Compounds Blocking Methylglyoxal-induced Protein Modification and Brain Endothelial Injury

Tóth, Anna Zsófia; Tóth, András; Walter, Fruzsina R.; Kiss, Lóránd; Veszelka, Szilvia; Ózsvári, Béla; Puskás, László G.; Heimesaat, Markus M.; Dohgu, Shinya; Kataoka, Yasufumi; Rákhely, Gábor; Deli, Mária A.

doi:10.1016/j.arcmed.2014.10.009

Cited by 31 publications

(34 citation statements)

References 73 publications

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“…hCMEC/D3 cell is an immortalized cell line derived from human brain microvascular endothelial cells of a female patient through co-expression of hTERT and the SV40 large T-antigen (Weksler et al, 2013). This cell line retains most of the morphological and functional characteristics of human brain endothelial cells and has been used as a reliable in vitro model of human BBB (Toth et al, 2014; Chen et al, 2015). In this study, hCMEC/D3 cells were cultured in EBM-2 medium (Lonza, Walkersville, MD) supplemented with EGM-2 Bullet-kit, which contains basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), EGFR, hydrocortisone, ascorbate, gentamycin, and 2.5% fetal bovine serum (FBS).…”

Section: Methodsmentioning

confidence: 99%

Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

Eum

Jaraki

András

et al. 2015

Toxicology and Applied Pharmacology

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Occludin is an essential integral transmembrane protein regulating tight junction (TJ) integrity in brain endothelial cells. Phosphorylation of occludin is associated with its localization to TJ sites and incorporation into intact TJ assembly. The present study is focused on the role of lipid rafts in polychlorinated biphenyl (PCB)-induced disruption of occludin and endothelial barrier function. Exposure of human brain endothelial cells to 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153) induced dephosphorylation of threonine residues of occludin and displacement of occludin from detergent-resistant membrane (DRM)/lipid raft fractions within 1 h. Moreover, lipid rafts modulated the reduction of occludin level through activation of matrix metalloproteinase 2 (MMP-2) after 24 h h PCB153 treatment. Inhibition of protein phosphatase 2A (PP2A) activity by okadaic acid or fostriecin markedly protected against PCB153-induced displacement of occludin and increased permeability of endothelial cells. The implication of lipid rafts and PP2A signaling in these processes was further defined by co-immunoprecipitation of occludin with PP2A and caveolin-1, a marker protein of lipid rafts. Indeed, a significant MMP-2 activity was observed in lipid rafts and was increased by exposure to PCB153. The pretreatment of MMP-2 inhibitors protected against PCB153-induced loss of occludin and disruption of lipid raft structure prevented the increase of endothelial permeability. Overall, these results indicate that lipid raft-associated processes, such as PP2A and MMP-2 activation, participate in PCB153-induced disruption of occludin function in brain endothelial barrier. This study contributes to a better understanding of the mechanisms leading to brain endothelial barrier dysfunction in response to exposure to environmental pollutants, such as ortho-substituted PCBs.

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Section: Methodsmentioning

confidence: 99%

Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

Eum

Jaraki

András

et al. 2015

Toxicology and Applied Pharmacology

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“…The best studied drugs include aminoguanidine, pyridoxamine, NAC, and monascin. Aminoguanidine was shown to prevent ECM and AGE deposition in the vessel wall . Accordingly, in STZ‐induced diabetic rats, it prevented histological features of nephropathy and decreased proteinuria .…”

Section: The Promise Of New Therapeutic Targetsmentioning

confidence: 98%

“…From the group of developed scavengers were the experimental drugs edaravone and alagebrium, both with limited effects . While alagebrium was shown to prevent MG‐induced insulin resistance, edaravone was shown to protect endothelial cells by inhibiting the RAGE axis . However, both missed the finding of consistent results in preventing MG‐induced diabetic complications.…”

