Current Protein and Peptide Science - Volume 21, Issue 9, 2020

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 been 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. Furthermore, glycation of nucleotides, proteins, and phospholipids by α-oxoaldehyde metabolites, such as glyoxal (GO) and methylglyoxal (MGO), causes 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 anti-glycation defense is well established. Glycation of proteins by MGO and GO results in protein misfolding, thereby affecting their structure and function. These findings provide evidence for the rationale that the functional modulation of the GLO pathway could be used as a potential therapeutic target. In the present review, we summarized the newly emerged literature on the GLO pathway, including enzymes regulating the process. In addition, we described 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.

Background: Stroke is one of the causes of death and disability globally. Brain attack is because of the acute presentation of stroke, which highlights the requirement for decisive action to treat it. Objective: The mechanism and in-vivo experimental models of stroke with various neuroprotective agents are highlighted in this review. Method: The damaging mechanisms may proceed by rapid, nonspecific cell lysis (necrosis) or by the active form of cell death (apoptosis or necroptosis), depending upon the duration and severity and of the ischemic insult. Results: Identification of injury mediators and pathways in a variety of experimental animal models of global cerebral ischemia has directed to explore the target-specific cytoprotective strategies, which are critical to clinical brain injury outcomes. Conclusion: The injury mechanism, available encouraging medicaments thereof, and outcomes of natural and modern medicines for ischemia have been summarized. In spite of available therapeutic agents (thrombolytics, calcium channel blockers, NMDA receptor antagonists and antioxidants), there is a need for an ideal drug for strokes.

Skeletal muscle is the largest organ in the body and constitutes almost 40% of body mass. It is also the primary site of insulin-mediated glucose uptake, and skeletal muscle insulin resistance, that is, diminished response to insulin, is characteristic of Type 2 diabetes (T2DM). One of the foremost reasons posited to explain the etiology of T2DM involves the modification of proteins by dicarbonyl stress due to an unbalanced metabolism and accumulations of dicarbonyl metabolites. The elevated concentration of dicarbonyl metabolites (i.e., glyoxal, methylglyoxal, 3-deoxyglucosone) leads to DNA and protein modifications, causing cell/tissue dysfunctions in several metabolic diseases such as T2DM and other age-associated diseases. In this review, we recapitulated reported effects of dicarbonyl stress on skeletal muscle and associated extracellular proteins with emphasis on the impact of T2DM on skeletal muscle and provided a brief introduction to the prevention/inhibition of dicarbonyl stress.

It has been well established that advanced glycation end-products (AGEs) have a strong correlation with diabetes and its secondary complications. Moreover, dicarbonyls, especially, methylglyoxal (MG) and glyoxal, accelerate AGEs formation and hence, have potential roles in the pathogenesis of diabetes. They can also induce oxidative stress and concomitantly decrease the efficiency of antioxidant enzymes. Increased proinflammatory cytokines (tumor necrosis factor-α and interleukin- 1β) are secreted by monocytes due to the dicarbonyl-modified proteins. High levels of blood dicarbonyls have been identified in diabetes and its associated complications (retinopathy, nephropathy and neuropathy). This review aims to provide a better understanding by including in-depth information about the formation of MG and glyoxal through multiple pathways with a focus on their biological functions and detoxifications. The potential role of these dicarbonyls in secondary diabetic complications is also discussed.

The non-enzymatic interaction of sugar and protein resulting in the formation of advanced glycation end products responsible for cell signaling alterations ultimately leads to the human chronic disorders such as diabetes mellitus, cardiovascular diseases, cancer, etc. Studies suggest that AGEs upon interaction with receptors for advanced glycation end products (RAGE) result in the production of pro-inflammatory molecules and free radicals that exert altered gene expression effect. To date, many studies unveiled the potent role of synthetic and natural agents in inhibiting the glycation reaction at a lesser or greater extent. This review focuses on the hazards of glycation reaction and its inhibition by natural antioxidants, including polyphenols.

Background: Non-enzymatic glycation of proteins plays a significant role in the pathogenesis of secondary diabetic complications via the formation of advanced glycation end products (AGEs) and increased oxidative stress. Methylglyoxal (MG), a highly reactive dicarbonyl of class α-oxoaldehyde that generates during glucose oxidation and lipid peroxidation, contributes to glycation. Objective: This comparative study focuses on methylglyoxal induced glycoxidative damage suffered by immunoglobulin G (IgG) and fibrinogen, and to unveil implication of structural modification of serum proteins in diabetes-associated secondary complications. Methods: The methylglyoxal induced structural alterations in IgG and fibrinogen were analyzed by UVvis, fluorescence, circular dichroism and Fourier transform infrared (FT-IR) spectroscopy. Ketoamine moieties, carbonyl contents, 5-Hydroxymethylfurfural (HMF) and malondyaldehyde were also quantified. Free lysine and arginine estimation, detection of non-fluorogenic carboxymethyllysine (CML) and fibril formation were confirmed by thioflavin T (ThT) assay. Results: Structural alterations, increased carbonyl contents and ketoamines were reported in MG glycated IgG and fibrinogen against their native analogues. Conclusion: The experiment results validate structural modifications, increased oxidative stress and AGEs formation. Thus, we can conclude that IgG-AGEs and Fib-AGEs formed during MG induced glycation of IgG and fibrinogen could impede normal physiology and might initiates secondary complications in diabetic patients.

The non-enzymatic glycosylation is a very common phenomenon in the physiological conditions which is mediated by distinct chemical entities containing reactive carbonyl species (RCS) and participates in the modification of various macromolecules particularly proteins. To date, various carbonyl species, i.e., glucose, fructose, D-ribose and methylglyoxal have been used frequently to assess the in-vitro non-enzymatic glycosylation. Similarly, 2'-Deoxyribose is one of the most abundant reducing sugar of the living organisms which forms the part of deoxyribonucleic acid and may react with proteins leading to the production of glycation intermediates, advanced glycation end products (AGEs) and highly reactive RCS. Thymidine phosphorylase derived degradation of thymidine contributes to the formation of 2'-Deoxyribose, therefore, acting as a major source of cellular 2'- Deoxyribose. Since albumin is a major serum protein which plays various roles including binding and transporting endogenous and exogenous ligands, it is more prone to be modified through different physiological modifiers; therefore, it may serve as a model protein for in-vitro experiments to study the effect of 2’Deoxyribose mediated modifications in the protein. In this study, Bovine Serum Albumin (BSA) was glycated with 50 and 100 mM 2'-Deoxyribose followed by examining secondary and tertiary structural modifications in BSA as compared to its native (unmodified) form by using various physicochemical techniques. We evident a significant modification in 2'-Deoxyribose-glycated BSA which was confirmed through increased hyperchromicity, keto amine moieties, carbonyl and hydroxymethylfurfural content, fluorescent AGEs, altered secondary structure conformers (α helix and β sheets), band shift in the amide-I region and diminished free lysine and free arginine content. These modifications were reported to be higher in 100 mM 2'-Deoxyribose-glycated BSA than 50 mM 2'- Deoxyribose-glycated BSA. Our findings also demonstrated that the rate of glycation is positively affected by the increased concentration of 2'-Deoxyribose. The results of the performed study can be implied to uncover the phenomenon of serum protein damage caused by 2'-Deoxyribose leading towards diabetic complications and the number of AGE-related diseases.