ABSTRACT
BACKGROUND/AIM: In a previous report, our group showed that oral administration of lipopolysaccharides (LPS) from Pantoea agglomerans can prevent the progression of streptozotocin (STZ)-induced diabetes-related cognitive dysfunction (DRCD) in mice without causing significant side-effects. However, the treatment effects of oral administration of LPS to DRCD remain unknown. MATERIALS AND METHODS: We modified our previous animal experimental model to investigate whether oral administration of LPS can recover cognitive function after DRCD onset. RESULTS: The Morris water maze (MWM) revealed a significant decrease in learning and memory abilities at 13 days after intracerebroventricular administration of STZ, thereby providing evidence of the occurrence of DRCD in the animal model. Oral administration of LPS (1 mg/kg per day) started after cognitive impairment was observed. After 28 days of treatment, mice receiving LPS via the oral route showed significant recovery of spatial learning ability, a symptom of early dementia, while only a trend toward recovery was seen for spatial memory compared to the untreated group. CONCLUSION: These results, limited to MWM, suggest that oral administration of LPS is a promising therapeutic strategy for restoring decreased spatial learning ability.
Subject(s)
Cognitive Dysfunction , Diabetes Mellitus, Experimental , Disease Models, Animal , Lipopolysaccharides , Maze Learning , Spatial Learning , Animals , Lipopolysaccharides/adverse effects , Lipopolysaccharides/administration & dosage , Mice , Administration, Oral , Cognitive Dysfunction/etiology , Cognitive Dysfunction/drug therapy , Male , Diabetes Mellitus, Experimental/complications , Spatial Learning/drug effects , Maze Learning/drug effects , Streptozocin/administration & dosageABSTRACT
Alzheimer's disease (AD) is an approaching, progressive public health crisis which presently lacks an effective treatment. Various non-invasive novel therapies like repetitive transcranial magnetic stimulation have shown potential to improve cognitive performance in AD patients. In the present study, the effect of extremely low intensity magnetic field (MF) stimulation on neurogenesis and cortical electrical activity was explored. Adult Wistar rats were divided into Sham, AD and AD + MF groups. Streptozotocin (STZ) was injected intracerebroventricularly, at a dose of 3 mg/kg body weight for developing AD model. The AD rats were then exposed to MF (17.96 µT) from 8th day of STZ treatment until 15th day, followed by cognitive assessments and electrocortical recording. In brain tissue samples, cresyl violet staining and BrdU immunohistochemistry were done. MF exposure, improved passive avoidance and recognition memory, attenuated neuronal degeneration and enhanced cell proliferation (BrdU positive cells) in comparison to AD rats. It also significantly restores delta wave power from frontal lobe. Our results suggest that early-stage MF exposure could be an asset for AD research and open new avenues in slowing down the progression of Alzheimer's disease.
Subject(s)
Alzheimer Disease , Disease Models, Animal , Rats, Wistar , Streptozocin , Animals , Alzheimer Disease/therapy , Alzheimer Disease/physiopathology , Streptozocin/toxicity , Streptozocin/administration & dosage , Male , Rats , Neurogenesis/radiation effects , Magnetic Field Therapy/methods , Brain , Cell ProliferationABSTRACT
INTRODUCTION: The brain-derived neurotrophic factor (BDNF) and transcription nuclear factor erythroid 2-related factor-2 (NRF-2) play an important role in Alzheimer's disease (AD). However, the interactive involvement of BDNF and NRF-2 in respect to antioxidant mechanisms in different parts of the AD brain is still unclear. Considering the above condition, used S-nitrosoglutathione (GSNO) to examine whether it modulates the BDNF and NRF-2 levels to activate signaling pathway to promote antioxidant levels in AD brains. METHOD: AD was induced by intracerebroventricular infusion of streptozotocin (ICV-STZ, 3 mg/kg) in Wistar rats. The effect of GSNO was analyzed by evaluating the retention of memory in months 1, 2, and 3. After the behavior study, rats were sacrificed and accessed the amyloid beta (Aß)-40, Aß42, glutathione (GSH), BDNF, and NRF-2 levels in the hippocampus, cortex, and amygdala tissue. RESULTS: Pretreatment with GSNO (50 µg/kg/intraperitoneal/day) restored the BDNF, and NRF-2 levels toward normalcy as compared with ICV-STZ + saline-treated animals. Also, GSNO treatment reversed the oxidative stress and increased the GSH levels toward normal levels. Further, reduced Aß levels and neuronal loss in different brain regions. As a result, GSNO treatment improved the cognitive deficits in ICV-STZ-treated rats. CONCLUSION: The results showed that endogenous nitric oxide donor GSNO improved the cognitive deficits and ICV-STZ-induced AD pathological conditions, possibly via attenuating the oxidative stress. Hence, the above finding supported that GSNO treatment may activate BDNF and NRF-2 antioxidant signaling pathways in the AD brain to normalize oxidative stress, which is the main causative factor for ICV-STZ-induced AD pathogenesis.
