The Effects of Taurine Supplementation on Metabolic Profiles, Pentosidine, Soluble Receptor of Advanced Glycation End Products and Methylglyoxal in Adults With Type 2 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVES: Advanced glycation end products, along with methylglyoxal (MGO) as their precursor, play a major role in increased complications of type 2 diabetes mellitus (T2DM). Taurine (2-aminoethanesulphonic acid), a conditionally essential amino acid, is found in most mammalian tissues. Taurine is known as an antiglycation compound. This study was designed to investigate the effects of taurine supplementation on metabolic profiles, pentosidine, MGO and soluble receptors for advanced glycation end products in patients with T2DM. METHODS: In this double-blind randomized controlled trial, 46 patients with T2DM were randomly allocated into taurine and placebo groups. Participants received either 3,000 mg/day taurine or placebo for 8 weeks. Metabolic profiles, pentosidine, MGO and soluble receptors for advanced glycation end products levels were assessed after 12 h of fasting at baseline and completion of the clinical trial. Independent t test, paired t test, Pearson correlation and analysis of covariance were used for analysis. RESULTS: The mean serum levels of fasting blood sugar (p=0.01), glycated hemoglobin (p=0.04), insulin (p=0.03), homeostasis model assessment-insulin resistance (p=0.004), total cholesterol (p=0.01) and low-density lipoprotein cholesterol (p=0.03) significantly were reduced in the taurine group at completion compared with the placebo group. In addition, after completion of the study, pentosidine (p=0.004) and MGO (p=0.006) were significantly reduced in the taurine group compared with the placebo group. CONCLUSIONS: The results of this trial show that taurine supplementation may decrease diabetes complications through improving glycemic control and advanced glycation end products.

The effects of Bushen Yiqi Huoxue prescription and its disassembled prescriptions on a diabetic retinopathy model in Sprague Dawley rats.

BACKGROUND: Diabetic retinopathy (DR) is one of the most serious complications in the late stages of diabetes, with a complex mechanism. As a complication affecting local lesions, few studies have compared differences of cytokine expression in the serum and retina. Owing to the specific value of traditional Chinese medicine (TCM) to complex diseases, TCM research has recently boomed in the prevention and treatment of diabetes. Bushen Yiqi Huoxue (BYH) prescription is a Chinese herbal compound that has been independently developed by our research group and has been proved to have a positive effect on DR; however, its specific mechanism and compatibility rule remain to be further explored. OBJECTIVE: To construct a DR model of Sprague Dawley (SD) rats, simultaneously detect multiple factor expression in the serum and retina of rats, explore the effect of BYH prescription and its disassembled prescriptions on DR, and discuss the influence of various compatibility combinations. METHODS: BYH prescription was disassembled into two new compatibilities in the absence of Rehmanniae Radix (Yiqi Huoxue prescription, YH prescription) or Ginseng Radix et Rhizoma (Bushen Huoxue prescription, BH prescription). Male SD rats were induced using streptozotocin + high-fat and high-sugar diet to establish DR models and were divided into groups, then the intragastric administration and sampling. The body weight and fasting blood glucose of rats were continuously recorded during feeding; pathophysiological status observation of the retina by haematoxylin and eosin (HE) staining; advanced glycation end products (AGEs) and haemoglobin A1c (HbA1c) level detection in the rat serum by enzyme-linked immunosorbent assay; and the Luminex technique was used to detect the ICAM-1, IL-1ß, IL-6, TNF-α and vascular endothelial growth factor (VEGF) expression concentrations in the retinal tissue and serum. RESULTS: The results of blood glucose, body weight and HE staining proved that the model was successfully constructed, and the three combinations could reduce the retinal injury in DR rats. Serum AGEs and HbA1c levels of the model group increased compared with the control group (CG). Compared with the DR model group, only AGEs decreased in the BYH group, while the AGEs and HbA1c levels were significantly inhibited in the YH and BH groups, showing a significant correlation between the expression of AGEs and HbA1c in the serum of DR rats. In the serum of rats, IL-1ß, IL-6, TNF-α and VEGF concentrations in the DR model group increased, although no statistical difference was observed in the ICAM-1 data compared with the CG. Compared with the DR model group, the IL-1ß, IL-6 and TNF-α expression decreased in the BYH group. Moreover, the IL-6 and TNF-α expression decreased in the YH group and only the IL-6 expression decreased in the BH group. In the retina tissue, the model group had higher ICAM-1, IL-1ß, IL-6, TNF-α and VEGF levels than the CG. Compared with the DR model group, TNF-α in the BYH group rats decreased, and the ICAM-1, IL-6 and TNF-α concentrations decreased in the YH and BH groups. Furthermore, differences in the ICAM-1 and VEGF expression in the serum and retina existed. CONCLUSION: BYH compound and its disassembled prescriptions could improve the DR model rats induced with streptozotocin + high-fat and high-sugar diet, respectively, by inhibiting chronic blood glucose, AGEs, or inflammation response. The expression level and location of each factor are different, confirming that the effect of TCM prescriptions is not the simple addition of each single drug or its chemical components, but the rationality of its internal compatibility combination. Further, ICAM-1 and VEGF have exactly different expression levels, suggesting more attention to be paid by other researchers or doctors in future studies.

