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PloS One 2022The micro- and macro-complications in diabetes mellitus (DM) mainly arise from the damage induced by Amadori and advanced glycation end products, as well as the released...
The micro- and macro-complications in diabetes mellitus (DM) mainly arise from the damage induced by Amadori and advanced glycation end products, as well as the released free radicals. The primary goal of DM treatment is to reduce the risk of micro- and macro-complications. In this study, we looked at the efficacy of aminoguanidine (AG) to prevent the production of early glycation products in alloxan-diabetic rabbits. Type1 DM was induced in rabbits by a single intravenous injection of alloxan (90 mg/kg body weight). Another group of rabbits was pre-treated with AG (100 mg/kg body weight) prior to alloxan injection; this was followed by weekly treatment with 100 mg/kg of AG for eight weeks. Glucose, insulin, and early glycation products (HbA1C and fructosamine) were measured in control, diabetic and AG treated diabetic rabbits. The effects of hyperglycemia on superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (Gpx), reduced glutathione (rGSH), nitric oxide, lipid peroxides, and protein carbonyl were investigated. Alloxan-diabetic rabbits had lower levels of SOD, CAT, Gpx, and rGSH than control rabbits. Nitric oxide levels were considerably greater. AG administration restored the activities of SOD, CAT, Gpx enzymes up to 70-80% and ameliorated the nitric oxide production. HbA1c and fructosamine levels were considerably lower in AG-treated diabetic rabbits. The observed control of hyperglycemia and amadori adducts in alloxan-diabetic rabbits by AG may be attributed to decrease of stress and restoration of antioxidant defenses.
Topics: Alloxan; Animals; Antioxidants; Case-Control Studies; Catalase; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Administration Schedule; Gene Expression Regulation; Glutathione; Glutathione Peroxidase; Guanidines; Hyperglycemia; Lipid Peroxidation; Nitric Oxide; Oxidative Stress; Rabbits; Superoxide Dismutase
PubMed: 34986201
DOI: 10.1371/journal.pone.0262233 -
PloS One 2011Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of...
Matrix metalloproteinases (MMP) are well-known biological targets implicated in tumour progression, homeostatic regulation, innate immunity, impaired delivery of pro-apoptotic ligands, and the release and cleavage of cell-surface receptors. Hence, the development of potent and selective inhibitors targeting these enzymes continues to be eagerly sought. In this paper, a number of alloxan-based compounds, initially conceived to bias other therapeutically relevant enzymes, were rationally modified and successfully repurposed to inhibit MMP-2 (also named gelatinase A) in the nanomolar range. Importantly, the alloxan core makes its debut as zinc binding group since it ensures a stable tetrahedral coordination of the catalytic zinc ion in concert with the three histidines of the HExxHxxGxxH metzincin signature motif, further stabilized by a hydrogen bond with the glutamate residue belonging to the same motif. The molecular decoration of the alloxan core with a biphenyl privileged structure allowed to sample the deep S(1)' specificity pocket of MMP-2 and to relate the high affinity towards this enzyme with the chance of forming a hydrogen bond network with the backbone of Leu116 and Asn147 and the side chains of Tyr144, Thr145 and Arg149 at the bottom of the pocket. The effect of even slight structural changes in determining the interaction at the S(1)' subsite of MMP-2 as well as the nature and strength of the binding is elucidated via molecular dynamics simulations and free energy calculations. Among the herein presented compounds, the highest affinity (pIC(50) = 7.06) is found for BAM, a compound exhibiting also selectivity (>20) towards MMP-2, as compared to MMP-9, the other member of the gelatinases.
Topics: Alloxan; Catalytic Domain; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Molecular Dynamics Simulation; Protease Inhibitors; Protein Binding; Thermodynamics
PubMed: 21998672
DOI: 10.1371/journal.pone.0025597 -
British Journal of Pharmacology Nov 19881. In order to elucidate the mechanism underlying the interactions between glucose and alloxan when competing for the sugar binding site of glucokinase from pancreatic...