Subject(s)
Alzheimer Disease , Brain-Derived Neurotrophic Factor , Disease Models, Animal , Memory Disorders , NF-E2-Related Factor 2 , Oxidative Stress , Rats, Wistar , S-Nitrosoglutathione , Signal Transduction , Streptozocin , Animals , Alzheimer Disease/chemically induced , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Oxidative Stress/drug effects , S-Nitrosoglutathione/pharmacology , S-Nitrosoglutathione/administration & dosage , Brain-Derived Neurotrophic Factor/metabolism , Brain-Derived Neurotrophic Factor/drug effects , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/drug effects , Rats , Signal Transduction/drug effects , Male , Streptozocin/pharmacology , Streptozocin/administration & dosage , Memory Disorders/chemically induced , Memory Disorders/drug therapy , Antioxidants/pharmacology , Antioxidants/administration & dosageABSTRACT
OBJECTIVE: This study aimed to compare two routes of administration and different dosages of streptozotocin (STZ) for the pharmacological induction of gestational diabetes mellitus (GDM) in pregnant CD1 females. MATERIALS AND METHODS: 35 female CD1 mice were divided into 5 groups (n = 7). Diabetes mellitus (DM) was induced with STZ by two routes and two doses: 1) Control Group without administration of STZ (CL), 2) Intraperitoneal Group with 200 mg of STZ/Kg of weight (IP200), 3) Intraperitoneal Group with 230 mg of STZ/Kg of weight (IP230), 4) Subcutaneous Group with 200 mg of STZ/Kg of weight (SC200) and 5) Subcutaneous Group with 230 mg of STZ/Kg of weight (SC230). Body weight, food and water intake, glycemia, Homeostatic Model Assessment of Insulin Resistance Index (HOMA-IR), survival, and birth rate were identified. RESULTS: The SC230 group turned out to be the most effective dose and route for the induction of GDM in pregnant females. This scheme managed to reproduce sustained hyperglycemia with high HOMA-IR, the presence of polyphagia, polydipsia, and weight loss. In addition, the birth rate and survival were high compared to the other doses and routes of administration. CONCLUSIONS: The administration of a single dose of 230 mg/kg of weight by subcutaneous route supposes advantages compared to previously used models since it decreases the physiological stress due to manipulation and the costs since it does not require repeated doses or adjuvants such as high lipid diets to potentiate the diabetogenic effect of STZ. Graphical Abstract: https://www.europeanreview.org/wp/wp-content/uploads/Graphical-abstract-12.jpg.
Subject(s)
Diabetes Mellitus, Experimental , Diabetes, Gestational , Streptozocin , Animals , Female , Pregnancy , Mice , Diabetes Mellitus, Experimental/chemically induced , Streptozocin/administration & dosage , Injections, Subcutaneous , Blood Glucose/metabolism , Blood Glucose/drug effects , Dose-Response Relationship, Drug , Injections, Intraperitoneal , Insulin Resistance , Body Weight/drug effectsABSTRACT
Purpose: To determine the effect of gallic acid or its combination with glibenclamide on some biochemical markers and histology of the cornea of streptozotocin (STZ) induced diabetic rats. Methods: Following induction of diabetes, 24 male albino rats were divided into four groups of six rats each. Groups 1 and 2 (control and diabetic) received rat pellets and distilled water; group 3 (gallic acid) received rat pellets and gallic acid (10 mg/kg, orally) dissolved in the distilled water; and group 4 (gallic acid + glibenclamide) received rat pellets, gallic acid (10 mg/kg, orally), and glibenclamide (5 mg/kg, orally) dissolved in the distilled water. The treatments were administered for three months after which the rats were sacrificed after an overnight fast. Blood and sera were collected for the determination of biochemical parameters, while their eyes were excised for histology. Results: STZ administration to the rats induced insulin resistance, hyperglycemia, microprotenuria, loss of weight, oxidative stress, inflammation, and alteration of their cornea histology, which was abolished following supplementation with gallic acid or its combination with glibenclamide. Conclusions: The study showed the potentials of gallic acid and glibenclamide in mitigating systemic complication and histological changes in the cornea of diabetic rats induced with STZ.
Subject(s)
Animals , Rats , Glyburide/administration & dosage , Streptozocin/administration & dosage , Cornea/drug effects , Diabetes Mellitus , Gallic Acid/administration & dosageABSTRACT
Black truffle, a culinary and medical fungus, is highly valued worldwide for its nutritional and therapeutic importance. To enhance the existing knowledge about the beneficial properties, this study investigates the antioxidant, antihyperlipidemic, and anti-inflammatory effects of black truffle extract in in vitro biochemical assays and animal study. Briefly, black truffle extract was administered orally to treat streptozotocin- (STZ-) induced diabetic Wistar rats for 45 days. At the end of the experimental duration, rats were sacrificed to perform biochemical and gene expression analyses related to lipid regulatory and inflammatory pathways. Our results indicated that total cholesterol, triglycerides, free fatty acids, phospholipids, and low-density lipoprotein in different tissues and circulation were significantly increased in diabetic rats. Furthermore, the ß-hydroxy ß-methylglutaryl-CoA enzyme was also significantly increased; lipoprotein lipase and lecithin-cholesterol acyltransferase enzymes were significantly decreased in diabetic rats. However, the above conditions were reversed upon black truffle extract feeding. Furthermore, black truffle extract was also found to downregulate the expression of proinflammatory cytokines (tumor necrosis factor-α and interleukin-6) and lipid regulatory genes (serum regulatory element-binding protein-1 and fatty acid synthase). The truffle extract-treated effects were comparable to glibenclamide and medication commonly used to treat diabetes mellitus. Overall, our results suggested that black truffle possesses strong antihyperlipidemic and anti-inflammatory effects on diabetic rats. These findings will enhance the current knowledge about the therapeutic importance of black truffles. They might be exploited as a possible food supplement or even as a natural source of pharmaceutical agents for diabetes prevention and treatment.