Glucopyranoside flavonoids isolated from leaves of Spinacia oleracea (spinach) inhibit the formation of advanced glycation end products (AGEs) and aldose reductase activity (RLAR).

BACKGROUND AND PURPOSE: The formation and accumulation of advanced glycation end products (AGEs) and rat lens aldose reductase (RLAR) generated in the glycation process play an outstanding role in the complications of diabetes. Owing to the adverse effects of AGEs on diabetic patients, the search for new anti-AGE agents from plants without side effects has had significant interest from the researchers in the last decades for the development of a therapy that improves diabetic complications. Spinach could reverse the formation of AGEs and RLAR. This study aimed to investigate the ability of 10 known glucopyranosides flavonoids isolated from Spinacia oleracea on the formation of AGEs and RLAR in vitro and in vivo experiments. MATERIALS AND METHODS: Methanol extract of leaves of spinach was subjected to bioassay-guided fractionation using to silica gel column chromatographic followed by gel filtration by Sephadex LH-20. BSA glucose system and in vitro bioassays using rat lens aldose reductase (RLAR) were employed to evaluated inhibitory activity on the formation of AGEs. The induced diabetes in zebrafish by immersing in a 111 mM glucose solution for 14 days, revealed increased glycation of proteins in the eyes. Measurements of glycated hemoglobin and fructosamine were used to verify the anti-AGEs effect of the isolated flavonoids. KEY RESULTS: Through bioassay-guided fractionation of methanol extract of leaves spinach, ten known glucopyranoside flavonoids (1-10) have been isolated, and spectroscopic studies established their structures. Among the isolated compounds are: patuletin-3-O-(2"-coumaroylglucosyl)-(1→6)-[apiosyl-(1→2)]- ß-d-glucopyranoside (7), patuletin 3-O-(2"-feruloyl glucosyl)-(1→6)-[apiosyl-(1→2)]- ß-d-glucopyranoside (8), they have shown potent inhibition on AGEs formation, stronger than the positive controls used in the different experiments. CONCLUSION AND IMPLICATIONS: The findings indicated that glucopyranoside flavonoids found in Spinacia oleracea might have therapeutic potential for decreasing protein glycation, and might ameliorate AGE-related diabetic complications.

Effects of Agriophyllum squarrosum extracts on glucose metabolism in KKAy mice and the associated underlying mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Agriophyllum squarrosum (L.) Moq. is a traditional Mongol medicine commonly used in the treatment of diabetes. AIM OF THE STUDY: To examine the effects of Agriophyllum squarrosum extract (ASE) on glucose metabolism in type 2 diabetic KKAy mice, and to investigate the mechanisms underlying these effects. MATERIAL AND METHODS: KKAy mice were divided into a model control group (MCG), a low-dose Agriophyllum squarrosum extract group (LASEG), a medium-dose Agriophyllum squarrosum extract group (MASEG), a high-dose Agriophyllum squarrosum extract group (HASEG), and a metformin group (MEG). Syngeneic C57BL/6 mice were used as a normal control group (NCG). Drugs were administered to all mice by gavage for 8 weeks. Random blood glucose levels were measured in the mice at baseline and after 2, 4, and 8 weeks of treatment. Glucose tolerance was measured after 6 weeks of drug administration. After 8 weeks, glycated serum proteins (GSP) and advanced glycation end-products (AGEs) in the serum of all mice were measured. Sections of mouse liver tissues were used for periodic acid-Schiff staining (PAS) and the content of hepatic glycogen was determined. Immunohistochemistry was used to determine the effects of ASE on liver phospho-insulin receptor substrate 2 (P-IRS2) protein expression. Western blotting was used to quantify the protein expression levels of phosphatidylinositol 3-kinase (PI3K), AKT, phospho-AKT (S473) (P-AKT), glycogen synthase kinase 3ß (GSK3ß), and glucose transporters 4 (GLUT4), while PCR was used to quantify the mRNA expression levels of insulin receptor substrate 2 (IRS2), PI3K, AKT, GSK3ß, and GLUT4. RESULTS: ASE treatment decreased random blood glucose levels in type 2 diabetic KKAy mice; increased glucose tolerance; decreased serum GSP and AGEs content; increased glycogen synthesis in liver tissues; upregulated the protein expression levels of PI3K, AKT, GLUT4, and P-IRS2; downregulated the protein expression level of GSK3ß in liver tissues; upregulated the mRNA expression levels of IRS2, PI3K, AKT, and GLUT4; and downregulated the mRNA expression level of GSK3ß in liver tissues. CONCLUSION: ASE treatment may increase glucose metabolism in KKAy mice and improve glucose tolerance. The underlying mechanisms of the beneficial effects of ASE may be associated with the increase of glycogen synthesis, the inhibition of AGEs production, the upregulation of IRS2, PI3K, AKT, and GLUT4 protein and mRNA expression, and the downregulation of GSK3ß protein and mRNA expression.

