Leishmaniasis is a highly prevalent, yet neglected disease caused by protozoan parasites of the genus Leishmania. In the search for newer, safer, and more effective antileishmanial compounds, we herein present a study of the mode of action in addition to a detailed structural and biological characterization of LQOF-G6 [N-benzoyl-N′-benzyl-N″-(4-tertbutylphenyl)guanidine]. X-ray crystallography and extensive NMR experiments revealed that LQOF-G6 nearly exclusively adopts the Z conformation stabilized by an intramolecular hydrogen bond. The investigated guanidine showed selective inhibitory activity on Leishmania major cysteine protease LmCPB2.8ΔCTE (CPB) with ~73% inhibition and an IC_50-CPB of 6.0 µM. This compound did not show any activity against the mammalian homologues cathepsin L and B. LQOF-G6 has been found to be nontoxic toward both organs and several cell lines, and no signs of hepatotoxicity or nephrotoxicity were observed from the analysis of biochemical clinical plasma markers in the treated mice. Docking simulations and experimental NMR measurements showed a clear contribution of the conformational parameters to the strength of the binding in the active site of the enzyme, and thus fit the differences in the inhibition values of LQOF-G6 compared to the other guanidines. Furthermore, the resulting data render LQOF-G6 suitable for further development as an antileishmanial drug.

Since lycopene has antioxidant activity, its combination with metformin may be useful to contrast diabetic complications related to oxidative stress. This study aimed to investigate the effects of metformin combined with lycopene on high-fat diet (HFD)-induced obese mice. Seventy-two C57BL-6J mice were divided into six groups: C (control diet-fed mice), H (HFD-fed mice for 17 weeks), H-V (HFD-fed mice treated with vehicle), H-M (HFD-fed mice treated with 50 mg/kg metformin), H-L (HFD-fed mice treated with 45 mg/kg lycopene), and H-ML (HFD-fed mice treated with 50 mg/kg metformin + 45 mg/kg lycopene). Treatments were administered for 8 weeks. Glucose tolerance, insulin sensitivity, fluorescent AGEs (advanced glycation end products), TBARS (thiobarbituric acid-reactive substances), and activities of antioxidant enzymes paraoxonase-1 (PON-1; plasma), superoxide dismutase, catalase and glutathione peroxidase (liver and kidneys) were determined. Metformin plus lycopene reduced body weight; improved insulin sensitivity and glucose tolerance; and decreased AGEs and TBARS in plasma, liver and kidneys. Combined therapy significantly increased the activities of antioxidant enzymes, mainly PON-1. Lycopene combined with metformin improved insulin resistance and glucose tolerance, and caused further increases in endogenous antioxidant defenses, arising as a promising therapeutic strategy for combating diabetic complications resulting from glycoxidative stress.

This study aimed to develop and validate a dual murine model integrating a high-fat diet (HFD) and a single streptozotocin (STZ) dose to induce diabetes mellitus (DM), alongside periodontitis (Perio) induced by ligature placement and oral inoculation with Porphyromonas gingivalis (P. gingivalis). The goal was to mimic human pathological conditions, creating a physiologically relevant environment to study the interplay between DM and Perio. A total of 128 six-week-old male C57BL/6J mice were randomly divided into four groups: Control, DM, Perio, and DM-P. DM was induced by HFD and STZ injection, and Perio by ligature placement and P. gingivalis infection. Evaluations occurred at baseline and days 7, 14, and 21. Alveolar bone loss was assessed by micro-computed tomography, and inflammation was examined histologically. DM mice showed elevated glucose levels and insulin resistance. Perio and DM-P groups experienced significant bone loss compared with Control and DM groups. The morphometric analysis revealed abundant inflammatory cells and reduced collagen fibers in Perio and DM-P groups, especially at day 7. This dual murine model successfully replicated the key features of DM and Perio, maintaining overall health of the animals, and good tolerability by those subjects to the stress of both interventional procedures.