Subject(s)
Anti-Inflammatory Agents/administration & dosage , Ascomycota/chemistry , Biological Products/administration & dosage , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Glyburide/administration & dosage , Hypoglycemic Agents/administration & dosage , Hypolipidemic Agents/administration & dosage , Lipid Metabolism/drug effects , Signal Transduction/drug effects , Streptozocin/administration & dosage , Administration, Oral , Animals , Case-Control Studies , Cytokines/metabolism , Gene Expression/drug effects , Inflammation/drug therapy , Lipid Metabolism/genetics , Male , Rats , Rats, Wistar , Treatment OutcomeABSTRACT
Non-alcoholic steatohepatitis (NASH) is a common chronic liver disease with no decisive treatment. The sodium glucose cotransporter 2 (SGLT2) inhibitor ipragliflozin was developed as a new oral hypoglycemic drug, which can improve NASH via an insulin-independent glucose-lowering effect by inhibiting glucose reabsorption in the renal proximal tubules. However, ipragliflozin appears to modulate steatosis or inflammation via different pathways. To elucidate the new mechanism of ipragliflozin for the treatment of NASH, we evaluated its effects in a NASH mouse model (STAM mice) with beta cell depletion, and compared the expression of microRNAs (miRNAs) in STAM mice treated with or without ipragliflozin (16.7 µg/day for 5 weeks). Ipragliflozin reduced aspartate transaminase and alanine aminotransferase levels, along with reduced hepatic steatosis, hepatocyte ballooning, lobular inflammation, and liver fibrosis. In addition, ipragliflozin upregulated mitochondrial transport-related and antioxidant defensive system-related genes in the liver. Among 2555 mouse miRNA probes, miR-19b-3p was commonly differentially expressed with ipragliflozin treatment for 5 weeks in both the liver and serum but in different directions, with a decrease in the liver and increase in the serum. Therefore, ipragliflozin can improve NASH development likely through the antioxidative stress pathway and by regulating miR-19b-3p.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Glucosides/pharmacology , Hypoglycemic Agents/pharmacology , Liver Cirrhosis/drug therapy , MicroRNAs/genetics , Non-alcoholic Fatty Liver Disease/drug therapy , Thiophenes/pharmacology , Alanine Transaminase/genetics , Alanine Transaminase/metabolism , Animals , Aspartate Aminotransferases/genetics , Aspartate Aminotransferases/metabolism , Blood Glucose/metabolism , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/metabolism , Disease Models, Animal , Fasting , Gene Expression Profiling , Gene Expression Regulation , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/pathology , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Liver Cirrhosis/genetics , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Male , Mice , Mice, Inbred C57BL , MicroRNAs/classification , MicroRNAs/metabolism , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Signal Transduction , Streptozocin/administration & dosage , Superoxide Dismutase/genetics , Superoxide Dismutase/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Type 2 diabetes is a major factor contributing to cognitive decline and Alzheimer's disease (AD). Treadmill running is considered to be a critical approach for mice and rats to lower blood sugar and improve learning and memory capacity. The growth factor receptor-bound protein 10 (Grb10) has been proposed to inhibit insulin signaling and defective brain insulin signaling resulted in the cognitive deficits in patients with AD. However, the positive roles of treadmill training on diabetic- related impaired cognitive function and their molecular mechanisms remain unclear. Here, to investigate whether there was neuroprotective effects of treadmill training on impaired cognitive function caused by diabetes, the rats were injected intraperitoneally with streptozotocin at a dose of 30 mg/kg to establish diabetic model (DM). We found that higher Grb10, BACE1 and PHF10 protein levels in the hippocampus of DM rats, lower phosphorylation IGF-1Rß and IRS-1(ser307). However, 8 weeks treadmill training effectively reduced abnormal Grb10, enhanced postsynaptic density protein PSD-93, PSD-95, SYN expressions of hippocampus, restored PI3K/Akt/ERK and mTOR/AMPK signaling, thus alleviated spatial learning and memory deficit, compared with DM group. Additionally, treadmill training also increased GLUT4 transportation. Overall, our findings suggest that treadmill intervention improved cognitive impairments caused by diabetes disease partly through modulating Grb10/ PI3K/Akt/ERK as well as mTOR/AMPK signaling.
