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Introduction: The objective of the study was to determine antidiabetic and antihyperlipidemic effects of Mangifera camptosperma leaves extract using streptozotocin-induced animal model. Methods: The leaves of M. camptosperma extracted with hydroethanolic (50:50) solvent using soxhlet apparatus. Traditional Chinese medicine (TCM) is often given as an adjuvant to alleviate diabetic symptoms. The plant extracts were used to determine presence of phytochemicals present in them using different tests. Diabetes was induced on animals using streptozotocin (STZ) 50 mg/kg through intra-peritoneal route. Oral administration of M. camptosperma extract at doses of 200 mg/kg and 400 mg/kg was used to assess its antidiabetic and antihyperlipidemic effects. Results: The phytochemical analysis showing presence of carbohydrates, alkaloids, tannins, glycosides, and flavonoids. The diabetic control group had blood glucose levels of 102 mg/kg and 126 mg/kg, respectively, after receiving the test medication, but the diabetic rats treated with the extract showed a substantial decrease to 90.11 ± 5.71 (200 mg/kg) and 82.12 ± 3.99 (400 mg/kg). If compared to the diabetic control group, the administration of 400 mg/kg of M. camptosperma for 21 days resulted in a substantial decrease (p < 0.05) in serum total cholesterol (106.12 ± 5.94 mg/dL) and triglyceride (83.11 ± 4.04 mg/dL), as well as an increase in HDL cholesterol (36.15 ± 3.04 mg/dL). This study found that while administered to diabetic rats, M. camptosperma lowered blood glucose levels and improved lipid profiles. Discussion: It can be concluded from the study that the plant extract may be useful in treating hyperlipidemic and type-2 diabetes as an alternative medicine.

Zebrafish is a developing vertebrate model with several advantages, including its small size, and high experimental efficiency. Malaysia exhibit one of the highest diabetes rates in the Western Pacific and incurring an annual cost of 600 million US dollars. The objective of the study is to determine the antidiabetic properties of green honey (GH) using a zebrafish model. Adult zebrafish, aged 3–4 months, were subjected to overfeeding and treated with streptozotocin (STZ) through intraperitoneal injection (IP) on days 7 and 9. The study assessed the oral sucrose tolerance test (OSTT) and the anti-diabetic effects of green honey. The evaluation was conducted at three time points: 30, 60, and 120 min after treatment and sucrose administration. The study utilised a model with a sample size of 5. The study was performed in six groups. These groups are (1) Normal control (non-diabetic, no intervention), (2) Normal control + GH (non-diabetic, supplemented with GH 3 μl), (3) DM control (diabetic, no intervention), (4) DM Gp1 (diabetic, 3 μL GH), (5) DM Gp2 (diabetic, 6 μ L GH), (6) DM Acarbose (diabetic, treated with acarbose). Fasting blood glucose levels for non-diabetic (non-DM) and diabetic (DM) groups were evaluated before and after the 10 days of diabetic induction. DM groups (excess of food and two injections of STZ) have caused a significant increment in the fasting blood glucose to 11.55 mmol/l (p

Rosmarinic acid (RA), a natural ester phenolic compound, is known to have antioxidant and anti-inflammatory properties. RA has also been reported to exhibit a hypoglycemic effect; however, the mechanisms underlying this effect have yet to be investigated. Therefore, the present study focused on the anti-diabetic effects and mechanism of RA in INS-1 cells using in vitro model. Streptozotocin (STZ) at a concentration of 3 mM was applied to INS-1 cells for 4 h to create a diabetic model. The cells were pretreated for 24 h with various concentrations (1 and 2.5 μM) of RA. The Cell viability, glucose-stimulated insulin secretion (GSIS), glucose uptake, lipid peroxidation, reactive oxygen species (ROS), apoptosis, and protein expression of Bcl-2, NF-κB, 1L-1β, and PARP were assessed. Results showed that STZ-treated INS-1 cells exhibited reduced cell viability, insulin release, insulin content, glucose uptake, and elevated MDA and ROS levels. Cells pretreated with RA maintained the function and morphology of β-cells against STZ-induced damage. Moreover, RA sustained high protein expression levels of Bcl-2 and low expression levels of NF-κB, IL-1β, and PARP. In conclusion, RA preserved β-cells function against STZ-induced damage by altering NF-κB and Bcl-2 pathways.

