Niosome-carvedilol protects DNA damage of supraphysiologic concentrations of insulin using comet assay: An in vitro study

Abstract

Introduction: Hyperinsulinemia occurs in type 2 diabetic patients with insulin resistance. This increase in insulin levels in the blood increases reactive oxygen species production and oxidative stress, resulting in DNA damage. Carvedilol (CRV) is a non-selective beta-blocker, and research has shown that this compound and its metabolites have anti-oxidative properties. Carvedilol can, directly and indirectly, reduce reactive oxygen species (ROS) and has a protective effect on DNA damage from oxidative stress. Given the insolubility of CRV in water, finding new methods to increase its solubility can be an essential step in research. This study aimed to determine whether carvedilol could have a protective effect on insulin-induced genomic damage. Methods: We treated cells with insulin alone, amorphous-CRV alone, and amorphous-CRV and niosomal-CRV with insulin and DNA damage were investigated using the comet method to achieve this goal. Results: Our results showed that insulin in the studied concentration has a significant genotoxic effect and non-cytotoxic at higher concentrations. CRV, both in amorphous and niosome form, reduced insulin-induced DNA damage by reducing ROS production. The comet assay results demonstrate that treating HUVEC cells in pretreatment condition with amorphous-CRV and niosome-CRV significantly reduces DNA damage of insulin.

Carbazoles: Role and Functions in Fighting Diabetes

“…In particular, treatment of HUVEC cells with niosome-carvedilol (1) nanoparticles 24 h before insulin administration resulted in a significant decrease in DNA fragmentation related to the insulin-treated group, confirming the better genoprotective effect of the drug loaded in the niosomes compared to the free drug. Treatment of HUVEC cells with niosome carvedilol (1) nanoparticles 24 h before insulin administration decreases DNA fragmentation compared to the insulin-treated group, confirming the greater genoprotective effect of the drug loaded in the niosomes compared to the free drug [7].…”

“…Data reported in the literature suggest that carbazoles are able to modulate glucose metabolism, block adrenergic hyperactivation, prevent damage to β cells of the pancreas, inhibit inflammatory and oxidative mediators, control the cryptochrome or inhibit α-glucosidase (Table 2). Therefore, carbazole represents a versatile scaffold for the preparation of biologically active derivatives, useful in the treatment of diabetes [6,7,[27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46].…”

“…The adrenergic system, in part through beta-2 adrenergic receptors, regulates glucose and lipid metabolism in the liver, adipose tissue, and skeletal muscle. Taking into consideration all these properties, several studies were focused on the evaluation of the efficacy of carvedilol (1) in preventing heart complications in patients with diabetes [7,[51][52][53]. In an earlier study on the efficacy and tolerability of long-term administration of carvedilol (1), Nodari et al [27] evaluated the drug's effects in patients with chronic heart failure, a number of whom were also diabetic.…”

“…Therefore, various studies have been conducted in order to formulate the drug in transport systems capable of guaranteeing the desired therapeutic effect without increasing the dose to be administered. Since a high insulin concentration significantly increases DNA fragmentation, Farahani-Zangaraki et al, in 2021 [7], used the Comet test to assess the genoprotective effects of carvediol included into niosomes against supraphysiological insulin levels in human umbilical vein endothelial cells (HUVEC) [62]. As a result, incorporating carvedilol (1) into the nanoparticles increased efficiency by about fivefold.…”

“…The damages caused by hyperglycemia are related to the alteration of several physiological pathways. Several studies have shown, for example, that high levels of glucose, fatty acids, and insulin in the blood promote the production of reactive oxygen species (ROS), which cause direct DNA damage and promote insulin resistance [7].…”