Subject(s)
Cognitive Dysfunction/therapy , Diabetes Complications/therapy , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/complications , Exercise Therapy , GRB10 Adaptor Protein/metabolism , Glucose Transporter Type 4/drug effects , Physical Conditioning, Animal , Running , Animals , Antibiotics, Antineoplastic/administration & dosage , Cognitive Dysfunction/chemically induced , Cognitive Dysfunction/metabolism , Diabetes Complications/chemically induced , Diabetes Complications/metabolism , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/metabolism , Physical Conditioning, Animal/physiology , Rats , Running/physiology , Streptozocin/administration & dosageABSTRACT
Multidirectional health-promoting activities of some plant-derived substances make them candidates for drugs used in diabetes and its complications such as osteoporosis. Berberine is a compound for which both antidiabetic and antiosteoporotic effects have been documented. The aim of the study was to investigate the effects of berberine on the skeletal disorders induced by experimental type 1 diabetes in rats. The experiments were performed on 3-month-old female rats, divided into three groups: I - healthy control rats, II - diabetic control rats, III - diabetic rats receiving berberine. Diabetes was induced by a single streptozotocin injection. Berberine administration (50â¯mg/kg/day p.o.) started two weeks later and lasted four weeks. Serum bone turnover markers and other biochemical parameters, bone mass and mineralization, histomorphometric parameters and mechanical properties were studied. Diabetes induced strong disorders of bone turnover, bone microarchitecture, and strength of cancellous bone. Berberine counteracted the effect of diabetes on the bone formation marker (osteocalcin) concentration, the growth plate, and some parameters of cancellous bone microarchitecture, but did not improve bone mineralization and bone mechanical properties in the diabetic rats. The lack of effect of berberine on bone quality does not support its use in the prevention of diabetes-induced bone damage.
Subject(s)
Berberine/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 1/drug therapy , Growth Plate/drug effects , Animals , Berberine/administration & dosage , Bone Density/drug effects , Bone Remodeling/drug effects , Female , Osteoporosis/prevention & control , Rats , Rats, Wistar , Streptozocin/administration & dosageABSTRACT
We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5), and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (≥90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line versus subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n = 108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n = 60; 53% ≥ fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.
Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Doxorubicin/pharmacology , Fluorouracil/pharmacology , Neuroendocrine Tumors/drug therapy , Pancreatic Neoplasms/drug therapy , Streptozocin/pharmacology , Adolescent , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Doxorubicin/administration & dosage , Doxorubicin/adverse effects , Everolimus/pharmacology , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Male , Middle Aged , Retrospective Studies , Streptozocin/administration & dosage , Streptozocin/adverse effects , Temozolomide/pharmacology , Treatment Outcome , Young AdultABSTRACT
AIM: To evaluate the effects of exercise training (ET) on cardiac extracellular matrix (ECM) proteins homeostasis and cardiac dysfunction in mice with diabetic cardiomyopathy. METHODS: Thirty-six male C57BL/6 mice were randomized into 3 groups for 8 weeks (12mice/group): Diabetic control-DC: Diabetes was induced by single streptozotocin injection (200 mg/kg i.p.); Diabetic exercise-DE: Diabetic mice underwent ET program on motorized-treadmill (6-times/week, 60min/session); Non-diabetic control-NDC: Vehicle-treated, sedentary, non-diabetic mice served as controls. Before euthanasia, all groups underwent transthoracic echocardiography (TTE). Post-mortem, left-ventricle (LV) samples were histologically analysed for ECM proteins (collagen, elastin), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). RESULTS: DC group showed significantly higher cardiac contents of collagen and MMP-9 and lower elastic concentration than NDC (p < 0.001). The implementation of ET completely outweighed those diabetes-induced changes (DE vs NDC, p > 0.05). TIMP-1 levels significantly increased across all groups (DC: 18.98 ± 3.47%, DE: 24.24 ± 2.36%, NDC: 46.36 ± 5.91%; p < 0.05), while MMP-9/TIMP-1 ratio followed a reverse pattern. ET tended to increase MMP-2 concentrations versus DC (p = 0.055), but did not achieve non-diabetic levels (p < 0.05). TIMP-2 cardiac concentrations remained unaltered throughout the study (p > 0.05). Importantly, ET ameliorated both LV end-systolic internal diameter (LVESD) (p < 0.001) and the percentage of LV fractional shortening (FS%) (p = 0.006) compared to DC. Despite that favorable effect, the cardiac function level of DE group remained worse than NDC group (%FS: p = 0.002; LVESD: p < 0.001). CONCLUSION: Systemic ET may favorably change ECM proteins, MMP-9 and TIMP-1 cardiac concentrations in mice with diabetic cardiomyopathy. Those results were associated with partial improvement of echocardiography-assessed cardiac function, indicating a therapeutic effect of ET in diabetic cardiomyopathy.
