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Cellular Physiology and Biochemistry :... Mar 2023Trazodone is a selective serotonin reuptake inhibitor; however, other mechanisms of the drug's anti-depressive properties have also been postulated. Hence, the aim of...
BACKGROUND/AIMS
Trazodone is a selective serotonin reuptake inhibitor; however, other mechanisms of the drug's anti-depressive properties have also been postulated. Hence, the aim of the study was to perform a systematic review and assess antiglycoxidative properties of trazodone in in vitro models.
METHODS
Trazodone's scavenging and chelating properties were measured with spectrophotometric method. The impact of the drug on carbonyl/oxidative stress was marked in the bovine serum albumin (BSA) model where sugars (glucose, fructose, galactose, ribose) and aldehydes (glyoxal and methylglyoxal) were used as glycation agents. Aminoguanidine and N-acetylcysteine (NAC) were applied as reference glycation/free radical inhibitors. Glycation biomarkers (kynurenine, N-formylkynurenine, dityrosine as well as advanced glycation end products contents) were assessed spectrofluorometrically. Concentrations of oxidation parameters (total thiols (TTs), protein carbonyls (PCs) and also advanced oxidation protein products (AOPPs) levels) were determined spectrophotometrically.
RESULTS
We demonstrated that trazodone poorly scavenged radicals (hydroxyl radical, nitric oxide, hydrogen peroxide and 2,2-diphenyl-1-picrylhydrazyl radical) and showed low ferrous ion chelating, unlike aminoguanidine and NAC. Sugars/aldehydes caused enhancement of glycation parameters, as well as a decrease of TTs and an increase of PCs and AOPPs levels compared to BSA incubated alone. Trazodone did not reduce oxidation parameters to the baseline (BSA) and significantly exacerbated glycation markers in comparison with both BSA and BSA+glycators. The content of glycation products was markedly lower in aminoguanidine and NAC than in trazodone. The molecular docking of trazodone to BSA revealed its very low affinity, which may indicate non-specific binding of trazodone, facilitating the attachment of glycation factors.
CONCLUSION
According to our findings, it may be concluded that trazodone poorly counteracts oxidation and intensifies glycation in vitro. A possible mechanism for antiglycoxidative effect of trazodone in vivo may be the enhancement of the body's adaptive response, as indicated by the results of our systematic review.
Topics: Antioxidants; Trazodone; Glycosylation; Advanced Oxidation Protein Products; Molecular Docking Simulation; Glycation End Products, Advanced; Serum Albumin, Bovine; Glyoxal; Glucose
PubMed: 36988041
DOI: 10.33594/000000617 -
Frontiers in Psychiatry 2023Agomelatine is an atypical antidepressant drug enhancing norepinephrine and dopamine liberation; nevertheless, additional mechanisms are considered for the drug's...
INTRODUCTION
Agomelatine is an atypical antidepressant drug enhancing norepinephrine and dopamine liberation; nevertheless, additional mechanisms are considered for the drug's pharmacological action. Since protein glycoxidation plays a crucial role in depression pathogenesis, agomelatine's impact on carbonyl/oxidative stress was the research purpose.
METHODS
Reactive oxygen species scavenging (hydroxyl radical, hydrogen peroxide, and nitrogen oxide) and antioxidant capacity (2,2-diphenyl-1-picrylhydrazyl radical and ferrous ion chelating assays) of agomelatine were marked. Agomelatine's antiglycoxidation properties were assayed in sugars (glucose, fructose, and galactose) and aldehydes- (glyoxal and methylglyoxal) glycated bovine serum albumin (BSA). Aminoguanidine and α-lipoic acid were used as standard glycation/oxidation inhibitors.