1. In order to elucidate the mechanism underlying the interactions between glucose and alloxan when competing for the sugar binding site of glucokinase from pancreatic B-cells or liver, the structural requirements of the enzyme for inhibition by alloxan and for protection by glucose were determined. 2. With a half-maximal inhibitory concentration of 5 microM, alloxan was the most potent pyrimidine derivative inhibitor of glucokinase. Uramil was a less potent enzyme inhibitor. A variety of other pyrimidine derivatives and related substances were ineffective. 3. Ninhydrin also inhibited glucokinase with a half-maximal inhibitory concentration of 5 microM. Isatin was a slightly less potent enzyme inhibitor. Several other indoline derivatives were ineffective. 4. Only glucose derivatives with a sufficiently bulky substituent in position C-2, such as the glucokinase substrates glucose and mannose and the inhibitors mannoheptulose, glucosamine, and N-acetylglucosamine, protected glucokinase against inhibition by alloxan by binding to the active site of the enzyme. Glucose epimers which differed in other positions did not protect the enzyme against alloxan inhibition. 5. DTT (dithiothreitol) protected glucokinase against inhibition by alloxan and reversed the inhibition of the enzyme induced by alloxan. Thus the mechanism of glucokinase inhibition by alloxan and other inhibitors, such as uramil and ninhydrin, is an oxidation of functionally essential SH groups of the enzyme, where the most reactive keto group of the inhibitor acts as the hydrogen acceptor. The protective action of glucose and several C-2 epimers demonstrates that these functionally essential SH groups are situated in the sugar binding site of the glucokinase. 6. The present results support our contention, that the pancreatic B-cell glucokinase is the major target mediating the inhibition of insulin secretion by alloxan.
Topics: Alloxan; Animals; Chemical Phenomena; Chemistry; Dithiothreitol; Drug Stability; Glucokinase; Glucose; Indenes; Mice; Mice, Obese; Ninhydrin; Rats; Rats, Inbred Strains
PubMed: 3207996
DOI: 10.1111/j.1476-5381.1988.tb11714.x -
Mediators of Inflammation 2021Alloxan (ALX) and streptozotocin (STZ) are extensively used to induce type 1 diabetes (T1D) in animal models. This study is aimed at evaluating the differences in immune...
Alloxan (ALX) and streptozotocin (STZ) are extensively used to induce type 1 diabetes (T1D) in animal models. This study is aimed at evaluating the differences in immune parameters caused by ALX and STZ. T1D was induced either with ALX or with STZ, and the animals were followed for up to 180 days. Both ALX and STZ induced a decrease in the total number of circulating leukocytes and lymphocytes, with an increase in granulocytes when compared to control mice (CT). STZ-treated mice also exhibited an increase in neutrophils and a reduction in the lymphocyte percentage in the bone marrow. In addition, while the STZ-treated group showed a decrease in total CD3, CD4CD8, and CD4CD8 T lymphocytes in the thymus and CD19 B lymphocytes in the pancreas and spleen, the ALX group showed an increase in CD4CD8 and CD19 only in the thymus. Basal levels of splenic interleukin- (IL-) 1 and pancreatic IL-6 in the STZ group were decreased. Both diabetic groups showed atrophy of the thymic medulla and degeneration of pancreatic islets of Langerhans composed of inflammatory infiltration and hyperemia with vasodilation. ALX-treated mice showed a decrease in reticuloendothelial cells, enhanced lymphocyte/thymocyte cell death, and increased number of Hassall's corpuscles. Reduced activation of splenic lymphocytes was found in the STZ-treated group. Furthermore, mice immunized with ovalbumin (OVA) showed a more intense antigen-specific paw edema response in the STZ-treated group, while production of anti-OVA IgG1 antibodies was similar in both groups. Thereby, important changes in immune cell parameters and were found at an early stage of T1D in the STZ-treated group, whereas alterations in the ALX-treated group were mostly found in the chronic phase of T1D, including increased mortality rates. These findings suggest that the effects of ALX and STZ influenced, at different times, lymphoid organs and their cell populations.
Topics: Alloxan; Animals; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Pancreas; Spleen; Streptozocin; Thymus Gland
PubMed: 34712101
DOI: 10.1155/2021/9940009 -
Oxidative Medicine and Cellular... 2022Plants are a significant source for the development of new phytomedicines due to their great clinical benefits, efficiency, cost-effectiveness, fewer side effects, and...