Liquiritigenin Reduces Blood Glucose Level and Bone Adverse Effects in Hyperglycemic Adult Zebrafish.

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia that induces other pathologies including diabetic retinopathy and bone disease. Adult Danio rerio (zebrafish) represents a powerful model to study both glucose and bone metabolism. Then, the aim of this study was to evaluate the effects of liquiritigenin (LTG) on blood glucose level and diabetes complications in hyperglycemic adult zebrafish. LTG is a flavonoid extracted from Glycyrrhiza glabra roots which possess important antioxidant, anti-inflammatory, and anti-diabetic properties. During four weeks of glucose treatment, LTG significantly prevented the onset of the hyperglycemia in adult zebrafish. Moreover, hyperglycemic fish showed increased advanced glycation end-products (AGEs) and parathormone levels whereas LTG completely prevented both of these metabolic alterations. Large bone-loss areas were found in the scales of glucose-treated fish whereas only small resorption lacunae were detected after glucose/LTG treatment. Biochemical and histological tartrate resistant acid phosphatase (TRAP) assays performed on explanted scales confirmed that LTG prevented the increase of osteoclastic activity in hyperglycemic fish. The osteoblastic alkaline phosphatase (ALP) activity was clearly lost in scales of glucose-treated fish whereas the co-treatment with LTG completely prevented such alteration. Gene expression analysis showed that LTG prevents the alteration in crucial bone regulatory genes. Our study confirmed that LTG is a very promising natural therapeutic approach for blood glucose lowering and to contrast the development of bone complications correlated to chronic hyperglycemia.

Carnosine supplementation does not affect serum concentrations of advanced glycation and precursors of lipoxidation end products in autism: a randomized controlled clinical trial.

BACKGROUND: Abundant evidence indicate the increased levels of oxidative stress in patients with autism. Advanced glycation end products and advanced lipoxidation end products and their precursors play a major role in increased oxidative stress in numerous metabolic and neurologic diseases. Carnosine is a natural dipeptide with antiglycation effects. The aim of this trial was to examine the effects of carnosine supplementation on the advanced glycation end products and the precursors of advanced lipoxidation end products in patients with autism. METHOD: This randomized double-blind, placebo-controlled clinical trial was conducted on 36 autistic children, 18 in the carnosine group and 18 in the placebo group. The groups received a daily supplement of 500 mg carnosine or placebo for two months, respectively. Plasma concentrations of glycation and precursors of lipoxidation markers were evaluated by enzyme-linked immunosorbent assay method. RESULTS: In all, 63.9% of the autistic children had normal nutritional status. Carnosine supplementation did not significantly alter plasma concentrations of advanced glycation end products and precursors of advanced lipoxidation end products in autistic children. CONCLUSION: The findings indicate that supplementation of carnosine could not change advanced glycation end products and precursor of advanced lipoxidation end products in autistic children.

Voluntary exercise reverses immune aging induced by oxidative stress in aging mice.

