An elevated frequency of DNA replication defects is associated with diabetes and cancer. However, data linking these nuclear perturbations to the onset or progression of organ complications remained unexplored. Here, we report that RAGE (Receptor for Advanced Glycated Endproducts), previously believed to be an extracellular receptor, upon metabolic stress localizes to the damaged forks. There it interacts and stabilizes the minichromosome-maintenance (Mcm2-7) complex. Accordingly, RAGE deficiency leads to slowed fork progression, premature fork collapse, hypersensitivity to replication stress agents and reduction of viability, which was reversed by the reconstitution of RAGE. This was marked by the 53BP1/OPT-domain expression and the presence of micronuclei, premature loss-of-ciliated zones, increased incidences of tubular-karyomegaly, and finally, interstitial fibrosis. More importantly, the RAGE-Mcm2 axis was selectively compromised in cells expressing micronuclei in human biopsies and mouse models of diabetic nephropathy and cancer. Thus, the functional RAGE-Mcm2/7 axis is critical in handling replication stress in vitro and human disease.

• MeSH
• diabetes mellitus * MeSH
• lidé MeSH
• MCM komplex, komponenta 2 * genetika   metabolismus   MeSH
• MCM proteiny metabolismus   MeSH
• myši MeSH
• nádory * MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• receptor pro konečné produkty pokročilé glykace * metabolismus   MeSH
• replikace DNA genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• MCM komplex, komponenta 2 * MeSH
• MCM proteiny MeSH
• MCM2 protein, human MeSH Prohlížeč
• proteiny buněčného cyklu MeSH
• receptor pro konečné produkty pokročilé glykace * MeSH

Metabolic syndrome (MetS) belongs to the serious health complications expanding in cardiovascular diseases, obesity, insulin resistance, and hyperglycemia. In this study, hypertriacylglycerolemic rats fed a high-fat-fructose diet (HFFD) were used as an experimental model of MetS to explore the effect of tested compounds. Effects of a new prospective pyridoindole derivative coded SMe1EC2 and the natural polyphenol rutin were tested. Endothelial nitric oxide synthase (NOS3) and nuclear factor kappa B (NF-?B) expression were assessed in the left ventricle immunohistochemically and left ventricle activity was monitored in isolated perfused rat hearts. NOS3 activity in the left ventricle decreased markedly as a result of a HFFD. NOS3 expression was upregulated by both substances. NF-?B expression was increased in the MetS group in comparison to control rats and the expression further increased in the SMe1EC2 treatment. This compound significantly improved the coronary flow in comparison to the control group during reperfusion of the heart followed after ischemia. Further, it tended to increase left ventricular systolic pressure, heart product, rate of maximal contraction and relaxation, and coronary flow during baseline assessment. Moreover, the compound SMe1EC2 decreased the sensitivity of hearts to electrically induced ventricular fibrillation. Contrary to this rutin decreased coronary flow in reperfusion. Present results suggest that despite upregulation of NOS3 by both substances tested, pyridoindole SMe1EC2 rather than rutin could be suitable in treatment strategies of cardiovascular disorders in MetS-like conditions.

• MeSH
• biometrie MeSH
• fruktosa škodlivé účinky   MeSH
• indoly farmakologie   terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• metabolický syndrom farmakoterapie   enzymologie   etiologie   MeSH
• myokard metabolismus   MeSH
• NF-kappa B metabolismus   MeSH
• potkani Wistar MeSH
• preklinické hodnocení léčiv MeSH
• pyridiny farmakologie   terapeutické užití   MeSH
• rutin farmakologie   terapeutické užití   MeSH
• srdce účinky léků   MeSH
• synthasa oxidu dusnatého, typ III metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fruktosa MeSH
• indoly MeSH
• NF-kappa B MeSH
• Nos3 protein, rat MeSH Prohlížeč
• pyridiny MeSH
• rutin MeSH
• SMe1EC2 MeSH Prohlížeč
• synthasa oxidu dusnatého, typ III MeSH

Diabetes mellitus is characterized by long standing hyperglycemia leading to numerous life-threatening complications. For type 1 diabetes mellitus, resulting from selective destruction of insulin producing cells by exaggerated immune reaction, the only effective therapy remains exogenous insulin administration. Despite accurate compliance to treatment of certain patients, transient episodes of hyperglycemia cannot be completely eliminated by this symptomatic treatment. Novel immunotherapeutic approaches based on tolerogenic dendritic cells, T regulatory cells and mesenchymal stem cells (MSCs) have been tested in clinical trials, endeavoring to directly modulate the autoimmune destruction process in pancreas. However, hyperglycemia itself affects the immune system and the final efficacy of cell-based immunotherapies could be affected by the different glycemic control of enrolled patients. The present review explores the impact of hyperglycemia on immune cells while providing greater insight into the molecular mechanisms of high glucose action and subsequent metabolic reprogramming of different immune cells. Furthermore, over-production of mitochondrial reactive oxygen species, formation of advanced glycation end products as a consequence of hyperglycemia and their downstream signalization in immune cells are also discussed. Since hyperglycemia in patients with type 1 diabetes mellitus might have an impact on immune-interventional treatment, the maintenance of a tight glucose control seems to be beneficial in patients considered for cell-based therapy.

• Klíčová slova
• cell-based therapy, dendritic cells, diabetes mellitus, hyperglycemia, immune tolerance,
• MeSH
• dendritické buňky imunologie   metabolismus   transplantace   MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• hyperglykemie imunologie   MeSH
• imunologická tolerance účinky léků   MeSH
• imunoterapie adoptivní metody   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• mezenchymální kmenové buňky imunologie   MeSH
• mitochondrie metabolismus   MeSH
• monitorování fyziologických funkcí MeSH
• přeprogramování buněk MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulační T-lymfocyty imunologie   transplantace   MeSH
• transplantace mezenchymálních kmenových buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• reaktivní formy kyslíku MeSH