Plants are a significant source for the development of new phytomedicines due to their great clinical benefits, efficiency, cost-effectiveness, fewer side effects, and more affordable therapies. Numerous plants used in traditional treatments, such as Scop., have been effective in the treatment of diabetes mellitus (DM). Therefore, the study is aimed at assessing the phytochemical, antioxidant, and antidiabetic properties of . The hypoglycemic and hypolipidemic activity was evaluated in Swiss male Albino mice by administering an oral dose of 150-250 mg/kg of extracts in alloxan-induced diabetic mice for 15 days. The antioxidant activity and phytochemical composition of the extracts were assessed by using , diphenyl--picrylhydrazyl (DPPH) and hydrogen peroxide scavenging assays and through standard chemical procedures. The effects of extracts on blood glucose, body weight, lipid profile, and biochemical parameters like total cholesterol (TC), triglyceride (TG), low-density lipids (LDL), high-density lipids (HDL), plasma insulin, liver glycogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), urea, and creatinine were determined according to standard procedures. The activities of antioxidant enzymes such as superoxide-dismutase (SOD), peroxidase (POD), and catalase (CAT) were also analyzed spectrophotometrically. The hypoglycemic and hypolipidemic effects with chloroform extracts of 250 mg/kg were found significant in the treatment of diabetes in alloxanised mice compared to the diabetic group. The haematological parameters such as TC, TG, HDL, LDL, creatinine, urea, AST, ALT, and ALP were significantly improved ( < 0.01) by the chloroform extract of 250 mg/kg compared to the diabetic group. Treatment for 15 days showed significant elevation ( < 0.01) of antioxidant enzymes. Fourier-transform infrared spectroscopic (FTIR) and gas chromatography-mass spectrometry (GC-MS), column chromatography (CC), and nuclear magnetic resonance (NMR) analyses tentatively identified different phytoconstitutents and metabolites in leaves, which have been reported to possess antihyperglycemic properties. In conclusion, the chloroform extract of 250 mg/kg of possesses significant hypoglycemic and hypolipidemic potential which may prove the claimed use of the plant in amelioration of diabetes and associated complications in folkloric medicine. Additional studies are required for the purification, characterization, and structural elucidation of bioactive compounds.
Topics: Mice; Animals; Antioxidants; Alloxan; Diabetes Mellitus, Experimental; Chloroform; Creatinine; Plant Extracts; Hypolipidemic Agents; Hypoglycemic Agents; Triglycerides; Blood Glucose; Anacardiaceae; Liver
PubMed: 36624877
DOI: 10.1155/2022/8802178 -
Biomedicine & Pharmacotherapy =... Apr 2023Diabetes and its complications are closely correlated with chronic hyperglycemia, causing severe oxidative stress and leading to glycation reaction with formation of...
Diabetes and its complications are closely correlated with chronic hyperglycemia, causing severe oxidative stress and leading to glycation reaction with formation of advanced glycation end products. However, medicinal plants are still a source of inspiration for the discovery of new treatments of several diseases, including diabetes. The present study was aimed to evaluate the antioxidant and antidiabetic properties of Oxalis pes-caprae flowers extract in alloxan-induced diabetic mice. The phytochemical and antioxidant activities of both aqueous and methanolic extracts were assessed by in-vitro testing such as free radical scavenging assays (DPPH and ABTS), ferrous ions (Fe) chelating activity and reducing power assay. Additionally, the detection of Amadori products and advanced glycation end products was used to determine the antiglycation potential. α-glucosidase and α-amylase inhibitory assessment was employed to determine the antidiabetic effect, while alloxan-induced diabetic mice were used to measure the in-vivo activities of antioxidants and carbohydrates enzymes. The effect of the methanolic extract on body weight and blood glucose level of extract-treated diabetic mice were also investigated. Among the tested extract, the methanolic extract was the richest in phenolic compounds which is directly related with their remarkable antioxidant, enzyme inhibitory and antiglycation activity. The oral administration of the two doses of Oxalis pes-caprae flowers (150 mg/kg and 250 mg/kg) daily for 3 weeks resulted in hypoglycemic effect compared to the reference drug, glibenclamide (10 mg/kg). Furthermore, the extract was shown to significantly increase the activities of antioxidants and glycolysis enzymes in the liver, kidney and spleen of diabetic mice, compared to diabetic control group. Therefore, Oxalis pes-caprae extract effectively exhibited hypoglycemic and antidiabetic effects as indicated by in-vitro and in-vivo studies, confirming the protective effects on hyperglycemia and oxidative damage.
