Protein glycation in diabetes mellitus

Shin, Aleks; Connolly, Shawn; Kabytaev, Kuanysh

doi:10.1016/bs.acc.2022.11.003

Cited by 14 publications

(7 citation statements)

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“…The late stage involves oxidation, polymerization, dehydration, and condensation reactions with other amino groups. This results in the formation of the final glycation products—AGEs ( Shen et al, 2020 ; Shin et al, 2023 ). In glycoxidation processes, the kynurenine pathway converts TRY via the intractable NFK to KN.…”

Section: Resultsmentioning

confidence: 99%

“…In the body, not only plasma proteins undergo glycoxidation. Intracellular proteins such as hemoglobin and extracellular matrix proteins such as collagen are also vulnerable to this process ( Vlassara and Palace, 2003 ; Shin et al, 2023 ). In animal studies, verapamil has been shown to reduce (in contrast to nifedipine and diltiazem) glycated hemoglobin (HbA1c) levels ( Kaymaz et al, 1995 ).…”

Section: Discussionmentioning

confidence: 99%

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Preliminary evaluation of the antiglycoxidant activity of verapamil using various in vitro and in silico biochemical/biophysical methods

Nesterowicz,

Lauko,

Dańkowska

et al. 2023

Front. Pharmacol.

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Introduction: Glycoxidative stress is essential for linking glucose disturbances and cardiovascular diseases. Unfortunately, contemporary antidiabetic drugs do not have an antiglycative effect but only lower blood glucose levels. Therefore, there is an intense search for substances that could inhibit protein glycation and prevent diabetic complications. A potential antioxidant activity has been demonstrated with verapamil, a phenylalkylamine derivative belonging to selective calcium channel blockers. Verapamil has a well-established position in cardiology due to its wide range of indications and good safety profile. Nevertheless, the antidiabetic activity of verapamil is still unclear. We are the first to comprehensively evaluate the verapamil’s effect on protein glycoxidation using various in vitro and in silico models.Methods: Bovine serum albumin (BSA) was used to assess the rate of glycoxidation inhibition by verapamil. As glycating factors, sugars (glucose, fructose, and ribose) and aldehyde (glyoxal) were used. Chloramine T was used as an oxidizing agent. Aminoguanidine (protein glycation inhibitor) and Trolox (antioxidant) were used as control substances. The biomarkers of oxidation (total thiols, protein carbonyls, advanced oxidation protein products), glycation (Amadori products, β-amyloid, advanced glycation end products [AGEs]), and glycoxidation (tryptophan, kynurenine, N-formylkynurenine, dityrosine) were evaluated using colorimetric and fluorimetric methods. The mechanism of antiglycative activity of verapamil was assessed using in silico docking to study its interaction with BSA, glycosidases, and seventeen AGE pathway proteins.Results: In all in vitro models, biomarkers of protein glycation, oxidation, and glycoxidation were significantly ameliorated under the influence of verapamil. The glycoxidation inhibition rate by verapamil is comparable to that of potent antiglycating agents and antioxidants. The molecular docking simulations showed that verapamil bound preferentially to amino acids prone to glycoxidative damage out of an α-glucosidase’s active center. Among all AGE pathway proteins, verapamil was best docked with the Janus kinase 2 (JAK2) and nuclear factor-κB (NF-κB).Discussion: The results of our study confirm the antiglycoxidant properties of verapamil. The drug’s action is comparable to recognized substances protecting against oxidative and glycation modifications. Verapamil may be particularly helpful in patients with cardiovascular disease and concomitant diabetes. Studies in animal models and humans are needed to confirm verapamil’s antiglycative/antidiabetic activity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Preliminary evaluation of the antiglycoxidant activity of verapamil using various in vitro and in silico biochemical/biophysical methods

Nesterowicz,

Lauko,

Dańkowska

et al. 2023

Front. Pharmacol.

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“…Proteins with a long metabolic turnover, as extracellular matrix proteins, are the most susceptible to non-enzymatic glycosylation, compared to most proteins that counteract the impact of glycation thanks to their high turnover rate and short half-life [ 143 ]. For instance, the fast hematic turnover of serum albumin offers the chance to monitor short-term diabetes [ 144 ]. It is known that proteins from saliva show a very quick turnover; nevertheless, few studies point out how the loss of functional activity of some salivary proteins is to be related to glycation processes.…”

Section: Glycosylationmentioning

confidence: 99%

The Post-Translational Modifications of Human Salivary Peptides and Proteins Evidenced by Top-Down Platforms

Messana

Manconi

Cabras

et al. 2023

IJMS

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In this review, we extensively describe the main post-translational modifications that give rise to the multiple proteoforms characterized to date in the human salivary proteome and their potential role. Most of the data reported were obtained by our group in over twenty-five years of research carried out on human saliva mainly by applying a top-down strategy. In the beginning, we describe the products generated by proteolytic cleavages, which can occur before and after secretion. In this section, the most relevant families of salivary proteins are also described. Next, we report the current information concerning the human salivary phospho-proteome and the limited news available on sulfo-proteomes. Three sections are dedicated to the description of glycation and enzymatic glycosylation. Citrullination and N- and C-terminal post-translational modifications (PTMs) and miscellaneous other modifications are described in the last two sections. Results highlighting the variation in the level of some proteoforms in local or systemic pathologies are also reviewed throughout the sections of the manuscript to underline the impact and relevance of this information for the development of new diagnostic biomarkers useful in clinical practice.

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“…Proteins with a long metabolic turnover, as extracellular matrix proteins, are the most susceptible to non-enzymatic glycosylation, compared to most proteins that counteract the impact of glycation thanks to their high turnover rate and short half-life [143]. For instance, the fast hematic turnover of serum albumin offers the chance to monitor shortterm diabetes [144]. It is known that proteins from saliva show a very quick turnover; nevertheless, few studies point out how the loss of functional activity of some salivary proteins is to be related to glycation processes.…”

Section: Glycosylation 71 Non-enzymatic Glycosylation (Glycation)mentioning

confidence: 99%

The Post-translational Modifications of Human Salivary Peptides and Proteins Evidenced by Top-Down Platforms

Messana,

Manconi,

Cabras

et al. 2023

Preprint

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In this review we extensively describe the main post-translational modifications that give rise to the multiple proteoforms characterized to date in the human salivary proteome and their potential role. Most of the data reported were obtained by our group in over twenty-five years of research carried out on human saliva mainly by applying a top-down strategy. At the beginning we describe the products generated by proteolytic cleavages, which can occur before and after secretion. In this section the most relevant families of salivary proteins are also described. Next, we report the current information concerning the human salivary phospho-proteome and the limited news available on sulfo-proteome. Three sections are dedicated to the description of the glycation and enzymatic glycosylation. Citrullination and N- and C- terminal PTMs and a miscellaneous of other modifications are described in the last two sections. Results highlighting the variation in the level of some proteoforms in local or systemic pathologies are also reviewed along the sections of manuscript to underline the impact and relevance of this information for the development of new diagnostic biomarkers useful in clinical practice.

show abstract

Protein glycation in diabetes mellitus

Cited by 14 publications

References 285 publications

Preliminary evaluation of the antiglycoxidant activity of verapamil using various in vitro and in silico biochemical/biophysical methods

Preliminary evaluation of the antiglycoxidant activity of verapamil using various in vitro and in silico biochemical/biophysical methods

The Post-Translational Modifications of Human Salivary Peptides and Proteins Evidenced by Top-Down Platforms

The Post-translational Modifications of Human Salivary Peptides and Proteins Evidenced by Top-Down Platforms

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