Excessive oxidative stress leads to aging due to persistent damage to the cells, tissues, and the entire organism. Immunosenescence is also a devastating consequence of oxidative stress, but there is a lack of research on effective ways to overcome it. In this study, we used physiologic and immunological aging mouse models that had sustained oxidative stress to investigate whether voluntary exercise and/or antioxidant treatment could overcome oxidative damage as well as aging. We established an aging model induced by continuously administering d-galactose (d-gal) to 6-week-old female C57BL/6J mice. We also assessed reversal of immunosenescence by providing free-wheel running and vitamin E (vit E) supplementation to this aging model. As an aging index, the level of advanced glycation end products (AGEs) in the blood was measured. Phenotypes of T cells in the thymus and spleen were examined as an index of immunosenescence. Intracellular reactive oxygen species (ROS) levels in the mouse spleen and levels of AGEs in the blood were significantly higher after 6 weeks of d-gal administration. In addition, immunosenescence was observed, in which the naïve:effector cell ratio in the spleen decreased. After 4 weeks of free-wheel running and vit E administration, both intracellular ROS and serum AGE levels decreased. Above all, free-wheel running restored the naïve:effector ratio of cytotoxic T lymphocytes reduced by d-gal administration. Taken together, these results suggest that voluntary exercise may be effective in restoring immunosenescence induced by oxidative stress.

Effectiveness of arginase inhibitors against experimentally induced stroke.

Stroke is a lethal disease, but it disables more than it kills. Stroke is the second leading cause of death and the most frequent cause of permanent disability in adults worldwide, with 90% of survivors having residual deficits. The pathophysiology of stroke is complex and involves a strong inflammatory response associated with oxidative stress and activation of several proteolytic enzymes. The current study was designed to investigate the effect of arginase inhibitors (L-citruline and L-ornithine) against ischemic stroke induced in rats by middle cerebral artery occlusion (MCAO). MCAO resulted in alteration in rat behavior, brain infarct, and edema associated with disruption of the blood-brain barrier (BBB). This was mediated through overexpression of arginase I and II, inducible NOS (iNOS), malondialdehyde (MDA), advanced glycation end products (AGEs), TNF-α, and IL-1ß and downregulation of endothelial nitric oxide synthase (eNOS). Treatment with L-citruline and L-ornithine and the standard neuroprotective drug cerebrolysin ameliorated all the deleterious effects of stroke. These results indicate the possible use of arginase inhibitors in the treatment of stroke after suitable clinical trials are done.

l-Carnosine supplementation attenuated fasting glucose, triglycerides, advanced glycation end products, and tumor necrosis factor-α levels in patients with type 2 diabetes: a double-blind placebo-controlled randomized clinical trial.

Considering the pathologic importance of metabolic disturbances, advanced glycation end products (AGEs), and chronic inflammation in diabetes mellitus and ameliorating potentials of l-carnosine in hampering these detritions and because these effects have not been investigated in patients with type 2 diabetes (T2D) so far, we conducted the current study. We hypothesized that l-carnosine would improve glycemic control, lipid profile, AGE, soluble receptor of AGEs (sRAGE), and inflammatory markers. In a randomized, double-blind, placebo-controlled clinical trial, 54 patients with T2D were recruited and assigned into either intervention group (n=27, receiving 2 capsules of l-carnosine 500 mg each) or control group (n=27). Blood samples and dietary intakes information were collected at baseline and after 12 weeks of intervention. l-Carnosine supplementation resulted in significant decrease in fat mass and an increase in fat-free mass in the intervention group compared with the placebo group (1.5% and 1.7%, respectively) (P<.05). A significant reduction in fasting blood glucose (13.1 mg/dL); glycated hemoglobin (.6%); and serum levels of triglycerides (29.8 mg/dL), carboxymethyl lysine (91.8 ng/mL), and tumor necrosis factor-α was detected in the l-carnosine group compared with the placebo group (P<.05). In the l-carnosine group, a significant reduction in serum pentosidine levels (2.8 ng/mL) was observed compared with those at baseline (P<.05). No significant differences were observed in dietary intake, body mass index, systolic and diastolic blood pressure, fasting insulin levels, homeostasis model assessment of insulin resistance and secretion, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, sRAGE, interleukin (IL)-6, and IL-1ß levels between the groups after adjusting for baseline values and covariates (P>.05). Collectively, l-carnosine lowered fasting glucose, serum levels of triglycerides, AGEs, and tumor necrosis factor-α without changing sRAGE, IL-6, and IL-1ß levels in T2D patients.

Increased levels of advanced glycation end products positively correlate with iron overload and oxidative stress markers in patients with ß-thalassemia major.