A hydrophobic Cu 2 O cathode (Cu x O-L) was designed to solve the challenge of low oxidation ability in electro-Fenton (EF) for treating emerging pollutants. This fabrication process involved forming Cu(OH) 2 nanorods by oxidizing copper foam (Cu-F) with (NH 4 ) 2 S 2 O 8 , followed by coating them with glucose via hydrothermal treatment. Finally, a self-assembled monolayer of 1-octadecanethiol was introduced to create a low-surface-energy, functionalized Cu x O-L cathode. Results exhibited an approximately 7.9-fold increase in hydroxyl radical (·OH) generation compared to the initial Cu-F. This enhancement was attributed to two key factors: (Ⅰ) the superior O 2 -capturing ability of Cu x O-L cathode, which led to high H 2 O 2 production due to a 2 nm thick hydrophobic gas layer facilitated O 2 -capturing; (Ⅱ) a relative high concentration of Cu + at the Cu x O-L cathode promoted the activation of H 2 O 2 into·OH. In addition, the performance of EF with the Cu x O-L cathode using sulfathiazole (STZ) as a model pollutant was evaluated. This study offers valuable insights into the design of O 2 -capturing cathodes in EF processes, particularly for treating emerging organic pollutants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The present study is to clarify the effect of insulin-producing cells (IPCs) derived from adipose tissue mesenchymal stem cells (AT-MSCs) on diabetic-induced impairments as the abnormalities of testicular tissues, oxidative stress of testes, and defects of spermatogenesis. Diabetes was stimulated by streptozotocin (STZ) injection in male adult Sprague Dawley (SD) rats. Diabetes was confirmed by taking two highly consecutive fasting blood sugar readings; more than 300 mg/dl; within one week. Five million of IPCs derived from AT-MSCs; encased in TheraCyte capsule; were then directly transplanted (one implant for each rat) subcutaneously in diabetic rats. Implants were maintained for 3 months and the fasting blood sugar of the transplanted rats was observed every month. At the end of the experiment; serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were also estimated. The sperm parameters (count, motility, and abnormality) were recorded. In testicular tissue; GPX4, Bcl2, and Bax levels were evaluated, while oxidative stress and antioxidant enzymes activities were measured in the testes homogenate. Also, histopathological alterations were examined in the testes cross-section. In the results, it was found that IPCs treatment enhanced the serum testosterone, FSH, and LH levels. Diabetic-induced impairments in the sperm parameters were noticeably improved post-IPCs transplantation in the diabetic rats. Moreover, the treatment improved the diabetic-associated testicular oxidative stress. Also, it was recognized that the Bax expression decreased, while, GPX4 and Bcl2 expression increased in the treated rats. Meanwhile, the abnormalities showed in the histopathological studies of the hyperglycemic rat's testes were attenuated post-treatment. So, IPCs transplantation improved diabetes and consequently protected against hyperglycemia-induced testicular damages.

Green coffee consumption has been stated to have a converse association with type 2 diabetes and metabolic syndrome. Hence, we assessed changes produced by the administration of different doses of green coffee on biomarkers related to renal and antioxidant systems. The study was carried out on 42 diabetic male albino rats; a high-fat diet (HFD) and a single dose of streptozotocin (STZ; 35 mg kg−1) were utilized for model induction. Diabetic rats were received green coffee water extract (GCWE; 50 and 100 mg kg−1) daily for 28 days. GCWE caused a remarkable recovery of kidney weight, kidney function, and aldosterone level, particularly. Proapoptotic, antiapoptotic and inflammatory markers were significantly improved and showing a great retain to their normal levels specifically in GCWE-treated groups. Also, a marked improvement in the antioxidants defense system was noted. GCWE has a great protective influence on kidney injury of HFD/STZ‐induced diabetic rats.

Several in vivo and in vitro studies reported a favorable effect of piperine (PIP) on vascular function. However, the potential impacts of PIP on macrovasculopathy in streptozotocin (STZ)-diabetic rats have not yet been studied. Thirty-two Sprague Dawley rats were used (n= 8/group). STZ-administered rats (50 mg/kg once, i.p) received PIP (30 mg/kg/day, orally) or its vehicle starting from day 15 till the end of the study (10 weeks). Control groups consisted of age-matched normal rats with or without PIP treatment. Metabolic and oxidative stress parameters were biochemically determined. Aortas were histologically examined. Ex vivo aortic reactivity to phenylephrine and acetylcholine was studied. Components of the TXNIP-NLRP3 pathway were assessed using real-time PCR, ELISA, and immunohistochemistry. Two-way ANOVA was used to compare groups. Statistical significance was set at P < 0.05. PIP treatment of diabetic rats significantly reduced levels of fasting glycemia, HbA 1c , and serum AGEs, TGs, TC, and LDL-C compared to control diabetic group. PIP diminished aortic endothelial denudation and fibrous tissue proliferation compared to control STZ aortas. PIP lessened aortic contractility to phenylephrine and improved aortic relaxation to acetylcholine relative to untreated STZ group. PIP administration to diabetic rats elicited significant enhancements in GSH and SOD levels, eNOS expression, and total nitrate/nitrite bioavailability compared to untreated STZ rats. Moreover, PIP attenuated aortic contents of ROS, MDA, TXNIP protein and mRNA, NF-κB p65 mRNA, NLRP3 mRNA, IL-1β protein, and caspase-3 and TNF-α expressions compared to untreated STZ levels. In conclusion, PIP might ameliorate diabetes-associated functional and structural aortic remodeling by targeting TXNIP-NLRP3 signaling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Aims: Cardiac affection is common in diabetic patients. Although insulin exerts a cardioprotective role, it may not be enough to totally prevent this affection. The current study aimed to compare the cardioprotective effect of insulin alone or combined with sitagliptin in a rat model of type 1 diabetes mellitus., Materials and Methods: Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ; 60 mg/kg). Diabetic rats were treated with insulin (3 IU), insulin (6 IU), or insulin (3 IU) + sitagliptin (10 mg/kg) for 42 days., Key Findings: Diabetic rats exhibited significant systolic and diastolic cardiac affection with significant elevation of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and brain natriuretic peptide (BNP) levels. Treatment with insulin prevented the deterioration of diabetes-induced cardiac condition, an effect that was significantly potentiated by the combined use of sitagliptin., Significance: The combined use of sitagliptin and insulin significantly improved the cardioprotective effect of insulin and prevented the early cardiac dysfunction in STZ diabetic rats., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disease characterized by cascading changes in cognition and behavior. G-protein-coupled receptor 55 (GPR55) has been used as a promising target for the treatment of diabetes, but its function in AD is unclear. The objective of this study was to investigate the neuroprotective effects of O-1602, a GPR55 agonist, on the streptozotocin (STZ)-induced