Section: The Promise Of New Therapeutic Targetsmentioning

confidence: 99%

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

Matafome

Rodrigues

Sena

et al. 2016

Medicinal Research Reviews

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Glucose and fructose metabolism originates the highly reactive byproduct methylglyoxal (MG), which is a strong precursor of advanced glycation end products (AGE). The MG has been implicated in classical diabetic complications such as retinopathy, nephropathy, and neuropathy, but has also been recently associated with cardiovascular diseases and central nervous system disorders such as cerebrovascular diseases and dementia. Recent studies even suggested its involvement in insulin resistance and beta-cell dysfunction, contributing to the early development of type 2 diabetes and creating a vicious circle between glycation and hyperglycemia. Despite several drugs and natural compounds have been identified in the last years in order to scavenge MG and inhibit AGE formation, we are still far from having an effective strategy to prevent MG-induced mechanisms. This review summarizes the endogenous and exogenous sources of MG, also addressing the current controversy about the importance of exogenous MG sources. The mechanisms by which MG changes cell behavior and its involvement in type 2 diabetes development and complications and the pathophysiological implication are also summarized. Particular emphasis will be given to pathophysiological relevance of studies using higher MG doses, which may have produced biased results. Finally, we also overview the current knowledge about detoxification strategies, including modulation of endogenous enzymatic systems and exogenous compounds able to inhibit MG effects on biological systems.

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“…В условиях гипергликемии химически активная глюкоза и продукты ее обмена, такие как глиоксаль и метилглиоксаль, оказывают повреждающее воздействие на белки плазмы и клеток крови, а tion, role of transcription factor Prep1 and small heat shock proteins, evaluation of novel methods of diagnostics of IR and therapeutic potential of brown and "beige" fat, determination of biotargets for new antidiabetic drugs. KEYWORDS: insulin resistance; diabetes mellitus; hyperglycaemia; metabolic syndrome; brown fat; "beige" adipocytes; insulin; oxidative stress; molecular mechanisms; PKB/Akt; Prep1; PPARγ, small heat shock proteins; endothelial dysfunction также гликируют белки сосудистого эндотелия [11]. Вместе с малоновым диальдегидом, накапливающимся в результате перекисного окисления избыточных липидов на более ранних стадиях патогенеза СД2, эти соединения обеспечивают развитие оксидативного и карбонильного стресса, нарушающих функции эндотелия.…”

Section: состояние проблемыunclassified

Type 2 diabetes and metabolic syndrome: identification of the molecular mechanisms, key signaling pathways and transcription factors aimed to reveal new therapeutical targets

Dedov¹,

Tkachuk²,

Gusev³

et al. 2018

Diabetes mellitus

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Type 2 diabetes mellitus (T2DM) is a socially important disease with only symptomatic therapy developed due to lack of knowledge about its pathogenesis and underlying mechanism. Insulin resistance (IR) is the first link of T2DM pathogenesis and results in decrease of ability of insulin to stimulate glucose uptake by target cells. Development of IR involves genetic predisposition, excessive nutrition, stress, obesity or chronic inflammation due to disruption of insulin signaling within cells. Molecular mechanisms and markers of IR are characterized rather poorly, which prevents early diagnosis and creation of preventive therapy. Euglycemic clamp test is still a golden standard for IR diagnosis in clinic. Hyperglycemia is a distant consequence of IR in which damaging effect of oxidative and carbonyl stress is realized and diagnosis of T2DM is stipulated. Molecular chaperones and small heat-shock proteins have a protective effect at the early stages of T2DM pathogenesis, preventing development of reticulum stress and apoptosis. Endothelial dysfunction is related to T2DM and its cardiovascular complications, however, it is unknown on which stage of pathogenesis these changes occur and what are their molecular inductors. Finally, transcriptional activity and adipogenic differentiation play an important role in formation of new fat depots from predecessor cells and activation of brown and beige fat demonstrating hypolipidemic and hypoglycemic properties. The aim of this study was investigation of pathophysiological mechanisms of development of IR and endothelial dysfunction, role of transcription factor Prep1 and small heat shock proteins, evaluation of novel methods of diagnostics of IR and therapeutic potential of brown and beige fat, determination of biotargets for new antidiabetic drugs.

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Compounds Blocking Methylglyoxal-induced Protein Modification and Brain Endothelial Injury

Cited by 31 publications

References 73 publications

Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2

Methylglyoxal in Metabolic Disorders: Facts, Myths, and Promises

Type 2 diabetes and metabolic syndrome: identification of the molecular mechanisms, key signaling pathways and transcription factors aimed to reveal new therapeutical targets

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