The impaired biosynthesis of the ß-globin chain in ß-thalassemia leads to the accumulation of unpaired alpha globin chains, failure in hemoglobin formation, and iron overload due to frequent blood transfusion. Iron excess causes oxidative stress and massive tissue injuries. Advanced glycation end products (AGEs) are harmful agents, and their production accelerates in oxidative conditions. This study was conducted on 45 patients with major ß-thalassemia who received frequent blood transfusions and chelation therapy and were compared to 40 healthy subjects. Metabolic parameters including glycemic and iron indices, hepatic and renal functions tests, oxidative stress markers, and AGEs (carboxymethyl-lysine and pentosidine) levels were measured. All parameters were significantly increased in ß-thalassemia compared to the control except for glutathione levels. Blood glucose, iron, serum ferritin, non-transferrin-bound iron (NTBI), MDA, soluble form of low-density lipoprotein receptor, glutathione peroxidase, total reactive oxygen species (ROS), and AGE levels were significantly higher in the ß-thalassemia patients. Iron and ferritin showed a significant positive correlation with pentosidine (P < 0.01) but not with carboxymethyl-lysine. The NTBI was markedly increased in the ß-thalassemia patients, and its levels correlated significantly with both carboxymethyl-lysine and pentosidine (P < 0.05). Our findings confirm the oxidative status generated by the iron overload in ß-thalassemia major patients and highlight the enhanced formation of AGEs, which may play an important role in the pathogenesis of ß-thalassemia major.

Cardamom powder supplementation prevents obesity, improves glucose intolerance, inflammation and oxidative stress in liver of high carbohydrate high fat diet induced obese rats.

BACKGROUND: Cardamom is a well-known spice in Indian subcontinent, used in culinary and traditional medicine practices since ancient times. The current investigation was untaken to evaluate the potential benefit of cardamom powder supplementation in high carbohydrate high fat (HCHF) diet induced obese rats. METHOD: Male Wistar rats (28 rats) were divided into four different groups such as Control, Control + cardamom, HCHF, HCHF + cardamom. High carbohydrate and high fat (HCHF) diet was prepared in our laboratory. Oral glucose tolerance test, organs wet weight measurements and oxidative stress parameters analysis as well as liver marker enzymes such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) activities were assayed on the tissues collected from the rats. Plasma lipids profiles were also measured in all groups of animals. Moreover, histological staining was also performed to evaluate inflammatory cells infiltration and fibrosis in liver. RESULTS: The current investigation showed that, HCHF diet feeding in rats developed glucose intolerance and increased peritoneal fat deposition compared to control rats. Cardamom powder supplementation improved the glucose intolerance significantly (p > 0.05) and prevented the abdominal fat deposition in HCHF diet fed rats. HCHF diet feeding in rats also developed dyslipidemia, increased fat deposition and inflammation in liver compared to control rats. Cardamom powder supplementation significantly prevented the rise of lipid parameters (p > 0.05) in HCHF diet fed rats. Histological assessments confirmed that HCHF diet increased the fat deposition and inflammatory cells infiltration in liver which was normalized by cardamom powder supplementation in HCHF diet fed rats. Furthermore, HCHF diet increased lipid peroxidation, decreased antioxidant enzymes activities and increased advanced protein oxidation product level significantly (p > 0.05) both in plasma and liver tissue which were modulated by cardamom powder supplementation in HCHF diet fed rats. HCHF diet feeding in rats also increased the ALT, AST and ALP enzyme activities in plasma which were also normalized by cardamom powder supplementation in HCHF diet fed rats. Moreover, cardamom powder supplementation ameliorated the fibrosis in liver of HCHF diet fed rats. CONCLUSION: This study suggests that, cardamom powder supplementation can prevent dyslipidemia, oxidative stress and hepatic damage in HCHF diet fed rats.

SIGNALING PATHWAYS REGULATED BY BRASSICACEAE EXTRACT INHIBIT THE FORMATION OF ADVANCED GLYCATED END PRODUCTS IN RAT BRAIN.

BACKGROUND: The goal of this study was identification signaling molecules mediated the formation of AGEs in brain of rats injected with CdCl2 and the role of camel whey proteins and Brassicaceae extract on formation of AGEs in brain. METHODS: Ninety male rats were randomly grouped into five groups; Normal control (GpI) and the other rats (groups II-V) were received a single dose of cadmium chloride i.p (5 µg/kg/b.w) for induction of neurodegeneration. Rats in groups III-V were treated daily with whey protein (1g/kg b.w) or Brassicaceae extract (1mg/kg b.w) or combined respectively for 12 weeks. RESULTS: It was found that whey protein combined with Brassicaceae extract prevented the formation of AGEs and enhance the antioxidant activity compared with untreated group (p <0.001). Serum tumor necrosis factor (TNF-α) and interleukine (IL-6) levels were significantly decreased (p<0.01) in rats treated with whey protein and Brassicaceae extract formation compared with untreated. The combined treatment showed a better impact than individual ones (p<0.001). The level of cAMP but not cGMP were lowered in combined treatment than individual (p<0.01). CONCLUSION: It can be postulated that Whey protein + Brassicaceae extract formation could have potential benefits in the prevention of the onset and progression of neuropathy in patients.