AD mouse model. A single intracerebroventricular (i.c.v.) injection of STZ into the brains of mice significantly induced cognitive impairment. In contrast, O-1602 (2.0 or 4.0 μg/mouse, i.c.v.) can improve the cognitive dysfunction caused by STZ in the Morris water maze (MWM) and novel object recognition (NOR) tests. Importantly, O-1602 treatment reversed STZ-induced GPR55 down-regulation, reduced the activity of β-secretase 1 (BACE1) and the level of Aβ 1-42 , and abolished the up-regulation of acetylcholinesterase (AChE) activity in the hippocampus and frontal cortex. Besides, O-1602 markedly suppressed STZ-induced oxidative stress, characterized by decreased malondialdehyde (MDA) level, and increased the levels of glutathione (GSH), superoxide dismutases (SOD), and catalase (CAT), as well as attenuated neuroinflammation as indicated by decreased series of pro-inflammatory cytokines and microglia activation. O-1602 treatment also ameliorated synaptic dysfunction by promoting the up-regulation of PSD-95 protein in the STZ-treated mice. Our results suggest that O-1602 has potent neuroprotective effects against STZ-induced neurotoxicity. Meanwhile, these findings suggest that GPR55 might be a novel and promising target for the treatment of AD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Vascular complications are a leading cause of morbidity and mortality among diabetic patients. This work aimed to investigate possible influences of dimethyl fumarate (DMF) on streptozotocin (STZ) diabetes-associated vascular complications in rats, exploring its potential to modulate ROS-TXNIP-NLRP3 inflammasome pathway. Two weeks after induction of diabetes (via a single injection of 50 mg/kg STZ, i.p.), diabetic rats were administered either DMF (25 mg/kg/day) or its vehicle for further eight weeks. Age-matched normal and DMF-administered non-diabetic rats served as controls. DMF treatment elicited a mild ameliorative effect on diabetic glycemia. DMF reduced serum TG and AGE levels and enhanced serum HDL-C concentrations in diabetic rats. Moreover, DMF significantly diminished aortic levels of ROS and MDA and restored aortic GSH, SOD and Nrf2 to near-normal levels in STZ rats. Aortic mRNA levels of TXNIP, NLRP3 and NF-κB p65 in diabetic rats were significantly reduced by DMF treatment. Serum and aortic protein levels of TXNIP and aortic contents of IL-1β, iNOS, NLRP3 and TGF-β1 were significantly lower in DMF-diabetic animals than non-treated diabetic rats. Furthermore, protein expression of TNF-α and caspase-3 in diabetic aortas was greatly attenuated by DMF administration. DMF enhanced eNOS mRNA and protein levels and increased bioavailable NO in diabetic aortas. Functionally, DMF attenuated contractile responses of diabetic aortic rings to KCl and phenylephrine and enhanced their relaxant responses to acetylcholine. DMF also mitigated diabetes-induced fibrous tissue proliferation in aortic tunica media. Collectively, these findings demonstrate that DMF offered vasculoprotective influences on diabetic aortas via attenuation of ROS-TXNIP-NLRP3 inflammasome pathway., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Endothelial dysfunction is a common complication of diabetes that mainly stems from increased reactive oxygen species, which makes antioxidants of great benefit. Resveratrol (RSV) is an antioxidant that shows protective effects in a variety of disease models where the ameliorative effect appears to be mediated, in part, via heme oxygenase-1 (HO-1) induction. However, the pathophysiological relevance of HO-1 in the ameliorative response of RSV in endothelial dysfunction is not clearly defined. The present study was conducted to investigate whether HO-1 plays a role in diabetes-induced vascular dysfunction. Streptozotocin-diabetic rats were treated with RSV (10 mg/kg) in presence or absence of an HO-1 blocker, Zinc protoporphyrin (ZnPP) to assess vascular function and indicators of disease status. We found that RSV treatment significantly abrogated diabetes induced vascular dysfunction. This improvement was associated with the ability of RSV to decrease oxidative stress markers alongside a reduction in the aortic TGF-β expression, elevation of NOS3 expression and aortic nitrite concentration as well as HO activity. These ameliorative effects were diminished when ZnPP was administered prior to RSV. Our results clearly demonstrate the protective effects of RSV in diabetes-associated endothelial dysfunction and verified a causal role of HO-1 in this setting., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A new series of octadec-9-enoic acid schiff base entities (S1-S30) were designed and synthesized targeting peroxisome proliferator activated receptor-gamma for agonist action. Molinspiration software (online) was used to estimate drug like molecular properties of the metabolites. Docking disquisition on co-crystallized protein of PPAR-γ (PDB ID 1FM9) was carried out which showed S21, S10 and S7 as best situated in the vital sites of receptor having docking scores -9.19, -8.68 and -8.64 respectively. Free binding energy measured using model of Maestro 9.0 and was in range of from -40.01 and -80.54 kcal/mol, significant when compared with pioglitazone (-51.58 Kcal/mol). Seven best docked derivatives were assessed for in-vivo oral glucose tolerance on normal rats and anti-hyperglycaemic activity by streptozotocin induced diabetes model. S21 unveiled to be the best measured analogue among all the synthesized entities. Encouraging outcomes motivates fatty acids for further development of more effective and safer compounds., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Diabetic cardiomyopathy is characterized by the deterioration of the myocardial function. Emerging evidences have indicated that leukocytic toll-like receptor 2 (TLR2) played an important role in the development of diabetic cardiomyopathy. Our study aimed to investigate whether TLR2 knockout (KO) exerted a cardioprotective effect in vivo. The establishment of diabetes model was set up in mice via intraperitoneal injection of streptozotocin (STZ). Results demonstrated that blocking of TLR2 significantly suppressed the enhanced left ventricular end-diastolic dimension (LVEDD), left ventricular end systolic diameter (LVESD) and the reduced the heart rate in diabetic cardiomyopathy mice. The decreased resting cell length, PS, TPS and + dL/dt while increased TR90 and - dL/dt caused by diabetic cardiomyopathy were remarkably inhibited by TLR2 KO. Besides that, the alleviated ΔFFI (360/380), decreased SERCA2a and p-NFATc3 expressions, extended Ca 2+ decay time and elevated Calcineurin A induced by diabetic cardiomyopathy were vastly repressed by TLR2 KO in cardiocytes. Moreover, TLR2 gene silence could ameliorate oxidative stress-induced apoptosis, evidences were the up-regulated superoxide generation and Bax/Bcl-2 expression while restrained GSH/GSSG ratio caused by diabetic cardiomyopathy were tremendously repressed in TLR2 KO mice. Furthermore, blocking of TLR2 remarkably attenuated the augmented fibrosis areas of heart tissues in mice with diabetic cardiomyopathy. The result of the enhanced α-SMA and collagenⅠ caused by diabetic cardiomyopathy were suppressed in heart tissues of TLR2 KO mice further validate it. All in all, our study demonstrated that diabetes-induced cardiac dysfunction could be attenuated by TLR2 KO., (Copyright © 2018 Elsevier Inc. All rights reserved.)

