Impact of citrus flavonoid supplementation on inflammation in lipopolysaccharide-induced periodontal disease in mice.

In general, the consumption of flavonoid-rich foods may influence the control/dysregulation of the magnitude and duration of inflammation and oxidative stress, which are known to contribute to multiple pathologies. Information regarding the impact of citrus flavonoid dietary supplementation on periodontal disease is still scarce. Herein, we investigated whether a diet supplemented with eriocitrin and eriodictyol could alter the course of the inflammatory response associated with LPS-induced periodontal disease in mice. Sixty BALB/c mice received a standard diet or a diet supplemented with different concentrations of eriocitrin or eriodictyol. After 30 days of food supplementation, a solution containing LPS from Escherichia coli was injected into the gingival tissues three times per week for four weeks. Neutrophils, mononuclear cells and eosinophils were assessed using a severity analysis system in H&E-stained sections and modified picrosirius red. The activities of myeloperoxidase (MPO), a marker of granulocyte infiltration, and eosinophil peroxidase (EPO) were determined spectrophotometrically. The oxidative damage was determined by measuring the malondialdehyde (MDA) content and anti-oxidative activity through the assessment of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Interleukin (IL)-1ß, TNF-α, and IL-10 were quantified by multiplex immunoassay. Periodontal inflammation was significantly inhibited by citrus flavonoid supplementation, including reduced flatness of the gingival epithelium and chronic and acute inflammatory cell infiltration, as well as loss of connective tissue in the gingival papillae. Both eriocitrin and eriodictyol inhibited gingival IL-1ß and TNF-α and increased IL-10 secondary to periodontitis. Significant protection and decreased MPO and EPO activity were detected in the periodontal tissue of citrus flavonoid-treated animals. In comparison with the LPS group, SOD, CAT and GPx activities were increased, while the MDA content was reduced, indicating decreased oxidative damage. These results suggest that a diet supplemented with the citrus flavonoids eriocitrin or eriodictyol may aid in the prevention of periodontitis, representing a potential method to enhance local immunity and host defense.

Rutin inhibits the in vitro formation of advanced glycation products and protein oxidation more efficiently than quercetin

Introduction: The exacerbated generation of advanced glycation end products (AGEs) triggers the onset of diabetic complications associated with hyperglycemia. The search for natural bioactive compounds that can inhibit AGE formation has gained immense interest. Quercetin and its glycoside derivative, rutin, are powerful antioxidants. They have been studied due to their potential to mitigate the disturbances observed in diabetes; however, studies comparing their antiglycation effects are limited. The aim of the present study was to compare the in vitro antiglycation potentials of quercetin and rutin. Methods: The in vitro model system of protein glycation was applied using bovine serum albumin (10 mg/mL) incubated with glucose (0.5 M) in the absence or presence of aminoguanidine (1 mM, prototype anti-AGE agent), metformin (1 mM), quercetin (100, 50, or 12.5 µM), or rutin (100, 50, or 12.5 µM). Before initiating incubations (day 0) and after 10, 20, and 30 days, aliquots were assayed for fluorescent AGEs. Markers of amino acid oxidation (dityrosine, N'-formylkynurenine, kynurenine), protein carbonyl groups (PCO), and protein crosslink formation were assessed after 30 days. Results: Both quercetin and rutin inhibited the formation of AGEs and decreased the PCO levels in a concentration-dependent manner, and moreover, the effect of rutin was more prominent than that of quercetin. Quercetin and rutin also decreased the formation of amino acid oxidation products and protein crosslinks; the best effects were observed in incubations with rutin. Conclusion: Rutin exhibited the most potent antiglycation and antioxidant activities, which may be attributed to the minor occurrence of interactions between albumin and rutin, making rutinnoside more available to exert its effects.

Lycopene Improves the Metformin Effects on Glycemic Control and Decreases Biomarkers of Glycoxidative Stress in Diabetic Rats.