Subject(s)
Diabetes Mellitus, Experimental/enzymology , Diabetic Cardiomyopathies/enzymology , Extracellular Matrix/enzymology , Matrix Metalloproteinase 9/genetics , Physical Conditioning, Animal/physiology , Tissue Inhibitor of Metalloproteinase-1/genetics , Animals , Blood Glucose/metabolism , Collagen/genetics , Collagen/metabolism , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/physiopathology , Diabetic Cardiomyopathies/chemically induced , Diabetic Cardiomyopathies/genetics , Diabetic Cardiomyopathies/physiopathology , Echocardiography , Elastin/genetics , Elastin/metabolism , Exercise Test , Extracellular Matrix/genetics , Gene Expression Regulation , Heart Ventricles/metabolism , Heart Ventricles/physiopathology , Male , Matrix Metalloproteinase 9/metabolism , Mice , Mice, Inbred C57BL , Signal Transduction , Streptozocin/administration & dosage , Tissue Inhibitor of Metalloproteinase-1/metabolismABSTRACT
Diabetic nephropathy (DN) is one of the major microvascular complications of diabetes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial cellular defense factor to cope with oxidative stress. Silent information regulator T1 (Sirt1) is a deacetylase with antioxidative stress activity. Fucoxanthin is a marine-derived carotenoid. This study was conducted to investigate whether fucoxanthin could alleviate oxidative stress by activating Sirt1/Nrf2 signaling to alleviate DN. In streptozotocin-induced diabetic rats, fucoxanthin treatment effectively improved renal function, alleviated glomerulosclerosis. Fucoxanthin reversed the decreased protein levels of Sirt1 and Nrf2 in the kidney of diabetic rats and glomerular mesangial cells cultured in high glucose. Conversely, EX527, a Sirt1 inhibitor, counteracted the effect of fucoxanthin on the expression of Nrf2. Furthermore, in vivo and vitro results showed that fucoxanthin treatment reversed the low expression and activity of superoxide dismutase and heme oxygenase 1, depending on Sirt1 activation. Our results suggest that fucoxanthin improves diabetic kidney function and renal fibrosis by activating Sirt1/Nrf2 signaling to reduce oxidative stress.
Subject(s)
Antioxidants/pharmacology , Diabetes Mellitus, Experimental/complications , Diabetic Nephropathies/drug therapy , Mesangial Cells/pathology , Xanthophylls/pharmacology , Animals , Antioxidants/therapeutic use , Carbazoles/pharmacology , Cells, Cultured , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Diabetic Nephropathies/etiology , Diabetic Nephropathies/pathology , Fibrosis , Heme Oxygenase (Decyclizing)/metabolism , Humans , Male , Mesangial Cells/drug effects , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Primary Cell Culture , Rats , Rats, Sprague-Dawley , Sirtuin 1/antagonists & inhibitors , Sirtuin 1/metabolism , Streptozocin/administration & dosage , Streptozocin/toxicity , Xanthophylls/therapeutic useABSTRACT
Diabetes associated oxidative stress and impaired cholinergic neurotransmission causes cognitive deficits. Although phloridzin shows antioxidant- and insulin sensitizing-activities, its ameliorative potential in diabetes-induced memory dysfunction remains unexplored. In the present study, type 2 diabetes (T2D) was induced by streptozotocin (35 mg/kg, intraperitoneal) in rats on ad libitum high-fat diet. Diabetic animals were treated orally with phloridzin (10 and 20 mg/kg) for four weeks. Memory functions were evaluated by passive avoidance test (PAT) and novel object recognition (NOR) test. Brains of rats were subjected to biochemical analysis of glutathione (GSH), brain-derived neurotrophic factor (BDNF), malonaldehyde (MDA) and acetylcholinesterase (AChE). Role of cholinergic system in the effects of phloridzin was evaluated by scopolamine pre-treatment in behavioral studies. While diabetic rats showed a significant decrease in step through latency in PAT, and exploration time and discrimination index in NOR test; a substantial increase in all parameters was observed following phloridzin treatment. Phloridzin reversed abnormal levels of GSH, BDNF, MDA and AChE in the brain of diabetic animals. Moreover, in silico molecular docking study revealed that phloridzin acts as a potent agonist at M1 receptor as compared to acetylcholine. Viewed collectively, reversal of T2D-induced memory impairment by phloridzin might be attributed to upregulation of neurotrophic factors, reduced oxidative stress and increased cholinergic signaling in the brain. Therefore, phloridzin may be a promising molecule in the management of cognitive impairment comorbid with T2D.