A small library of new benzothiazole clubbed oxadiazole-Mannich bases (M-1 to M-22) were synthesized and characterized by IR, NMR, Mass and Elemental analysis results. Molecular docking studies were done to assess the binding mode and interactions of synthesized hits at binding site of receptor Peroxisome proliferator-activated receptor, PPAR-γ or PPARG (PDB 1FM9). Among the synthesized compounds, nine compounds were selected on the basis of docking score and evaluated for their in vivo anti-diabetic activity using Oral Glucose Tolerance Test (OGTT) in normal rats followed by Streptozotocin (STZ) - induced diabetes. Results indicated that compound M-14 (161.39 ± 4.38) showed the highest reduction of blood glucose level comparable to that of the standard drug glibenclamide (140.29 ± 1.24) in STZ model. Other compounds exhibited moderate to good anti hyperglycaemic activity. ADME studies was done using Molinspiration online software, revealed that all compounds (except M-11) are likely to be orally active as they obeyed Lipinski's rule of five., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Diabetes mellitus has become the third human killer following cancer and cardiovascular disease. Millions of patients, often children, suffer from type 1 diabetes (T1D). Stem cells created hopes to regenerate damaged body tissues and restore their function., Aim: This work aimed at clarifying and comparing the therapeutic potential of differentiated and non-differentiated mesenchymal stem cells (MSCs) as a new line of therapy for T1D., Methods: 40 Female albino rats divided into group I (control): 10 rats and group II (diabetic), III and IV, 10 rats in each, were injected with streptozotocin (50mg/kg body weight). Group III (MSCs) were transplanted with bone marrow derived MSCs from male rats and group IV (IPCs) with differentiated insulin producing cells. Blood and pancreatic tissue samples were taken from all rats for biochemical and histological studies., Results: MSCs reduced hyperglycemia in diabetic rats on day 15 while IPCs normalizes blood glucose level on day 7. Histological and morphometric analysis of pancreas of experimental diabetic rats showed improvement in MSCs-treated group but in IPCs-treated group, β-cells insulin immunoreactions were obviously returned to normal, with normal distribution of β-cells in the center and other cells at the periphery. Meanwhile, most of the pathological lesions were still detected in diabetic rats., Conclusion: MSCs transplantation can reduce blood glucose level in recipient diabetic rats. IPCs initiate endogenous pancreatic regeneration by neogenesis of islets. IPCs are better than MSCs in regeneration of β-cells. So, IPCs therapy can be considered clinically to offer a hope for patients suffering from T1D., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim: The present study was designed to investigate the potential of Cyclosporine (CsA) and Tacrolimus, the inhibitors of calcineurin (CaN) in cognitive deficits of mice., Methods: Streptozotocin [STZ, 3mg/kg, injected intracerebroventricular (i.c.v.)] was used to induce memory deficits in NIH mice, while aged mice separately taken served as a natural model of dementia. Morris water maze (MWM) test was employed to evaluate learning and memory of the animals. A battery of biochemical and histopathological studies was also performed. Extent of oxidative stress was measured by estimating the levels of brain glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity was estimated to assess cholinergic activity. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation., Results: STZ i.c.v. and aging results in marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ i.c.v. treated mice and aged mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH level. Further the stained micrographs of STZ treated mice and aged mice indicate pathological changes, severe neutrophilic infiltration and amyloid deposition. Cyclosporine and Tacrolimus treatment significantly attenuated STZ induced and age related memory deficits, biochemical and histopathological alterations., Conclusion: The findings demonstrate the potential of CaN inhibitors Cyclosporine and Tacrolimus in memory dysfunctions which may probably be attributed to anti-cholinesterase, anti-amyloid, anti-oxidative and anti-inflammatory effects. It is concluded that CaN can be explored as a potential therapeutic target in dementia., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Streptozotocin (STZ) has been extensively used over the last three decades to induce diabetes in various animal species and to help screen for hypoglycemic drugs. STZ induces clinical features in animals that resemble those associated with diabetes in humans. For this reason STZ treated animals have been used to study diabetogenic mechanisms and for preclinical evaluation of novel antidiabetic therapies. However, the physiochemical characteristics and associated toxicities of STZ are still major obstacles for researchers using STZ treated animals to investigate diabetes. Another major challenges in STZ-induced diabetes are sustaining uniformity, suitability, reproducibility and induction of diabetes with minimal animal lethality. Lack of appropriate use of STZ was found to be associated with increased mortality and animal suffering. During STZ use in animals, attention should be paid to several factors such as method of preparation of STZ, stability, suitable dose, route of administration, diet regimen, animal species with respect to age, body weight, gender and the target blood glucose level used to represent hyperglycemia. Therefore, protocol for STZ-induced diabetes in experimental animals must be meticulously planned. This review highlights specific skills and strategies involved in the execution of STZ-induced diabetes model. The present review aims to provide insight into diabetogenic mechanisms of STZ, specific toxicity of STZ with its significance and factors responsible for variations in diabetogenic effects of STZ. Further this review also addresses ways to minimize STZ-induced mortality, suggests methods to improve STZ-based experimental models and best utilize them for experimental studies purported to understand diabetes pathogenesis and preclinical evaluation of drugs., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