Background: Biochemical events provoked by oxidative stress and advanced glycation may be inhibited by combining natural bioactives with classic therapeutic agents, which arise as strategies to mitigate diabetic complications. The aim of this study was to investigate whether lycopene combined with a reduced insulin dose is able to control glycemia and to oppose glycoxidative stress in kidneys of diabetic rats. Methods: Streptozotocin-induced diabetic rats were treated with 45 mg/kg lycopene + 1 U/day insulin for 30 days. The study assessed glycemia, insulin sensitivity, lipid profile and paraoxonase 1 (PON-1) activity in plasma. Superoxide dismutase (SOD) and catalase (CAT) activities and the protein levels of advanced glycation end-product receptor 1 (AGE-R1) and glyoxalase-1 (GLO-1) in the kidneys were also investigated. Results: An effective glycemic control was achieved with lycopene plus insulin, which may be attributed to improvements in insulin sensitivity. The combined therapy decreased the dyslipidemia and increased the PON-1 activity. In the kidneys, lycopene plus insulin increased the activities of SOD and CAT and the levels of AGE-R1 and GLO-1, which may be contributing to the antialbuminuric effect. Conclusions: These findings demonstrate that lycopene may aggregate favorable effects to insulin against diabetic complications resulting from glycoxidative stress.

Bixin (C₂₅H₃₀O₄; 394.51 g/mol) is the main apocarotenoid found in annatto seeds. It has a 25-carbon open chain structure with a methyl ester group and carboxylic acid. Bixin increases the expression of antioxidant enzymes, which may be interesting for counteracting oxidative stress. This study investigated whether bixin-rich annatto extract combined with metformin was able to improve the disturbances observed in high-fat diet (HFD)-induced obesity in mice, with an emphasis on markers of oxidative damage and antioxidant defenses. HFD-fed mice were treated for 8 weeks with metformin (50 mg/kg) plus bixin-rich annatto extract (5.5 and 11 mg/kg). This study assessed glucose tolerance, insulin sensitivity, lipid profile and paraoxonase 1 (PON-1) activity in plasma, fluorescent AGEs (advanced glycation end products), TBARSs (thiobarbituric acid-reactive substances), and the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver and kidneys. Treatment with bixin plus metformin decreased body weight gain, improved insulin sensitivity, and decreased AGEs and TBARSs in the plasma, liver, and kidneys. Bixin plus metformin increased the activities of PON-1, SOD, CAT, and GSH-Px. Bixin combined with metformin improved the endogenous antioxidant defenses in the obese mice, showing that this combined therapy may have the potential to contrast the metabolic complications resulting from oxidative stress.

Cissus verticillata (plant-insulin) is used in the Brazilian popular medicine to treat symptoms of diabetes. Studies about its ability to contrast glycoxidative stress is lacking, which may add mechanistic information about its effects on treat diabetic complications. This study investigated the ability of Cissus verticillata leaf hydroethanolic extract (CvExt) to scavenge reactive oxygen species (ROS) and to inhibit the formation of advanced glycation end products (AGEs). ROS scavenging assays were used to test CvExt antioxidant activity. Incubations of bovine serum albumin with glucose (0.5 M) or methylglyoxal (2 mM) and CvExt (250, 125, and 62.5 μg/mL) were used to test the antiglycation activity, by monitoring fluorescent AGEs, markers of amino acid oxidation, and protein carbonyl groups (PCO). The plant extract was submitted to liquid−liquid extractions, fractions were analyzed by liquid chromatography with tandem mass spectrometry, and the data obtained were subjected to partial least-squares discriminant analysis. CvExt scavenged ROS inhibited the formation of AGEs and amino acid oxidation products, and decreased PCO levels. The main metabolites found in CvExt were flavonoids, cinnamic acid derivatives, coumarins, free amino acids, and some lipophilic compounds. CvExt inhibited glycoxidative stress in vitro, which can be associated with its complex chemical composition.