INTRODUCTION: Oxidative stress and exacerbated generation of advanced glycation end products (AGEs) participate in the onset of diabetic complications. Lycopene is a potent antioxidant; evidence accounts for its ability to mitigate diabetic disturbances, including the deleterious events of advanced glycation. Therefore, this carotenoid has emerged as a candidate to be used in combination with antidiabetic drugs, such as metformin, attempting to counteract the glycoxidative stress. This study investigated the effects of the treatments with lycopene or metformin, alone or in combination, on glycoxidative stress biomarkers and antioxidant defenses in diabetic rats. METHODS: Streptozotocin-induced diabetic rats were treated for 35 days with lycopene (45 mg/kg) or metformin (250 mg/kg), alone or as mixtures in yoghurt. Plasma levels of glucose, triglycerides, cholesterol, thiobarbituric acid reactive substances and protein carbonyl groups (biomarkers of oxidative damage), fluorescent AGEs (biomarkers of advanced glycation), and paraoxonase 1 activity (antioxidant enzyme) were assessed. Changes in the hepatic and renal levels of glycoxidative damage biomarkers and the activities of antioxidant enzymes were investigated. RESULTS: The combination of lycopene with metformin maintained the beneficial effects of the isolated treatments, improving the glucose tolerance and lipid profile, lessening biomarkers of oxidative damage, and increasing the paraoxonase 1 activity. Besides, the combined therapy caused further decreases in postprandial glycemia, plasma levels of cholesterol and AGEs, avoided lipid peroxidation (plasma, kidney), and increased antioxidant defenses, mainly the activity of superoxide dismutase (liver, kidney), indicating the maintenance of the lycopene effects. CONCLUSION: Lycopene combined with metformin may act synergistically in the control of postprandial glycemia, dyslipidemia and glycoxidative stress, as well as increased antioxidant defenses, arising as a promising therapeutic strategy to mitigate diabetic complications.

Pentoxifylline mitigates renal glycoxidative stress in obese mice by inhibiting AGE/RAGE signaling and increasing glyoxalase levels.

AIM: The pharmacological properties of pentoxifylline have been re-evaluated, particularly in chronic kidney disease in diabetes, favored by its anti-inflammatory action. Definitive evidences of renal outcomes are lacking, which indicates the need for investigation of novel mechanisms of action of pentoxifylline. We postulated that components associated with the metabolism of advanced glycation end products (AGEs) may be modulated by pentoxifylline, which consequently decreases the detrimental effects of obesity on kidneys. MAIN METHODS: C57BL-6J mice were fed a high-fat diet for 14 weeks and treated with 50 mg/kg pentoxifylline during the last 7 weeks. Changes in the renal levels of AGE metabolism-associated components were investigated, with particular focus on the receptor for AGEs (RAGE), its downstream components, and components related to AGE detoxification, including glyoxalase 1 (GLO 1). KEY FINDINGS: Pentoxifylline reduced body weight gain, improved insulin sensitivity and glucose tolerance, downregulated biomarkers of glycoxidative stress, and enhanced plasma paraoxonase 1 activity. In the kidneys, pentoxifylline inhibited glomerular expansion, lipid deposition, reduced pro-inflammatory cytokine levels, and induced the activation of AMP-activated protein kinase. Pentoxifylline inhibited the renal accumulation of AGEs and reduced the levels of RAGE and its downstream components, and consequently mitigated oxidative stress and apoptosis. Pentoxifylline also increased the renal levels of GLO 1 and the activities of antioxidant enzymes. Urinary albumin levels were observed to be lowered, which reconfirmed the antialbuminuric effects of pentoxifylline. SIGNIFICANCE: The novel mechanisms of action help explain the renoprotective effects of pentoxifylline and the attenuation of obesity-associated renal complications related to glycoxidative stress.

Curcumin, Alone or in Combination with Aminoguanidine, Increases Antioxidant Defenses and Glycation Product Detoxification in Streptozotocin-Diabetic Rats: A Therapeutic Strategy to Mitigate Glycoxidative Stress.

Both oxidative stress and the exacerbated generation of advanced glycation end products (AGEs) have crucial roles in the onset and progression of diabetic complications. Curcumin has antioxidant and antidiabetic properties; its combination with compounds capable of preventing the advanced glycation events, such as aminoguanidine, is an interesting therapeutic option to counteract diabetic complications. This study is aimed at investigating the effects of treatments with curcumin or aminoguanidine, alone or in combination, on metabolic alterations in streptozotocin-diabetic rats; the focus was mainly on the potential of these bioactive compounds to oppose the glycoxidative stress. Curcumin (90 mg/kg) or aminoguanidine (50 and 100 mg/kg), alone or in combination, slightly decreased glycemia and the biomarkers of early protein glycation, but markedly decreased AGE levels (biomarkers of advanced glycation) and oxidative damage biomarkers in the plasma, liver, and kidney of diabetic rats. Some novel insights about the in vivo effects of these bioactive compounds are centered on the triggering of cytoprotective machinery. The treatments with curcumin and/or aminoguanidine increased the activities of the antioxidant enzymes (paraoxonase 1, superoxide dismutase, and catalase) and the levels of AGE detoxification system components (AGE-R1 receptor and glyoxalase 1). In addition, combination therapy between curcumin and aminoguanidine effectively prevented dyslipidemia in diabetic rats. These findings demonstrate the combination of curcumin (natural antioxidant) and aminoguanidine (prototype therapeutic agent with anti-AGE activity) as a potential complementary therapeutic option for use with antihyperglycemic agents, which may aggregate beneficial effects against diabetic complications.

Trigonelline and curcumin alone, but not in combination, counteract oxidative stress and inflammation and increase glycation product detoxification in the liver and kidney of mice with high-fat diet-induced obesity.