In the present study the role of glial activation and post synaptic toxicity in ICV Streptozotocin (STZ) induced memory impaired rats was explored. In experiment set up 1: Memory deficit was found in Morris water maze test on 14-16 days after STZ (ICV; 3mg/Kg) administration. STZ causes increased expression of GFAP, CD11b and TNF-α indicating glial activation and neuroinflammation. STZ also significantly increased the level of ROS, nitrite, Ca(2+) and reduced the mitochondrial activity in synaptosomal preparation illustrating free radical generation and excitotoxicity. Increased expression and activity of Caspase-3 was also observed in STZ treated rat which specify apoptotic cell death in hippocampus and cortex. STZ treatment showed decrease expression of post synaptic markers CaMKIIα and PSD-95, while, expression of pre synaptic markers (synaptophysin and SNAP-25) remains unaltered indicating selective post synaptic neurotoxicity. Oral treatment with Memantine (10mg/kg) and Ibuprofen (50 mg/kg) daily for 13 days attenuated STZ induced glial activation, apoptotic cell death and post synaptic neurotoxicity in rat brain. Further, in experiment set up 2: where memory function was not affected i.e. 7-9 days after STZ treatment. The level of GFAP, CD11b, TNF-α, ROS and nitrite levels were increased. On the other hand, apoptotic marker, synaptic markers, mitochondrial activity and Ca(2+) levels remained unaffected. Collective data indicates that neuroinflammatory process and oxidative stress occurs earlier to apoptosis and does not affect memory function. Present study clearly suggests that glial activation and post synaptic neurotoxicity are the key factors in STZ induced memory impairment and neuronal cell death., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Generation of surrogate β-cells is the need of the day to compensate the short supply of islets for transplantation to diabetic patients requiring daily shots of insulin. Over the years several sources of stem cells have been claimed to cater to the need of insulin producing cells. These include human embryonic stem cells, induced pluripotent stem cells, human perinatal tissues such as amnion, placenta, umbilical cord and postnatal tissues involving adipose tissue, bone marrow, blood monocytes, cord blood, dental pulp, endometrium, liver, labia minora dermis-derived fibroblasts and pancreas. Despite the availability of such heterogonous sources, there is no substantial breakthrough in selecting and implementing an ideal source for generating large number of stable insulin producing cells. Although the progress in derivation of β-cell like cells from embryonic stem cells has taken a greater leap, their application is limited due to controversy surrounding the destruction of human embryo and immune rejection. Since multipotent mesenchymal stromal cells are free of ethical and immunological complications, they could provide unprecedented opportunity as starting material to derive insulin secreting cells. The main focus of this review is to discuss the merits and demerits of MSCs obtained from human peri- and post-natal tissue sources to yield abundant glucose responsive insulin producing cells as ideal candidates for prospective stem cell therapy to treat diabetes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: Lipoprotein lipase (LPL) is a key regulator of circulating triglyceride rich lipoprotein hydrolysis. In brain LPL regulates appetite and energy expenditure. Angiopoietin-like 4 (Angptl4) is a secreted protein that inhibits LPL activity and, thereby, triglyceride metabolism, but the impact of Angptl4 on central lipid metabolism is unknown. Methods: We induced type 1 diabetes by streptozotocin (STZ) in whole-body Angptl4 knockout mice (Angptl4-/-) and their wildtype littermates to study the role of Angptl4 in central lipid metabolism. Results: In type 1 (streptozotocin, STZ) and type 2 (ob/ob) diabetic mice, there is a ~2-fold increase of Angptl4 in the hypothalamus and skeletal muscle. Intracerebroventricular insulin injection into STZ mice at levels which have no effect on plasma glucose restores Angptl4 expression in hypothalamus. Isolation of cells from the brain reveals that Angptl4 is produced in glia, whereas LPL is present in both glia and neurons. Consistent with the in vivo experiment, in vitro insulin treatment of glial cells causes a 50% reduction of Angptl4 and significantly increases LPL activity with no change in LPL expression. In Angptl4-/- mice, LPL activity in skeletal muscle is increased 3-fold, and this is further increased by STZ-induced diabetes. By contrast, Angptl4-/- mice show no significant difference in LPL activity in hypothalamus or brain independent of diabetic and nutritional status. Conclusion: Thus, Angptl4 in brain is produced in glia and regulated by insulin. However, in contrast to the periphery, central Angptl4 does not regulate LPL activity, but appears to participate in the metabolic crosstalk between glia and neurons.