RESULTS
Agomelatine did not show meaningful scavenging/antioxidant capacity vs. standards. Sugars/aldehydes increased glycation (↑kynurenine, ↑N-formylkynurenine, ↑dityrosine, ↑advanced glycation end products, and ↑β-amyloid) and oxidation (↑protein carbonyls and ↑advanced oxidation protein products) parameters in addition to BSA. Standards restored BSA baselines of glycation and oxidation markers, unlike agomelatine which sometimes even intensifies glycation above BSA + glycators levels. Molecular docking analysis of agomelatine in BSA demonstrated its very weak binding affinity.
DISCUSSION
Agomelatine's very low affinity to the BSA could proclaim non-specific bonding and simplify attachment of glycation factors. Thereby, the drug may stimulate brain adaptation to carbonyl/oxidative stress as the systematic review indicates. Moreover, the drug's active metabolites could exert an antiglycoxidative effect.
PubMed: 37181902
DOI: 10.3389/fpsyt.2023.1164459 -
Pharmaceuticals (Basel, Switzerland) Sep 2023Histamine H2 receptor antagonists are a group of drugs that inhibit gastric juice secretion in gastrointestinal diseases. However, there is evidence to suggest that H2...
Histamine H2 receptor antagonists are a group of drugs that inhibit gastric juice secretion in gastrointestinal diseases. However, there is evidence to suggest that H2 blockers have a broader spectrum of activity. The antioxidant properties of H2 blockers have not been fully elucidated, and their anti-glycation potential has not been studied to date. Therefore, this is the first study to compare the antioxidant and antiglycation potentials of the most popular H2 antagonists (ranitidine, cimetidine, and famotidine) on protein glycoxidation in vitro. Bovine serum albumin (BSA) was glycated using sugars (glucose, fructose, galactose, and ribose) as well as aldehydes (glyoxal and methylglyoxal). In the analyzed group of drugs, ranitidine was the only H2 blocker that significantly inhibited BSA glycation in all tested models. The contents of protein carbonyls, protein glycoxidation products (↓dityrosine, ↓N-formylkynurenine), and early (↓Amadori products) and late-stage (↓AGEs) protein glycation products decreased in samples of glycated BSA with the addition of ranitidine relative to BSA with the addition of the glycating agents. The anti-glycation potential of ranitidine was comparable to those of aminoguanidine and Trolox. In the molecular docking analysis, ranitidine was characterized by the lowest binding energy for BSA sites and could compete with protein amino groups for the addition of carbonyl groups. H2 blockers also scavenge free radicals. The strongest antioxidant properties are found in ranitidine, which additionally has the ability to bind transition metal ions. The systematic literature review also revealed that the anti-glycation effects of ranitidine could be attributed to its antioxidant properties. Ranitidine showed anti-glycation and antioxidant properties. Further research is needed, particularly in patients with diseases that promote protein glycation.
PubMed: 37765081
DOI: 10.3390/ph16091273 -
Journal of Enzyme Inhibition and... Dec 2023An important drug used in the treatment of Parkinson's disease is amantadine. We are the first to perform a comprehensive study based on various glycation and oxidation...
An important drug used in the treatment of Parkinson's disease is amantadine. We are the first to perform a comprehensive study based on various glycation and oxidation factors, determining the impact of amantadine on protein glycoxidation. Sugars (glucose, fructose, galactose) and aldehydes (glyoxal, methylglyoxal) were used as glycation agents, and chloramine T was used as an oxidant. Glycoxidation biomarkers in albumin treated with amantadine were generally not different from the control group (glycation/oxidation factors), indicating that the drug did not affect oxidation and glycation processes. Molecular docking analysis did not reveal strong binding sites of amantadine on the bovine serum albumin structure. Although amantadine poorly scavenged hydroxyl radical and hydrogen peroxide, it had significantly lower antioxidant and antiglycation effect than all protein oxidation and glycation inhibitors. In some cases, amantadine even demonstrated glycoxidant, proglycation, and prooxidant properties. In summary, amantadine exhibited weak antioxidant properties and a lack of antiglycation activity.
