In Vivo and Ex Vivo Evaluation of 1,3-Thiazolidine-2,4-Dione Derivatives as Euglycemic Agents.

Thiazolidinediones (TZDs), used to treat type 2 diabetes mellitus, act as full agonists of the peroxisome proliferator-activated receptor gamma. Unfortunately, they produce adverse effects, including weight gain, hepatic toxicity, and heart failure. Our group previously reported the design, synthesis, in silico evaluation, and acute oral toxicity test of two TZD derivatives, compounds 40 (C40) and 81 (C81), characterized as category 5 and 4, respectively, under the Globally Harmonized System. The aim of this study was to determine whether C40, C81, and a new compound, C4, act as euglycemic and antioxidant agents in male Wistar rats with streptozotocin-induced diabetes. The animals were randomly divided into six groups (n = 7): the control, those with diabetes and untreated, and those with diabetes and treated with pioglitazone, C40, C81, or C4 (daily for 21 days). At the end of the experiment, tissue samples were collected to quantify the level of glucose, insulin, triglycerides, total cholesterol, and liver enzymes, as well as enzymatic and nonenzymatic antioxidant activity. C4, without a hypoglycemic effect, displayed the best antioxidant activity. Whereas C81 could only attenuate the elevated level of blood glucose, C40 generated euglycemia by the end of the treatment. All compounds produced a significant decrease in triglycerides.

Diabetic Retinopathy: Important Biochemical Alterations and the Main Treatment Strategies.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by impaired glucose homeostasis, insulin resistance and hyperglycemia. Among its serious multisystemic complications is diabetic retinopathy (DR), which develops slowly and often insidiously. This disorder-the most common cause of vision loss in working-age adults-is characterized by functional and morphological changes in the retina. It results from the exacerbation of ischemic and inflammatory conditions prompted by alterations in the blood vessels, such as the development of leukostasis, thickening of the basement membrane, retinal neovascularization and fibrovascular tissue formation at the vitreoretinal interface. The pathogenic alterations are usually triggered at the biochemical level, involving a greater activity in 4 pathways: the polyol pathway, the hexosamine pathway, the formation of advanced glycation end-products and the activation of protein kinase C isoforms. When acting together, these pathways give rise to increased levels of reactive oxygen species and decreased levels of endogenous antioxidant agents, thus generating oxidative stress. All current therapies are aimed at the later stages of DR, and their application implies side effects. One possible strategy for preventing the complications of DM is to counteract the elevated superoxide production stemming from a high level of blood glucose. Accordingly, some treatments are under study for their capacity to reduce vascular leakage and avoid retinal ischemia, retinal neovascularization and macular edema. The present review summarizes the biochemical aspects of DR and the main approaches for treating it.

Current molecular aspects in the development and treatment of diabetes.

Diabetes mellitus (DM) leads to microvascular, macrovascular, and neurological complications. Less is understood about the mechanisms of this disease that give rise to weak bones. The many molecular mechanisms proposed to explain the damage caused by chronic hyperglycemia are organ and tissue dependent. Since all the different treatments for DM involve therapeutic activity combined with side effects and each patient represents a unique condition, there is no generalized therapy. The alterations stemming from hyperglycemia affect metabolism, osmotic pressure, oxidative stress, and inflammation. In part, hemodynamic modifications are linked to the osmotic potential of the excess of carbohydrates implicated in the disease. The change in osmotic balance increases as the disease progresses because hyperglycemia becomes chronic. The aim of the current contribution is to provide an updated overview of the molecular mechanisms that participate in the development and treatment of diabetes.

Study of new interactions of glitazone's stereoisomers and the endogenous ligand 15d-PGJ2 on six different PPAR gamma proteins.

Diabetes mellitus is a chronic disease characterized by hyperglycemia, insulin resistance and hyperlipidemia. Glitazones or thiazolidinediones (TZD) are drugs that act as insulin-sensitizing agents whose molecular target is the peroxisome proliferator-activated receptor gamma (PPARγ). The euglycemic action of TZD has been linked with the induction of type 4 glucose transporter. However, it has been shown that the effect of TZD depends on the specific stereoisomer that interacts with PPARγ. Therefore, this work is focused on exploring the interactions and geometry adopted by glitazone's stereoisomers and one endogenous ligand on different conformations of the six crystals of the PPARγ protein using molecular docking and molecular dynamics (MD) simulations accompanied by the MMGBSA approach. Specifically, the 2,4-thiazolidinedione ring, pioglitazone (PIO), rosiglitazone (ROSI) and troglitazone (TRO) stereoisomers (exogenous ligands), as well as the endogenous ligand 15d-PGJ2, were evaluated. The six crystallographic structures of PPARγ are available at Protein Data Bank as the PDB entries 2PRG, 4PRG, 3T03, 1I7I, 1FM6, and 4EMA. According to the results, a boomerang shape and a particular location of ligands were found with low variations according to the protein conformations. The 15d-PGJ2, TZD, PIO, ROSI and (S,S)-TRO enantiomers were mostly stabilized by twenty hydrophobic residues: Phe226, Pro227, Leu228, Ile281, Phe282, Cys285, Ala292, Ile296, Ile326, Tyr327, Met329, Leu330, Leu333, Met334, Val339, Ile341, Met348, Leu353, Phe363 and Met364. Most hydrogen bond interactions were found between the polar groups of ligands with Arg288, Ser289, Lys367, Gln286, His323, Glu343 and His449 residues. An energetic analysis revealed binding free energy trends that supported known experimental findings of other authors describing better binding properties for PIO, ROSI and (S,S)-TRO than for 15d-PGJ2 and the TZD ring.

In silico design, chemical synthesis and toxicological evaluation of 1,3-thiazolidine-2,4-dione derivatives as PPARγ agonists.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the metabolism of lipids and carbohydrates. The exogenous ligands of these receptors are thiazolidinediones (TZDs), which are used to treat type 2 diabetes mellitus (DM2). However, drugs from this group produce adverse effects such as hepatic steatosis. Hence, the aim of this work was to design a set of small molecules that can activate the γ isoform of PPARs while minimizing the adverse effects. The derivatives were designed containing the polar head of TZD and an aromatic body, serving simultaneously as the body and tail. Two ligands were selected out of 130 tested. These compounds were synthesized in a solvent-free reaction and their physicochemical properties and toxicity were examined. Acute oral toxicity was determined by administering these compounds to female Wistar rats in increasing doses (as per the OECD protocol 425). The median lethal dose (LD50) of the compound substituted with a hydroxyl heteroatom was above 2000 mg/kg, and that of the compound substituted with halogens was 700-1400 mg/kg. The results suggest that the compounds can interact with PPARγ and elicit biological responses similar to other TZDs, but without showing adverse effects. The compounds will be subsequently evaluated in a DM2 animal model.