A hollow-fiber liquid-phase microextraction (HF-LPME) method has been developed for the preconcentration of trace sulfonamides in water samples. Six commonly used sulfonamides including sulfamethazine (SMZ), sulfamerazine (SMR), sulfadiazine (SDZ), sulfadimethoxine (SDM), sulfamethoxazole (SMX), and sulfathiazole (STZ) were determined by CE with electrochemical detection (CE-ED) after microextraction. Several factors that affect extraction efficiency, separation, and detection were investigated. Under the optimum conditions, above sulfonamide compounds could achieve baseline separation within 35min, exhibiting a linear calibration over three orders of magnitude (r(2)≥0.998); the obtained enrichment factors were between 121 (for SDZ) and 996 (for SDM), and the LODs were in the range of 0.033-0.44ng/mL. The proposed HF-LPME/CE-ED method has been applied for the sensitive analyses of the real-world water samples with recoveries in the range of 75.1-109%., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Dispersive liquid-liquid microextraction with solidification of floating organic drop (DLLME-SFO) is one of the most interesting sample preparation techniques developed in recent years. Although several applications have been reported, the potentiality and limitations of this simple and rapid extraction technique have not been made sufficiently explicit. In this work, the extraction efficiency of DLLME-SFO for pollutants from different chemical families was determined. Studied compounds include: 10 polycyclic aromatic hydrocarbons, 5 pesticides (chlorophenoxy herbicides and DDT), 8 phenols and 6 sulfonamides, thus, covering a large range of polarity and hydrophobicity (LogKow 0-7, overall). After optimization of extraction conditions using 1-dodecanol as extractant, the procedure was applied for extraction of each family from 10-mL spiked water samples, only adjusting sample pH as required. Absolute recoveries for pollutants with LogKow 3-7 were >70% and recovery values within this group (18 compounds) were independent of structure or hydrophobicity; the precision of recovery was very acceptable (RSD<12%) and linear behavior was observed in the studied concentration range (r(2)>0.995). Extraction recoveries for pollutants with LogKow 1.46-2.8 were in the range 13-62%, directly depending on individual LogKow values; however, good linearity (r(2)>0.993) and precision (RSD<6.5%) were also demonstrated for these polar solutes, despite recovery level. DLLME-SFO with 1-dodecanol completely failed for extraction of compounds with LogKow≤1 (sulfa drugs), other more polar extraction solvents (ionic liquids) should be explored for highly hydrophilic pollutants., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Chronic exposure to high glucose induces the expression of cystathionine gamma-lyase (CSE), a hydrogen sulfide-producing enzyme, in pancreatic beta-cells, thereby suppressing apoptosis. The aim of this study was to examine the effects of hydrogen sulfide on the onset and development of type 2 diabetes. Middle-aged (6-month-old) wild-type (WT) and CSE knockout (CSE-KO) mice were fed a high-fat diet (HFD) for 8weeks. We determined the effects of CSE knockout on beta-cell function and mass in islets from these mice. We also analyzed changes in gene expression in the islets. After 8weeks of HFD, blood glucose levels were markedly increased in middle-aged CSE-KO mice, insulin responses were significantly reduced, and DNA fragmentation of the islet cells was increased. Moreover, expression of thioredoxin binding protein-2 (TBP-2, also known as Txnip) was increased. Administration of NaHS, a hydrogen sulfide donor, reduced TBP-2 gene levels in isolated islets from CSE-KO mice. Gene levels were elevated when islets were treated with the CSE inhibitor dl-propargylglycine (PPG). These results provide evidence that CSE-produced hydrogen sulfide protects beta-cells from glucotoxicity via regulation of TBP-2 expression levels and thus prevents the onset/development of type 2 diabetes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with (68)Gallium ((68)Ga). After intravenous injection of (68)Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that (68)Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of (68)Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with (68)Ga-DOTA-octreotide could be a potential tool for evaluating BCM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Nicotinamide rescues β-cell damage and diabetes in rodents, but a large-scale clinical trial failed to show the benefit of nicotinamide in the prevention of type 1 diabetes. Recent studies have shown that Sirt1 deacetylase, a putative protector of β-cells, is inhibited by nicotinamide. We investigated the effects of isonicotinamide, which is a derivative of nicotinamide and does not inhibit Sirt1, on streptozotocin (STZ)-induced diabetes in mice., Research Design and Methods: Male C57BL/6 mice were administered with three different doses of STZ (65, 75, and 100 mg/kg BW) alone or in combination with subsequent high-fat feeding. The mice were treated with isonicotinamide (250 mg/kg BW/day) or phosphate-buffered saline for 10 days. The effects of isonicotinamide on STZ-induced diabetes were assessed by blood glucose levels, glucose tolerance test, and immunohistochemistry., Results: Isonicotinamide effectively prevented hyperglycemia induced by higher doses of STZ (75 and 100mg/kg BW) alone and low-dose STZ (65 mg/kg BW) followed by 6-week high-fat diet in mice. The protective effects of isonicotinamide were associated with decreased apoptosis of β-cells and reductions in both insulin content and insulin-positive area in the pancreas of STZ-administered mice. In addition, isonicotinamide inhibited STZ-induced apoptosis in cultured isolated islets., Conclusions: These data clearly demonstrate that isonicotinamide exerts anti-diabetogenic effects by preventing β-cell damage after STZ administration. These findings warrant further investigations on the protective effects of isonicotinamide and related compounds against β-cell damage in diabetes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Diabetes associated hyperglycemia results in generation of reactive oxygen species which induces oxidative stress and initiate massive DNA damage leading to overactivation of poly (ADP-ribose) polymerase (PARP). In this study, we have elucidated the involvement of oxidative stress-PARP pathway using pharmacological interventions (melatonin, as an anti-oxidant and nicotinamide, as a PARP inhibitor) in diabetes-induced neurobehavioral and neurochemical alterations. Sprague-Dawley rats were rendered diabetic by a single intraperitoneal injection of streptozotocin. Behavioral and cognitive deficits were assessed after 8weeks of diabetes induction using a functional observation battery, passive avoidance and rotarod test. Acetylcholinesterase activity was significantly decreased in hippocampus of diabetic rats as compared to control rats. Diabetic animals showed significant increase in malondialdehyde levels and reduction in NAD levels in hippocampus. Glutamate and GABA levels were also altered in hippocampus of the diabetic animals. Two week treatment with melatonin (3 and 10mg/kg) and nicotinamide (300 and 1000mg/kg) alone and in combination significantly improved the neurobehavioral parameters which were altered in diabetes. Neurotransmitter (glutamate and GABA) levels were improved by these interventions. Our results emphasize that simultaneous inhibition of oxidative stress-PARP overactivation cascade can be beneficial in treatment of diabetes associated CNS changes., (© 2013.)