Topics: Mice; Animals; Antioxidants; alpha-Glucosidases; Alloxan; alpha-Amylases; Diabetes Mellitus, Experimental; Plant Extracts; Hypoglycemic Agents; Hyperglycemia; Phytochemicals; Glycation End Products, Advanced
PubMed: 36774725
DOI: 10.1016/j.biopha.2023.114393 -
Medicina (Kaunas, Lithuania) 2017Glycemic homeostasis refers to glucose balance or control within circulation in living organisms. It is normally and largely compromised in diabetes. The compromise when... (Review)
Review
Glycemic homeostasis refers to glucose balance or control within circulation in living organisms. It is normally and largely compromised in diabetes. The compromise when exacerbated, leads to several complications including retinopathy, nephropathy and neuropathy which are collectively known as diabetic complications and are the principal actors in co-morbidity and eventual mortality often associated with diabetes. The ability of therapeutic compounds including medicinal plants to restore glycemic balance or homeostasis in hyperglycemic condition is an index of their antidiabetic function and relevance. Alloxan and streptozotocin are the most popular diabetogenic agents used for assessing the antidiabetic or hypoglycemic capacity of test compounds. Notably, alloxan is far less expensive and more readily available than streptozotocin. On this ground, one will logically expect a preference for use of alloxan in experimental diabetes studies. Surprisingly, a sub meta-analysis of randomly selected studies conducted within the last one and half decade revealed otherwise. This observation necessitated the review of alloxan as a diabetogenic agent in animal studies.
Topics: Alloxan; Animals; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Experimental; Disease Models, Animal; Humans; Hypoglycemic Agents; Rats, Wistar
PubMed: 29548636
DOI: 10.1016/j.medici.2018.02.001 -
Annals of the New York Academy of... Dec 2008Protection of pancreatic beta cells is an approach to prevent autoimmune type 1 diabetes (T1D) and to protect transplanted islets. Reactive oxygen species (ROS) are... (Review)
Review
Protection of pancreatic beta cells is an approach to prevent autoimmune type 1 diabetes (T1D) and to protect transplanted islets. Reactive oxygen species (ROS) are important mediators of beta cell death during the development of T1D. We have examined the role of elevated ROS dissipation in the prevention of T1D using the ALR mouse strain. The selection of ALR, for resistance against alloxan-induced free radical-mediated diabetes, led to a strain of mice with an elevated systemic as well as pancreatic ROS dissipation. Independent genetic mapping studies have identified ALR-derived diabetes protective loci. Conplastic and congenic mouse as well as cell line studies have confirmed the genetic mapping and demonstrated that the elevated ROS dissipation protects ALR beta cells from autoimmune destruction. Our data support the hypothesis that elevated ROS dissipation protects beta cells against autoimmune destruction and prevents T1D development.
Topics: Alloxan; Animals; Cytoprotection; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Drug Resistance; Genetic Predisposition to Disease; Genome, Mitochondrial; Humans; Insulin-Secreting Cells; Metabolic Networks and Pathways; Mice; Mice, Inbred Strains; Quantitative Trait Loci; Reactive Oxygen Species
PubMed: 19120287
DOI: 10.1196/annals.1447.045 -
BMC Endocrine Disorders Oct 2022NADPH oxidase 1 (Nox1), which is highly expressed in the colon, is thought to play a potential role in host defense as a physical and innate immune barrier against...
