DM and 190 patients had newly diagnosed T2DM. Serum levels of AGEs (methylglyoxal (MG) and N-carboxymethyl lysine (CML)) and subclinical atherosclerotic markers (brachial flow-mediated vasodilation (FMD) and IMT-CC) were measured. AGEs levels (all p < 0.001) and IMT-CC (p = 0.025) were higher in patients with established vs. newly diagnosed T2DM, whereas FMD did not differ between the two groups. Patients with established T2DM and severe endothelial dysfunction (i.e., FMD < 2%) had higher serum MG levels, IMT-CC, HOMA-IR and fasting insulin levels than those with newly diagnosed T2DM and non-severe endothelial dysfunction (i.e., FMD ≥ 2%) (all p < 0.05). Serum CML levels were greater in patients with established vs. newly diagnosed T2DM, regardless of endothelial dysfunction severity. Serum AGEs levels and IMT-CC were significantly higher in patients with established vs. newly diagnosed T2DM, highlighting the progressively increased risk of ASCVD in the course of T2DM. Establishing therapeutic strategies to reduce AGEs production and delay the onset of cardiovascular complications in newly diagnosed T2DM patients or minimize ASCVD risk in established T2DM patients is needed.

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Methylglyoxal Metabolism and Aging-Related Disease: Moving from Correlation toward Causation

Cited by 89 publications

References 102 publications

Deamidated Human Triosephosphate Isomerase is a Promising Druggable Target

Deamidated Human Triosephosphate Isomerase is a Promising Druggable Target

Transcriptomic Analyses for Identification and Prioritization of Genes Associated With Alzheimer’s Disease in Humans

Endothelial Dysfunction and Advanced Glycation End Products in Patients with Newly Diagnosed Versus Established Diabetes: From the CORDIOPREV Study

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