In this manuscript, a new method based on the use of off-line dispersive solid-phase extraction (dSPE) combined with ultra-high performance liquid chromatography with diode-array detection was developed to determine 11 sulfonamide antibiotics (sulfanilamide, sulfacetamide, sulfadiazine, sulfathiazole, sulfamerazine, sulfadimidin, sulfamethoxypyridazine, sulfadoxine, sulfamethoxazole, sulfisoxazole and sulfadimethoxine) in mineral waters with different mineral content. For this purpose, pristine multi-walled carbon nanotubes (MWCNTs) and magnetic-MWCNTs (m-MWCNTs) were used as sorbents. Magnetic nanoparticles were synthesized by means of a solvothermal process, assembled onto CNTs through an "aggregation wrap" mechanism and characterized by scanning electron microscopy. Parameters affecting the extraction such as volume and pH of the sample, amount of sorbent and type and volume of eluent were optimized. Once optimum extraction conditions (250 mL of water at pH 6.0 and elution with 25 mL of MeOH) were obtained, the extraction efficiency of the different carbon nanomaterials was compared. Results demonstrated the higher extraction capacity of pristine MWCNTs with recoveries between 61 and 110% (except for sulfacetamide which ranged between 40 and 53%) and between 22 and 77% for m-MWCNTs. Limits of detection lower than 32 ng/L were achieved for all of the analyzed samples., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose: The quality of bioanalytical data is dependent upon selective, sensitive, and reproducible analytical methods. With evolving technologies available, bioanalytical scientists must assess which is most appropriate for their molecule through proper method validation. For an early stage PEGylated insulin program, the characteristics of four platforms, ELISA, ECL, Gyrolab, and LC-MS/MS, were evaluated using fit-for-purpose method development and validation, while also evaluating costs., Method: Methods selected for validation required acceptable performance based on satisfaction of a priori criteria prior to proceeding to subsequent stages of validation. LBA pre-validation included reagent selection, evaluation of matrix interference, and range determination. LC-MS/MS pre-validation included selection of a signature peptide; optimization of sample preparation, HPLC, and LC-MS/MS conditions; and calibration range determination. Pre-study validation tested accuracy and precision (mean bias criteria±30%; precision≤30%). Pharmacokinetic (PK) parameters were estimated for an in vivo study with WinNonlin noncompartmental analysis. Statistics were performed with JMP using ANOVA and Tukey-Kramer post hoc analysis. A cost analysis was performed for a 200-sample PK study using the methods from this study., Results: All platforms, except Gyrolab, were taken through validation. However, a typical Gyrolab method was included for the cost analysis. Ranges for the ELISA, ECLA, and LC-MS/MS were 8.52-75, 2.09-125, and 100-1000 ng/mL, respectively, and accuracy and precision fell within a priori criteria. PK samples were analyzed in the 3 validated methods. PK profiles and parameters are similar for all methods, except LC-MS/MS, which differed at t=24h and with AUC0-24. Further investigation into this difference is warranted. The cost analysis identified the Gyrolab platform as the most expensive and ELISA as the least expensive, with method specific consumables attributing significantly to costs., Conclusions: ECLA had a larger dynamic range and sensitivity, allowing accurate assessment of PK parameters. Although this method was more expensive than the ELISA, it was the most appropriate for the early stage PEGylated insulin program. While this case study is specific to PEGylated human insulin, it highlights the importance of evaluating and selecting the most appropriate platform for bioanalysis during drug development., (© 2013.)

Background: Hyperglycemia-induced reactive oxygen species (ROS) generation contributes to development of diabetic cardiomyopathy. Nuclear factor E2-related factor 2 (Nrf2), a redox-sensing transcription factor, induces the antioxidant enzyme expressions. Diallyl trisulfide (DATS) is the most powerful antioxidant among the sulfur-containing compounds in garlic oil. We investigated whether DATS inhibits hyperglycemia-induced ROS production via Nrf2-mediated activation of antioxidant enzymes in cardiac cells exposed to high glucose (HG)., Methods and Results: Treatment of H9c2 cells with HG resulted in an increase in intracellular ROS level and caspase-3 activity, which were markedly reduced by the administration of DATS (10 μM). DATS treatment significantly increased Nrf2 protein stability and nuclear translocation, upregulated downstream gene HO-1, and suppressed its repressor Keap1. However, apoptosis was not inhibited by DATS in cells transfected with Nrf2-specific siRNA. Inhibition of PI3K/Akt signaling by LY294002 (PI3K inhibitor) or PI3K-specific siRNA not only decreased the level of DATS-induced Nrf2-mediated HO-1 expression, but also diminished the protective effects of DATS. Similar results were also observed in high glucose-exposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats fed DATS at a dose of 40 mg/kg BW., Conclusions: Our findings indicate that DATS protects against hyperglycemia-induced ROS-mediated apoptosis by upregulating the PI3K/Akt/Nrf2 pathway, which further activates Nrf2-regulated antioxidant enzymes in cardiomyocytes exposed to HG., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Hyperglycemia is an important risk factor for cardiovascular diseases no matter if it resulted from type I or type II diabetes mellitus. High glucose-induced generation of reactive oxygen species (ROS) can lead to diabetic cardiomyopathy. In our previous study, we showed that NADPH oxidase-related ROS-induced apoptosis is mediated via the JNK-dependent activation of NF-κB in cardiomyocytes exposed to high glucose (HG)., Objective: In this study, we investigated the mechanisms governing the anti-apoptotic effect of diallyl trisulfide (DATS) on HG-exposed cardiac cells both in vitro and in vivo., Methods: H9c2 cells were incubated