Subject(s)
Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/complications , Memory Disorders/drug therapy , Phlorhizin/pharmacology , Acetylcholine/agonists , Acetylcholine/metabolism , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Humans , Male , Maze Learning/drug effects , Memory/drug effects , Memory Disorders/diagnosis , Memory Disorders/etiology , Molecular Docking Simulation , Nerve Growth Factors/agonists , Nerve Growth Factors/metabolism , Oxidative Stress/drug effects , Phlorhizin/therapeutic use , Rats , Receptor, Muscarinic M1/agonists , Receptor, Muscarinic M1/metabolism , Receptor, Muscarinic M1/ultrastructure , Scopolamine/pharmacology , Streptozocin/administration & dosage , Streptozocin/toxicity , Synaptic Transmission/drug effects , Up-Regulation/drug effectsABSTRACT
Type 2 diabetes mellitus has been a major health issue with increasing morbidity and mortality due to macrovascular and microvascular complications. The urgent need for improved methods to control hyperglycemic complications reiterates the development of innovative preventive and therapeutic treatment strategies. In this perspective, xanthone compounds in the pericarp of the mangosteen fruit, especially α-mangostin (MGN), have been recognized to restore damaged pancreatic ß-cells for optimal insulin release. Therefore, taking advantage of the robust use of nanotechnology for targeted drug delivery, we herein report the preparation of MGN loaded nanosponges for anti-diabetic therapeutic applications. The nanosponges were prepared by quasi-emulsion solvent evaporation method. Physico-chemical characterization of formulated nanosponges with satisfactory outcomes was performed with Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Zeta potential, hydrodynamic diameter, entrapment efficiency, drug release properties, and stability studies at stress conditions were also tested. Molecular docking analysis revealed significant interactions of α-glucosidase and MGN in a protein-ligand complex. The maximum inhibition by nanosponges against α-glucosidase was observed to be 0.9352 ± 0.0856 µM, 3.11-fold higher than acarbose. In vivo studies were conducted on diabetic rats and plasma glucose levels were estimated by HPLC. Collectively, our findings suggest that MGN-loaded nanosponges may be beneficial in the treatment of diabetes since they prolong the antidiabetic response in plasma and improve patient compliance by slowly releasing MGN and requiring less frequent doses, respectively.
Subject(s)
Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Glycoside Hydrolase Inhibitors/pharmacology , Hypoglycemic Agents/pharmacology , Nanostructures/chemistry , Xanthones/pharmacology , Animals , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/metabolism , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/chemistry , Male , Molecular Docking Simulation , Molecular Structure , Particle Size , Rats , Rats, Sprague-Dawley , Streptozocin/administration & dosage , Xanthones/chemical synthesis , Xanthones/chemistry , alpha-Glucosidases/metabolismABSTRACT
Numerous studies highlight that astaxanthin (ASTX) ameliorates hyperglycemic condition and hyperglycemia-associated chronic complications. While periodontitis and periodontic tissue degradation are also triggered under chronic hyperglycemia, the roles of ASTX on diabetes-associated periodontal destruction and the related mechanisms therein are not yet fully understood. Here, we explored the impacts of supplemental ASTX on periodontal destruction and systemic complications in type I diabetic mice. To induce diabetes, C57BL/6 mice received a single intraperitoneal injection of streptozotocin (STZ; 150 mg/kg), and the hyperglycemic mice were orally administered with ASTX (12.5 mg/kg) (STZ+ASTX group) or vehicle only (STZ group) daily for 60 days. Supplemental ASTX did not improve hyperglycemic condition, but ameliorated excessive water and feed consumptions and lethality in STZ-induced diabetic mice. Compared with the non-diabetic and STZ+ASTX groups, the STZ group exhibited severe periodontal destruction. Oral gavage with ASTX inhibited osteoclastic formation and the expression of receptor activator of nuclear factor (NF)-κB ligand, 8-OHdG, γ-H2AX, cyclooxygenase 2, and interleukin-1ß in the periodontium of STZ-injected mice. Supplemental ASTX not only increased the levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and osteogenic transcription factors in the periodontium, but also recovered circulating lymphocytes and endogenous antioxidant enzyme activity in the blood of STZ-injected mice. Furthermore, the addition of ASTX blocked advanced glycation end products-induced oxidative stress and growth inhibition in human-derived periodontal ligament cells by upregulating the Nrf2 pathway. Together, our results suggest that ASTX does not directly improve hyperglycemia, but ameliorates hyperglycemia-triggered periodontal destruction and oxidative systemic complications in type I diabetes.