Consumption of diets with low advanced glycation end products improves cardiometabolic parameters: meta-analysis of randomised controlled trials.

Studies examining the effects of consumption of diets low in advanced glycation end products (AGEs) on cardiometabolic parameters are conflicting. Hence, we performed a meta-analysis to determine the effect of low AGE diets in reducing cardiometabolic risk factors. Seventeen randomised controlled trials comprising 560 participants were included. Meta-analyses using random effects models were used to analyse the data. Low AGE diets decreased insulin resistance (mean difference [MD] -1.3, 95% CI -2.3, -0.2), total cholesterol (MD -8.5 mg/dl, 95% CI -9.5, -7.4) and low-density lipoprotein (MD -2.4 mg/dl, 95% CI -3.4, -1.3). There were no changes in weight, fasting glucose, 2-h glucose and insulin, haemoglobin A1c, high-density lipoprotein or blood pressure. In a subgroup of patients with type 2 diabetes, a decrease in fasting insulin (MD -7 µU/ml, 95% CI -11.5, -2.5) was observed. Tumour necrosis factor α, vascular cell adhesion molecule-1, 8-isoprostane, leptin, circulating AGEs and receptor for AGEs were reduced after consumption of low AGE diets with increased adiponectin and sirtuin-1. Our findings suggest that diets low in AGEs may be an effective strategy for improving cardiometabolic profiles in individuals with and without type 2 diabetes.

Prevention of advanced glycation end-products formation in diabetic rats through beta-cell modulation by Aegle marmelos.

BACKGROUND: Although the anti-diabetic activity of Aegle marmelos (AM) is known, however, its anti-glycation activity is not reported yet. In this study, we have investigated its anti-glycation activity under in vitro and in vivo conditions and determined possible mechanism(s) in streptozotocin-induced diabetic rats. METHODS: Effective dose of AM (400 mg/kg) was administrated orally to diabetic rats for 42 days. Thereafter, blood glucose, serum insulin, HbA1c, antioxidant status, and advanced glycation end-products (AGEs) were measured. AGEs and its receptor (RAGE) in kidney were analyzed by immunohistochemistry and immunoblotting. Additionally, pancreatic sections were co-stained for insulin and glucagon and images were acquired using NIKON TE2000E fluorescence microscopy. RESULTS: Oral administration of AM extract resulted in a significant increase in serum insulin by better functioning of ß-cell and preserving pancreatic ß-cell integrity in diabetic rats. Treatment of AM extract significantly (p = 0.000) prevented the formation of HbA1c in the diabetic rats (8.20 ± 0.18% vs. 11.92 ± 0.59%). The circulatory AGEs level found in diabetic rat was significantly (p = 0.002) attenuated by AM treatment (0.66 ± 0.05 mg/ml vs. 1.18 ± 0.19 mg/ml). AM treatment also reduced AGEs accumulation around Bowman's capsule and in tubular basement membrane around arteries in diabetic rat kidney. The accumulation of RAGE was very similar to that of AGEs in diabetic rats and RAGE accumulation was also prevented by AM treatment. The extract showed potent antioxidant activity both under in vitro and in vivo systems. Eugenol, one of the active constituent of AM fruit extract, showed acute blood glucose-lowering activity in diabetic rats and enhanced glucose-stimulated insulin secretion from mice islets. CONCLUSION: AM extract prevents AGEs formation by modulating ß-cell function, and eugenol may play important role in preventing complications of diabetes in this rat model.

Berberine exerts renoprotective effects by regulating the AGEs-RAGE signaling pathway in mesangial cells during diabetic nephropathy.

