Hydroxyethylcellulose-Based Hydrogels Containing Liposomes Functionalized with Cell-Penetrating Peptides for Nasal Delivery of Insulin in the Treatment of Diabetes.

Liposomes functionalized with cell-penetrating peptides are a promising strategy to deliver insulin through the nasal route. A hydrogel based on hydroxyethylcellulose (HEC) aqueous solution was prepared, followed by a subsequent addition of liposomes containing insulin solution functionalized with trans-activator of transcription protein of HIV-1 (TAT) or Penetratin (PNT). The formulations were characterized for rheological behavior, mucoadhesion, syringeability, in vitro release and in vivo efficacy. Rheological tests revealed non-Newtonian fluids with pseudoplastic behavior, and the incorporation of liposomes (HLI, HLITAT and HLIPNT) in hydrogels did not alter the behavior original pseudoplastic characteristic of the HEC hydrogel. Pseudoplastic flow behavior is a desirable property for formulations intended for the administration of drugs via the nasal route. The results of syringeability and mucoadhesive strength from HEC hydrogels suggest a viable vehicle for nasal delivery. Comparing the insulin release profile, it is observed that HI was the system that released the greatest amount while the liposomal gel promoted greater drug retention, since the liposomal system provides an extra barrier for the release through the hydrogel. Additionally, it is observed that both peptides tested had an impact on the insulin release profile, promoting a slower release, due to complexation with insulin. The in vitro release kinetics of insulin from all formulations followed Weibull's mathematical model, reaching approximately 90% of release in the formulation prepared with HEC-based hydrogels. Serum insulin levels and the antihyperglycemic effects suggested that formulations HI and HLI have potential as carriers for insulin delivery by the nasal pathway, a profile not observed when insulin was administered by subcutaneous injection or by the nasal route in saline. Furthermore, formulations functionalized with TAT and PNT can be considered promoters of late and early absorption, respectively.

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.

In vitro inhibition of protein glycation and advanced glycation end products formation by hydroethanolic extract and two fractions of Simaba trichilioides roots.

Long-term hyperglycemia maintenance is responsible for increased protein glycation and formation of advanced glycation end products (AGEs), both are associated with the onset of diabetes mellitus complications. Efforts have been made to discover new agents having antiglycation potential. The aim of this study was to investigate the effects of the hydroethanolic extract and the ethyl acetate and methanolic fractions of Simaba trichilioides roots on the formation of AGEs. In an in vitro model system of protein glycation, incubations with hydroethanolic extract, ethyl acetate or methanolic fractions of S. trichilioides decreased the fluorescent AGEs, and markers of tyrosine and tryptophan oxidation. Protein crosslinking was reduced in the presence of the ethyl acetate fraction of S. trichilioides. Simaba trichilioides roots seem to be a promising source of compounds having ability to prevent glycoxidation changes, with potential applications in complementary therapies for management of 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.

Prevention of Elevation in Plasma Triacylglycerol with High-Dose Bezafibrate Treatment Abolishes Insulin Resistance and Attenuates Glucose Intolerance Induced by Short-Term Treatment with Dexamethasone in Rats.

OBJECTIVE: Fibrates are used as lipid-lowering drugs and are well tolerated as cotreatments when glucose metabolism disturbances are also present. Synthetic glucocorticoids (GCs) are diabetogenic drugs that cause dyslipidemia, dysglycemia, glucose intolerance, and insulin resistance when in excess. Thus, we aimed to describe the potential of bezafibrate in preventing or attenuating the adverse effects of GCs on glucose and lipid homeostasis. METHODS: Male Wistar rats were treated with high-dose bezafibrate (300 mg/kg, body mass (b.m.)) daily for 28 consecutive days. In the last five days, the rats were also treated with dexamethasone (1 mg/kg, b.m.). RESULTS: Dexamethasone treatment reduced the body mass gain and food intake, and bezafibrate treatment exerted no impact on these parameters. GC treatment caused an augmentation in fasting and fed glycemia, plasma triacylglycerol and nonesterified fatty acids, and insulinemia, and bezafibrate treatment completely prevented the elevation in plasma triacylglycerol and attenuated all other parameters. Insulin resistance and glucose intolerance induced by GC treatment were abolished and attenuated, respectively, by bezafibrate treatment. CONCLUSION: High-dose bezafibrate treatment prevents the increase in plasma triacylglycerol and the development of insulin resistance and attenuates glucose intolerance in rats caused by GC treatment, indicating the involvement of dyslipidemia in the GC-induced insulin resistance.