Subject(s)
Antioxidants/metabolism , Diabetes Mellitus, Experimental/complications , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Periodontitis/drug therapy , Periodontitis/etiology , Streptozocin/administration & dosage , Adolescent , Alveolar Process/pathology , Animals , Blood Glucose/metabolism , Catalase/blood , Cell Proliferation , Cytokines/metabolism , DNA Damage , Diabetes Mellitus, Experimental/blood , Dietary Supplements , Feeding Behavior , Glycation End Products, Advanced/metabolism , Humans , Hyperglycemia/complications , Inflammation Mediators/metabolism , Injections , Lymphocytes/immunology , Male , Mice, Inbred C57BL , Osteoclasts/drug effects , Osteoclasts/pathology , Periodontal Ligament/pathology , Periodontitis/blood , Reactive Oxygen Species/metabolism , Superoxide Dismutase/blood , Up-Regulation , Xanthophylls/pharmacology , Xanthophylls/therapeutic use , Young AdultABSTRACT
AIMS: To examine the effects of low-dose insulin or a soluble guanylate cyclase activator (sGC) on lower urinary tract dysfunction (LUTD) in rats with diabetes mellitus (DM). MAIN METHODS: Female Sprague-Dawley rats were divided into non-DM control (N), DM induced by streptozotocin (65 mg/kg), with low-dose insulin (DI), DM with vehicle (D), and DM with sGC (GC) groups. In GC group, BAY 60-2770 (1 mg/kg/day) was orally administered in 6-8 weeks after DM. Voiding assay at 2, 4, and 8 weeks after DM, cystometry, and urethral pressure recordings at 8 weeks of DM were performed. mRNA levels of NO-related markers and cGMP protein levels in the urethra, and ischemia and inflammation markers in the bladder were evaluated by RT-PCR. KEY FINDINGS: Moderate levels of high blood glucose were maintained in Group DI versus Group D. The 24-h voided volume was significantly higher in Group D versus Groups N and DI. Non-voiding contractions were significantly greater, and voiding efficiency and urethral pressure reduction were significantly lower in Group D versus Groups N, DI, and GC. Urethral cGMP levels were significantly lower in Group D versus Groups N and GC. mRNA levels of PDE5 in the urethra and ischemia and inflammation markers in the bladder increased in Group D versus Group N or DI was reduced after sGC treatment. SIGNIFICANCE: DI rats with a lesser degree of bladder and urethral dysfunction might be useful as a slow-progressive DM model. sGC activation could be an effective treatment of LUTD in DM.
Subject(s)
Benzoates/administration & dosage , Biphenyl Compounds/administration & dosage , Diabetes Mellitus, Experimental/complications , Enzyme Activators/administration & dosage , Hydrocarbons, Fluorinated/administration & dosage , Insulin/administration & dosage , Soluble Guanylyl Cyclase/metabolism , Urologic Diseases/complications , Animals , Biomarkers/metabolism , Blood Glucose/metabolism , Body Weight , Cyclic GMP/metabolism , Dose-Response Relationship, Drug , Enzyme Activation , Female , Nitric Oxide/metabolism , Rats , Rats, Sprague-Dawley , Streptozocin/administration & dosage , Urethra/metabolism , Urologic Diseases/drug therapyABSTRACT
BACKGROUND: According to recent evidence, psychobiotics exert beneficial effects on central nervous system-related diseases, such as mental disorders. Lactobacillus plantarum PS128 (PS128), a novel psychobiotic strain, improves motor function, depression, and anxiety behaviors. However, the psychobiotic effects and mechanisms of PS128 in Alzheimer's disease (AD) remain to be explored. OBJECTIVES: The goal of the current study was to evaluate the beneficial effects of PS128 and to further elucidate its mechanism in AD mice. METHODS: PS128 (1010 colony-forming unit (CFU)/ml) was administered via oral gavage (o.g.) to 6-month-old male wild-type B6 and 3 × Tg-AD mice (harboring the PS1M146V, APPswe and TauP30IL transgenes) that received an intracerebroventricular injection of streptozotocin (icv-STZ, 3 mg/kg) or vehicle (saline) for 33 days. After serial behavioral tests, fecal short-chain fatty acid levels and AD-related pathology were assessed in these mice. RESULTS: Our findings show that intracerebroventricular injection of streptozotocin accelerated cognitive dysfunction associated with increasing levels of glycogen synthase kinase 3 beta (GSK3ß) activity, tau protein phosphorylation at the T231 site (pT231), amyloid-ß (Aß) deposition, amyloid-ß protein precursor (AßPP), ß-site AßPP-cleaving enzyme (BACE1), gliosis, fecal propionic acid (PPA) levels and cognition-related neuronal loss and decreasing postsynaptic density protein 95 (PSD95) levels in 3 × Tg-AD mice. PS128 supplementation effectively prevented the damage induced by intracerebroventricular injection of streptozotocin in 3 × Tg-AD mice. CONCLUSIONS: Based on the experimental results, intracerebroventricular injection of streptozotocin accelerates the progression of AD in the 3 × Tg-AD mice, primarily by increasing the levels of gliosis, which were mediated by the propionic acid and glycogen synthase kinase 3 beta pathways. PS128 supplementation prevents damage induced by intracerebroventricular injection of streptozotocin by regulating the propionic acid levels, glycogen synthase kinase 3 beta activity, and gliosis in 3 × Tg-AD mice. Therefore, we suggest that PS128 supplementation is a potential strategy to prevent and/or delay the progression of AD.