In this study, we explored the effect of berberine treatment on the AGEs-RAGE pathway in a rat model of diabetic nephropathy, and we investigated the mechanism by which key factors caused kidney injury and the effects of berberine. In vivo, berberine improved fasting blood glucose, body weight, the majority of biochemical and renal function parameters and histopathological changes in the diabetic kidney. Western blotting and immunohistochemistry revealed significant increases in the levels of AGEs, RAGE, P-PKC-ß and TGF-ß1 in injured kidneys, and these levels were markedly decreased by treatment with berberine. In vitro, berberine inhibited mesangial cell proliferation. Cells treated with berberine showed reduced levels of AGEs, accompanied by decreased RAGE, p-PKC and TGF-ß1 levels soon afterwards. Berberine exhibited renoprotective effects in diabetic nephropathy rats, and the molecular mechanism was associated with changes in the levels and regulation of the AGEs-RAGE-PKC-ß-TGF-ß1 signaling pathway.

Delayed progression of diabetic cataractogenesis and retinopathy by Litchi chinensis in STZ-induced diabetic rats.

CONTEXT: The study was carried out to evaluate the effect of the aqueous fruit pericarp extract of Litchi chinensis (APLC) on parameters which leads to diabetic cataractogenesis and retinopathy in the streptozotocin-induced diabetic rats. OBJECTIVE: The objective of the study is to evaluate the APLC for in vivo antioxidant activity and its role in inhibiting the polyol pathway and formation of advanced glycation end products (AGEs). MATERIALS AND METHODS: The diabetic animals were treated with L. chinensis for a period of 12 weeks. At the end of 12 weeks, the animals were killed and the biochemical pathways involved in the pathogenesis of cataract such as oxidative stress by protein content, superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and polyolpathway by aldose reductase (AR) in lens homogenates, alterations in protein carbonyl content (PCO) and AGEs in both serum and lens the APLC-treated diabetic rats were compared against diabetic control rats. Cataract progression due to hyperglycemia was monitored by slit lamp bio microscope and classified into four stages. Fundoscope test and retinal histopathology were done for assessing retinopathy. RESULTS: Statistically significant reduction in glucose, and elevation of protein content, SOD, CAT, and GSH levels and decreased levels of AR and PCO in lens homogenate and significant reduction in AGEs serum and lens homogenate were observed. Slit lamp examination, fundoscope, and histopathology showed improvement in retinal changes in APLC-treated rats compared to diabetic control animals. CONCLUSION: The treatment with APLC found to delay the progression of diabetic cataractogenesis and retinopathy, which might be due to its antioxidant activity, because of the presence of active phytochemicals in APLC.

Effects of Omega-3 Fatty Acid Supplementation on Inflammatory Cytokines and Advanced Glycation End Products in Patients With Diabetic Nephropathy: a Randomized Controlled Trial.

INTRODUCTION: This study was performed to evaluate the effects of omega-3 fatty acid supplementation on inflammatory cytokines and advanced glycation end products (AGEs) in patients with diabetic nephropathy (DN). MATERIALS AND METHODS: This randomized double-blind placebo-controlled trial was done on 60 patients with DN who were randomly divided into 2 groups to receive either 1000 mg/d of omega-3 fatty acid from flaxseed oil (n = 30) or placebo (n = 30) for 12 weeks. The primary outcome variables were tumor necrosis factor-α, receptor tumor necrosis factor-α and growth differentiation factor 15. Fasting blood samples were taken at the onset and the end of the study to quantify the related markers. RESULTS: Compared with the placebo, omega-3 fatty acid supplementation resulted in a significant decrease in serum AGEs (-2.3 ± 2.8 AU versus 0.2 ± 2.5 AU, P = .001). Despite a significant reduction in serum level of receptor for AGEs (-0.1 ± 0.3 AU, P = .02) in the omega-3 fatty acid group, no significant difference was found between the two groups in terms of their effects on the receptor for AGEs. Supplementation with omega-3 fatty acid had no significant effect on the inflammatory cytokines as compared with the placebo. CONCLUSIONS: Our study demonstrated that omega-3 fatty acid supplementation among DN patients had favorable effects on AGEs and the receptor for AGEs.

The effects of n-3 long-chain polyunsaturated fatty acid supplementation on AGEs and sRAGE in type 2 diabetes mellitus.