with media containing 5.5 or 33 mM of glucose for 36 h in the presence or absence of DATS., Results: We found that DATS treatment led to a dose-dependent decrease in ROS levels as well as protein levels of p22phox, gp91phox, phosphorylated JNK, and phosphorylated c-Jun. In addition, DATS inhibited the HG-induced activation of caspase 3 as well as the nuclear translocation of NF-κB. Similar results were observed in HG-exposed neonatal primary cardiomyocytes and streptozotocin-treated diabetic rats. Echocardiographic data showed that DATS administration led to a marked increase in fractional shortening and cardiac output., Conclusion: DATS appears to suppress high glucose-induced cardiomyocyte apoptosis by inhibiting NADPH oxidase-related ROS and its downstream JNK/NF-κB signaling, and may possess the potential on the therapy of diabetic cardiomyopathy., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The small heterodimer partner (SHP; NR0B2) regulates the transcription of a variety of target genes and controls a variety of physiological functions in various tissues. However, the role of SHP in beta cell has not been fully determined yet. We used SHP knockout (SHP KO) mice to investigate the role of SHP in multiple low-dose streptozotocin (MLDS)-induced diabetes. Blood glucose and insulin levels were measured until 20 days, and intraperitoneal glucose tolerance and glucose-stimulated insulin secretion tests were performed. The expression of apoptotic genes and beta cell markers were detected by quantitative realtime-polymerase chain reaction, immunostaining and western blot analysis. SHP KO mice showed significantly lower blood glucose, higher insulin levels, and enhanced glucose tolerance compared with wild type (WT) mice after MLDS treatment. Moreover, beta cell mass and pancreatic insulin content were remarkably increased in SHP KO mice. In the response to glucose stimulation, islets of SHP KO showed increased insulin secretion via up-regulation of beta cell enriched transcription factors compared to WT mice after streptozotocin (STZ) treatment. In quantification for beta cell apoptosis at day 1 post STZ treatment, the SHP KO mice showed significantly increased anti-apoptotic gene expression and decreased release of apoptotic markers cytochrome c, smac/diablo, and only a few apoptotic beta cells were found in SHP KO pancreas through inactivation of caspase-3, compared to those of WT. These data demonstrate that SHP deficiency ameliorates hyperglycemia and preserves islet function by inhibiting apoptosis of pancreatic beta cells and up-regulating of their enriched transcriptional factors., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The worldwide rapid increase in diabetes poses a significant challenge to current therapeutic approaches. Single-dose mesenchymal stem cell (MSC) infusion ameliorates hyperglycemia but fails to restore normoglycemia in diabetic animals. We therefore hypothesized that multiple intravenous MSC infusions may reverse hyperglycemia in type 2 diabetes (T2D) rats. We administered serial allogenous bone-marrow derived MSC infusions (1 × 10(6)cells/infusion) via the tail vein once every 2 weeks to T2D rats, induced by high-fat diet and streptozocin (STZ) administration. Hyperglycemia decreased only transiently after a single infusion in early-phase (1 week) T2D rats, but approximated normal levels after at least three-time infusions. This normal blood level was maintained for at least 9 weeks. Serum concentrations of both insulin and C-peptide were dramatically increased after serial MSC infusions. Oral glucose tolerance tests revealed that glucose metabolism was significantly ameliorated. Immunofluorescence analysis of insulin/glucagon staining revealed the restoration of islet structure and number after multiple MSC treatments. When multiple-MSC treatment was initiated in late-phase (5 week) T2D rats, the results were slightly different. The results of this study suggested that a multiple-MSC infusion strategy offers a viable clinical option for T2D patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Testicular damage is a common clinical problem in diabetic individuals that severely affects the quality of life. The present study investigates the possible protective mechanisms of telmisartan, an angiotensin II-receptor antagonist in the germ cell of diabetic rat. Male SD rats were used and randomized into six groups: control, telmisartan control, diabetic control and diabetic group treated with telmisartan at the doses of 3, 6 and 12mg/kg/day, per oral for 4 weeks. Diabetes was induced by injecting a single dose of streptozotocin (STZ), (55mg/kg) dissolved in ice-cold 10mM citrate buffer; pH 4.4 and administered i.p. immediately after preparation to the SD rats. At the end of the study, rats were sacrificed and the levels of nitrite, superoxide, malondialdehyde (MDA), glutathione (reduced and peroxidase) and superoxide dismutase (SOD) were measured. Germ cell toxicity was evaluated by using sperm count, sperm comet assay, histology of testes and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Further to confirm the oxidative and nitrosative damage, immunohistological quantification of 8-oxo-dG (8-oxo-7,8-dihydro-2'-deoxyguanosine) and 3-nitrotyrosine were evaluated respectively. Results showed that telmisartan significantly restored the levels of nitrite, superoxide, malondialdehyde, and glutathione and superoxide dismutase in diabetic testes. Further, telmisartan significantly increased the sperm counts, reduced apoptotic cell death, sperm DNA damage, oxidative and nitrosative damage in diabetic rat. Western blot analysis showed that telmisartan reduced the testicular inflammation and cell death by down-regulating the expression of NF-κB, IL-6, TNF-α, p-ERK1/2, iNOS, caspase-3 and increasing the PPAR-γ expression. Results clearly indicate that telmisartan significantly reduced the both oxidative and nitrosative stress, inflammation and cell death in diabetic testes. The present results confirmed that telmisartan exhibited beneficial role in the germ cell of diabetic rat., (Copyright © 2013 Elsevier B.V. All rights reserved.)