Subject(s)
Cognitive Dysfunction/prevention & control , Lactobacillus plantarum/metabolism , Neuroprotective Agents/pharmacology , Alzheimer Disease , Animals , Disease Models, Animal , Gliosis/metabolism , Glycogen Synthase Kinase 3 beta/metabolism , Male , Mice , Mice, Inbred C57BL , Propionates/metabolism , Streptozocin/administration & dosageABSTRACT
BACKGROUND: Endothelial progenitor cells have shown the ability to enhance neovascularization. In this study, the authors tested whether intraosseous delivery of simvastatin could mobilize endothelial progenitor cells and enhance recovery in a hindlimb ischemia model. METHODS: There are eight groups of rats in this study: normal control; type 1 diabetes mellitus control group control without drug intervention; and type 1 diabetes mellitus rats that randomly received intraosseous simvastatin (0, 0.5, or 1 mg) or oral simvastatin administration (0, 20, or 400 mg). All type 1 diabetes mellitus rats had induced hindlimb ischemia. The number of endothelial progenitor cells in peripheral blood, and serum markers, were detected. The recovery of blood flow at 21 days after treatment was used as the main outcome. RESULTS: The authors demonstrated that endothelial progenitor cell mobilization was increased in the simvastatin 0.5- and 1-mg groups compared with the type 1 diabetes mellitus control and simvastatin 0-mg groups at 1, 2, and 3 weeks. Serum vascular endothelial growth factor levels were significantly increased at 2 weeks in the simvastatin 0.5- and 1-mg groups, in addition to the increase of the blood flow and the gastrocnemius weight at 3 weeks. Similar increase can also been seen in simvastatin 400 mg orally but not in simvastatin 20 mg orally. CONCLUSION: These findings demonstrate that a single intraosseous administration of simvastatin mobilized endothelial progenitor cells at a dose one-hundredth of the required daily oral dose in rats, and this potent mobilization of endothelial progenitor cells markedly improved diabetic limb ischemia by means of neovascularization.
Subject(s)
Chronic Limb-Threatening Ischemia/drug therapy , Diabetes Mellitus, Type 1/complications , Endothelial Progenitor Cells/drug effects , Neovascularization, Physiologic/drug effects , Simvastatin/administration & dosage , Animals , Chronic Limb-Threatening Ischemia/etiology , Collateral Circulation/drug effects , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 1/chemically induced , Endothelial Progenitor Cells/physiology , Hindlimb/blood supply , Humans , Infusions, Intraosseous , Male , Rats , Streptozocin/administration & dosage , Streptozocin/toxicityABSTRACT
OBJECTIVE: To examine the mechanisms of Nogo-B (RTN4B) in the protection of blood-retinal barrier in experimental diabetic retinopathy. METHODS: The level of Nogo-B in vitreous and plasma samples was detected with ELISA. Diabetes was induced in Sprague-Dawley rats with intraperitoneal injection of streptozotocin. The rats were injected intravitreally with adeno-associated virus (AAV) for knockdown the expression of Nogo-B in retina or/and as AAV negative control. The permeability of blood-retinal barrier was detected with Rhodamine-B-dextran leakage assay. The expressions of Nogo-B, junctional proteins, inflammatory factors and signaling pathways were examined with Western blot and quantitative real-time PCR. RESULTS: Nogo-B expression was significantly upregulated in clinical samples and experimental diabetic rat models. Under normal condition, Nogo-B knockdown resulted in the increased permeability of retinal blood vessels. In diabetic rat retinas, the vascular leakage was increased significantly, which was partially decreased by Nogo-B knockdown through increasing p/t-Src (Tyr529) and p/t-Akt (Ser473), and decreasing p/t-ERK1/2. CONCLUSION: Nogo-B was increased in diabetic retinopathy and silencing Nogo-B is a promising therapy for diabetic retinopathy.
Subject(s)
Diabetes Mellitus, Experimental/genetics , Diabetic Retinopathy/genetics , Phosphatidylinositol 3-Kinases/genetics , Proto-Oncogene Proteins c-akt/genetics , Receptors, Cell Surface/genetics , src-Family Kinases/genetics , Animals , Blood-Retinal Barrier/metabolism , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/metabolism , Diabetic Retinopathy/metabolism , Diabetic Retinopathy/pathology , Diabetic Retinopathy/therapy , Gene Expression Regulation , Male , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Cell Surface/antagonists & inhibitors , Receptors, Cell Surface/metabolism , Retina/metabolism , Retina/pathology , Retinal Vessels/metabolism , Retinal Vessels/pathology , Signal Transduction , Streptozocin/administration & dosage , src-Family Kinases/metabolismABSTRACT
Acute kidney injury (AKI) is one of the major complications with increased oxidative stress and inflammation in diabetic patients. Hyperglycemia stimulates the formation of advanced glycation end products (AGEs). However, hyperglycemia directly triggers the interaction between AGEs and transmembrane AGEs receptors (RAGE), which enhances oxidative stress and increases the production of inflammatory substances. Therefore, diabetes plays a pivotal role in kidney injury. Hydralazine, a vasodilator and antihypertensive drug, was found to have the ability to reduce ROS, oxidative stress, and inflammation. We applied Hydralazine co-culture with AGEs in rat mesangial cells (RMC) and to renal ischemia/reperfusion(I/R) injury models in streptozotocin-induced diabetic rats. Hydralazine significantly decreased AGEs-induced RAGE, iNOS, and COX-2 expressions in RMC. Compared to the diabetic with AKI group, hydralazine decreased inflammation-related protein, and JAK2, STAT3 signaling in rat kidney tissue. Our studies indicate that Hydralazine has the potential to become a beneficial drug in the treatment of diabetic acute kidney injury.