In diabetes mellitus, chronic hyperglycemia leads to formation of advanced glycation end products (AGEs). Binding of AGEs to receptors of AGE (RAGE) causes deleterious effects. In populations with a high consumption of n-3 long-chain polyunsaturated fatty acids, a lower prevalence of diabetes mellitus has been reported. We aimed to investigate the effects of n-3 fatty acid (EPA and DHA) supplementation on the levels of AGEs (carboxymethyl lysine (CML) and pentosidine), sRAGE, and nuclear factor kappa B (NF-kB) in type 2 diabetes mellitus (T2DM). T2DM patients (n = 38) treated with oral hypoglycemic agents, without insulin were supplemented with n-3 fatty acids (1.2 g/day) for 2 months. Plasma CML, pentosidine, sRAGE, and NF-kB levels were measured by ELISA both before and after the supplementation. n-3 fatty acid supplementation significantly reduced fasting glucose (p < 0.01), glycated hemoglobin (HbA1c) (p < 0.05), and pentosidine (p < 0.05) levels. The supplementation induced percentage changes in pentosidine and HbA1c and in pentosidine and creatinine were observed to be correlated (r = 0.349, p < 0.05) and (r = 0.377, p < 0.05), respectively. Waist circumference and systolic and diastolic pressures were significantly decreased due to n-3 supplementation (p < 0.001, p < 0.01, p < 0.01), respectively. Our results show that supplementation with n-3 fatty acid has beneficial effects on waist circumference; systolic and diastolic blood pressures; and the levels of glucose, HbA1c, and pentosidine in T2DM patients. However, the supplementation failed to decrease these parameters to the reference ranges for healthy subjects. In addition, the supplementation did not appear to induce any significant differences in CML, sRAGE, or NF-kB.

Zerumbone, a Phytochemical of Subtropical Ginger, Protects against Hyperglycemia-Induced Retinal Damage in Experimental Diabetic Rats.

Diabetic retinopathy (DR), the most ordinary and specific microvascular complication of diabetes, is a disease of the retina. Zerumbone (ZER) is a monocyclic sesquiterpene compound, and based on reports, it is the predominant bioactive compound from the rhizomes of Zingiber zerumbet. The aim of the current study is to evaluate the protective effect of zerumbone against DR in streptozotocin (STZ)-induced diabetic rats. STZ-diabetic rats were treated with ZER (40 mg/kg) once a day orally for 8 weeks. ZER administration significantly (p < 0.05) lowered the levels of plasma glucose (32.5% ± 5.7% lower) and glycosylated hemoglobin (29.2% ± 3.4% lower) in STZ-diabetic rats. Retinal histopathological observations indicated that disarrangement and reduction in thickness of retinal layers were reversed in ZER-treated diabetic rats. ZER downregulated both the elevated levels of advanced glycosylated end products (AGEs) and the higher levels of the receptors for AGEs (RAGE) in retinas of diabetic rats. What's more, ZER significantly (p < 0.05) ameliorated diabetes-induced upregulation of tumor necrosis factor-α, interleukin (IL)-1 and IL-6. ZER also attenuated overexpression of vascular endothelial growth factor and intercellular adhesion molecule-1, and suppressed activation of nuclear factor (NF)-κB and apoptosis in the retinas of STZ-diabetic rats. Our results suggest ZER possesses retinal protective effects, which might be associated with the blockade of the AGEs/RAGE/NF-κB pathway and its anti-inflammatory activity.

Eplerenone restores 24-h blood pressure circadian rhythm and reduces advanced glycation end-products in rhesus macaques with spontaneous hypertensive metabolic syndrome.

Hypertension is often associated with metabolic syndrome (MetS), and serves as a risk factor of MetS and its complications. Blood pressure circadian rhythm in hypertensive patients has been suggested to contribute to cardiovascular consequences and organ damage of hypertension. But circadian changes of BP and their response to drugs have not been clearly investigated in non-human primates (NHPs) of MetS with hypertension. Here, we identified 16 elderly, hypertensive MetS rhesus monkeys from our in-house cohort. With implanted telemetry, we investigate BP changes and its circadian rhythm, together with the effect of antihypertensive drugs on BP and its diurnal fluctuation. MetS hypertensive monkeys displayed higher BP, obesity, glucose intolerance, and dyslipidemia. We also confirmed impaired 24-h BP circadian rhythm in MetS hypertensive monkeys. Importantly, Eplerenone, a mineralocorticoid receptor blocker, exerts multiple beneficial effects in MetS hypertensive monkeys, including BP reduction, 24-h BP circadian rhythm restoration, and decreased plasma concentration of inflammation factors and advanced glycation end-products. In summary, we identified a naturally-developed hypertensive MetS NHP model, which is of great value in the studies on pathogenesis of MetS-associated hypertension and development of novel therapeutic strategies. We also provided multiple novel mechanistic insights of the beneficial effect of Eplerenone on MetS with hypertension.