The development of obesity-associated complications is related to various pathogenic events including chronic inflammation, oxidative stress and generation of advanced glycation end products (AGEs). Due to their antioxidant, anti-inflammatory and antiglycation properties, trigonelline and curcumin are interesting candidates to counteract complications of obesity and diabetes mellitus. The current study aimed to investigate the effects of treatment with curcumin or trigonelline mixed into yoghurt, alone or in combination, on mice fed high-fat diet (HFD); the focus was mainly on the potential of these phytochemicals to counteract oxidative and glycative stress. Yoghurt alone improved glucose tolerance and reduced proinflammatory cytokine levels in HFD mice; however, it did not affect the antioxidant status. Trigonelline-enriched yoghurt prevented fat accumulation in adipose tissue, improved both insulin sensitivity and glucose tolerance and exerted anti-inflammatory and antiglycation activities (reduced AGEs and AGE receptor levels and increased the levels of components related to AGE detoxification) in liver and kidney of HFD mice. Curcumin-enriched yoghurt exerted anti-inflammatory and potent antioxidant properties (increased antioxidant enzyme activities and decreased lipid peroxidation) in liver and kidney of HFD mice. However, several beneficial effects were nullified when trigonelline and curcumin were administered in combination. Trigonelline and curcumin have emerged as promising complementary therapy candidates for liver and kidney complications associated with obesity. However, the administration of these phytochemicals in combination, at least in HFD mice, was not effective; inhibition of biotransformation processes and/or the reaching of toxic doses during combined treatment may be prevailing over the individual pharmacodynamic actions of these phytochemicals.

Curcumin combined with metformin decreases glycemia and dyslipidemia, and increases paraoxonase activity in diabetic rats.

BACKGROUND: Combination of current antidiabetic agents with natural antioxidants to manage diabetes mellitus and its complications has appeared as an emerging trend. Curcumin, a yellow pigment isolated from Curcuma longa rhizomes, has gained attention due to its beneficial effects in controlling the disturbances observed in diabetes mellitus. The purpose of this study was to investigate if yoghurt enriched with curcumin and metformin, individually or as mixtures, ameliorates physiometabolic parameters, glycoxidative stress biomarkers, and paraoxonase 1 (PON 1) activity in diabetic rats. METHODS: Streptozotocin-diabetic rats (6-week-old Wistar rats) were treated for 30 days with curcumin and metformin, isolated or as mixtures in yoghurt (10 rats/group). After treatments, the plasma levels of glucose, triacylglycerol, cholesterol, thiobarbituric acid reactive substances (TBARS, a biomarker of lipid oxidation), fluorescent advanced glycation end products (AGEs), and the activity of PON 1, an antioxidant enzyme were assessed. Data were analyzed using one-way analysis of variance (ANOVA) followed by Student-Newman-Keuls test. RESULTS: Treatment of diabetic rats with curcumin or metformin alone decreased the plasma levels of glucose, triacylglycerol, cholesterol, TBARS, and fluorescent AGEs, as well as increased the activity of PON 1. The combination of metformin with curcumin further decreased dyslipidemia and TBARS levels in diabetic rats, indicating synergy, and maintained the high levels of PON 1. CONCLUSION: These findings indicated that curcumin combined with metformin may act synergistically on dyslipidemia and oxidative stress, as well as increased PON 1 levels. Therefore, it might be a promising strategy for combating diabetic complications, mainly the cardiovascular events.

Curcumin improves the effect of a reduced insulin dose on glycemic control and oxidative stress in streptozotocin-diabetic rats.

Insulin with natural antioxidants is emerging as a combination treatment for diabetes mellitus that attempts to exert effective glycemic control without adverse effects. The present study aimed to investigate the additive effects on metabolic disturbances, oxidative damage, and antioxidant defenses in streptozotocin-diabetic rats treated with curcumin and a reduced insulin dose. The best results were obtained in the treatment of diabetic rats with 4-U/day insulin; however, the glycemia levels in these rats were lower than those in normal rats, indicating a risk of hypoglycemia. Isolated treatments using curcumin or insulin in a reduced dose (1 U/day) decreased glycemia, dyslipidemia, and biomarkers of liver and kidney damage and increased the activity of hepatic antioxidants (superoxide dismutase and glutathione peroxidase), however, only to a lesser extent than 4-U/day insulin, without improvements in catalase activity or plasma lipid peroxidation. Decreases in glycemia, dyslipidemia, and tissue damage markers were more evident in the curcumin + 1-U/day insulin treatment than those seen in isolated treatments. The activity of hepatic antioxidants, including catalase, was further increased, and biomarkers of oxidative damage were decreased. Curcumin with a reduced insulin dose appears to be a promising strategy for combating the complications associated with diabetes and oxidative stress.