BACKGROUND
NADPH oxidase 1 (Nox1), which is highly expressed in the colon, is thought to play a potential role in host defense as a physical and innate immune barrier against commensal or pathogenic microbes in the gastrointestinal epithelium. Diabetes can be caused by several biological factors, including insulin resistance is one of them. Alloxan is widely used to induce insulin-dependent diabetes in experimental animals. Alloxan increases the generation of reactive oxygen species as a result of metabolic reactions in the body, along with a massive increase in cytosolic calcium concentration.
METHODS
Using a universal method, a superoxide radical (О)-thermostable associate between NADPH-containing lipoprotein (NLP) and NADPH oxidase (Nox)- NLP-Nox was isolated and purified from the small intestine (SI) of control (C) and alloxan-induced diabetic (AD) albino rats.
RESULTS
In comparison to the C indices, in AD in the SI, an increase in the specific content of NLP-Nox associate and a decrease in the stationary concentration of produced О in liquid phase (in solution) and gas phase (during blowing by oxygen of the NLP-Nox solution) were observed. The NLP-Nox of SI associate in C and AD rats produced О by an immediate mechanism, using NLP as a substrate. The phenomenon of the hiding of the optical absorption maxima of the Nox in oxidized states at pH10,5 was observed in the composition of these SI associates of the C and AD rat groups. The characteristic absorption maxima of the «hidden» Nox were observed under these conditions after reduction by potassium dithionite.
CONCLUSION
Thus, at AD, the decrease in the stationary concentration of produced О in the solution and gas phase was compensated for by an increase in the specific amount of associate. In addition, the decrease in the stationary concentration of produced О by NLP-Nox associates at AD can be linked to a decrease in the level of NADPH in NLP-Nox composition. This could be used as a new mechanism of AD pathogenesis.
Topics: Animals; Alloxan; Calcium; Diabetes Mellitus, Experimental; Dithionite; Insulins; Intestine, Small; Lipoproteins; NADP; NADPH Oxidase 1; NADPH Oxidases; Oxygen; Potassium; Reactive Oxygen Species; Superoxides; Rats
PubMed: 36258207
DOI: 10.1186/s12902-022-01160-x -
Frontiers in Endocrinology 2021To investigate whether the microvascular permeability of lumbar marrow and bone trabecular changes in early-stage diabetic rabbits can be quantitatively evaluated using...
PURPOSE
To investigate whether the microvascular permeability of lumbar marrow and bone trabecular changes in early-stage diabetic rabbits can be quantitatively evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), quantitative computed tomography, and texture-analyzed permeability parameter map of DCE-MRI.
MATERIALS AND METHODS
This prospective study included 24 rabbits that were randomly assigned to diabetic (n = 14) and control (n = 10) groups. All rabbits underwent sagittal MRI of the lumbar region at 0, 4, 8, 12, and 16 weeks after alloxan injection. Pearson correlation coefficient was performed to determine the correlation between permeability parameter and bone mineral density (BMD). Repeated-measures ANOVA was used to analyze the changes in lumbar BMD over time in each group and the texture parameters of diabetic rabbit lumbar marrow at different time points. Mann-Whitney U rank sum test was used to compare the differences of each index between the two groups and calculate the area under the curve (AUC).
RESULTS
BMD was correlated with , , and but not with . At weeks 0-16, the BMD of the rabbits in the diabetic and normal groups was not statistically significant, but the change in BMD showed an overall downward trend. For texture analysis, entropy, energy, and Uniformized positive pixel (UPP) parameters extracted from the map showed significant differences from week 0 to 16 between the two groups. The identification ability at 8-12 weeks was higher than that at 12-16 weeks, and the AUCs were 0.734, 0.766, and 0.734, respectively (P < 0.05 for all).
CONCLUSIONS
The changes in BMD measured using quantitative computed tomography occurred later than those measured using bone trabecular morphometry. Texture analysis parameters based on DCE-MRI quantitative parameter Ktrans map are feasible to identify early changes in lumbar marrow structure in diabetic rabbits.
Topics: Alloxan; Animals; Bone Density; Bone Marrow; Cancellous Bone; Diabetes Mellitus, Experimental; Magnetic Resonance Imaging; Male; Prospective Studies; Rabbits; Tomography, X-Ray Computed
PubMed: 35002967
DOI: 10.3389/fendo.2021.785604