Topics: Antioxidants; Glycation End Products, Advanced; Molecular Docking Simulation; Serum Albumin, Bovine; Amantadine
PubMed: 36325591
DOI: 10.1080/14756366.2022.2137161 -
Current Drug Metabolism 2016Diabetes mellitus (DM) is a pandemic metabolic disease characterized by a chronically elevated blood glucose concentration (hyperglycemia) due to insulin dysfunction.... (Review)
Review
BACKGROUND
Diabetes mellitus (DM) is a pandemic metabolic disease characterized by a chronically elevated blood glucose concentration (hyperglycemia) due to insulin dysfunction. Approximately 50% of diabetics show diabetes complications by the time they are diagnosed. Vascular dysfunction, nephropathy and neuropathic pain are common diabetes complications. Chronic hyperglycemia contributes to reactive oxygen species (ROS) generation such as methylglyoxal (MGO).
METHODS
Peer reviewed research papers were studied through bibliographic databases searching focused on review questions and inclusion/exclusion criteria. The reviewed papers were appraised according to the searching focus. The characteristics of screened papers were described, and a deductive qualitative content analysis methodology was applied to the included studies using a conceptual framework to yield this comprehensive systematic review.
RESULTS
Sixty-six papers were included in this review. Eleven papers related methylglyoxal generation to carbohydrates metabolism, ten papers related lipid metabolism to methylglyoxal and 5 papers showed the proteolytic pathways that contribute to methylglyoxal generation. Methylglyoxal metabolism was derived from 7 papers. Descriptive figure 1 was drawn to explain methylglyoxal sources and how diabetes increases methylglyoxal generation. Furthermore, twenty-six papers related methylglyoxal to diabetes complications from which 9 papers showed methylglyoxal ability to induce insulin dysfunction, an effect which was described in schematic figure 2. Additionally, fifteen papers revealed methylglyoxal contribution to vascular dysfunction and 3 papers showed methylglyoxal to cause neuropathic pain. Methylglyoxal-induced vascular dysfunction was drawn in a comprehensive figure 3. This review correlated methylglyoxal with diabetes and diabetes complications which were summarised in table 1.
CONCLUSION
The findings of this review suggesting methylglyoxal as an essential therapeutic target for managing diabetes in the future.
Topics: Blood Glucose; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Humans; Hyperglycemia; Insulin; Insulin Resistance; Neuralgia; Pyruvaldehyde
PubMed: 26965039
DOI: 10.2174/1389200217666151222155216 -
Biomedicine & Pharmacotherapy =... Nov 2020The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and...
The glyoxalase system is a ubiquitous enzymatic network which plays important roles in biological life. It consists of glyoxalase 1 (GLO1), glyoxalase 2 (GLO2), and reduced glutathione (GSH), which perform an essential metabolic function in cells by detoxifying methylglyoxal (MG) and other endogenous harmful metabolites into non-toxic d-lactate. MG and MG-derived advanced glycation endproducts (AGEs) are associated with various diseases, such as diabetes, cardiovascular disease, neurodegenerative disorders and cancer, and GLO1 is a key rate-limiting enzyme in the anti-glycation defense. The abnormal activity and expression of GLO1 in various diseases make this enzyme a promising target for drug design and development. This review focuses on the regulatory mechanism of GLO1 in diverse pathogenic conditions with a thorough discussion of GLO1 regulators since their discovery, including GLO1 activators and inhibitors. The different classes, chemical structure and structure-activity relationship are embraced. Moreover, assays for the discovery of small molecule regulators of the glyoxalase system are also introduced in this article. Compared with spectrophotometer-based assay, microplate-based assay is a more simple, rapid and quantitative high-throughput method. This review will be useful to design novel and potent GLO1 regulators and hopefully provide a convenient reference for researchers.
Topics: Animals; Biological Products; Cardiovascular Diseases; Drug Evaluation, Preclinical; Enzyme Inhibitors; Glycosylation; Humans; Lactoylglutathione Lyase; Neoplasms; Pyruvaldehyde
PubMed: 32858501
DOI: 10.1016/j.biopha.2020.110663