scholarly journals Does Hyperglycemia Cause Oxidative Stress in the Diabetic Rat Retina?

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 794
Author(s):  
Mohammad Shamsul Ola
Keyword(s):  
Oxidative Stress ◽  
Diabetic Retinopathy ◽  
Citric Acid Cycle ◽  
Ex Vivo ◽  
Diabetic Rat ◽  
Ros Generation ◽  
Short Term ◽  
Diabetic Retina ◽  
Oxidation Of Glucose

Diabetes, being a metabolic disease dysregulates a large number of metabolites and factors. However, among those altered metabolites, hyperglycemia is considered as the major factor to cause an increase in oxidative stress that initiates the pathophysiology of retinal damage leading to diabetic retinopathy. Diabetes-induced oxidative stress in the diabetic retina and its damaging effects are well known, but still, the exact source and the mechanism of hyperglycemia-induced reactive oxygen species (ROS) generation especially through mitochondria remains uncertain. In this study, we analyzed precisely the generation of ROS and the antioxidant capacity of enzymes in a real-time situation under ex vivo and in vivo conditions in the control and streptozotocin-induced diabetic rat retinas. We also measured the rate of flux through the citric acid cycle by determining the oxidation of glucose to CO2 and glutamate, under ex vivo conditions in the control and diabetic retinas. Measurements of H2O2 clearance from the ex vivo control and diabetic retinas indicated that activities of mitochondrial antioxidant enzymes are intact in the diabetic retina. Short-term hyperglycemia seems to influence a decrease in ROS generation in the diabetic retina compared to controls, which is also correlated with a decreased oxidation rate of glucose in the diabetic retina. However, an increase in the formation of ROS was observed in the diabetic retinas compared to controls under in vivo conditions. Thus, our results suggest of diabetes/hyperglycemia-induced non-mitochondrial sources may serve as major sources of ROS generation in the diabetic retina as opposed to widely believed hyperglycemia-induced mitochondrial sources of excess ROS. Therefore, hyperglycemia per se may not cause an increase in oxidative stress, especially through mitochondria to damage the retina as in the case of diabetic retinopathy.

miR-187 modulates cardiomyocyte apoptosis and oxidative stress in myocardial infarction mice via negatively regulating DYRK2

2021 ◽  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Protective Effect ◽  
Myocardial Infarct ◽  
Annexin V ◽  
Cardiomyocyte Apoptosis ◽  
Ros Generation ◽  
Downstream Target

Myocardial infarction is a serious representation of cardiovescular disease, MicroRNAs play a role in modifying I/R injury and myocardial infarct remodeling. The present study therefore examined the potential role of miR-187 in cardiac I/R injury and its underlying mechanisms. miR-187 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with miR-187 mimic or inhibitor to confirm the function of miR-187 in H/R. DYRK2 was inhibited or overexpressed in cardiomyocytes H/R models by pretreatment with DYRK2 inhibitor. A myocardium I/R mouse model was established. Circulating levels of miR-187 or DYRK2 was detected by quantitative realtime PCR and protein expression was detected by western blotting. The cell viability in all groups was determined by MTT assay and the apoptosis ratio was detected by flow cytometry after staining with Annexin V-FITC. The effect of miR-187 on cellular ROS generation was examined by DCFH-DA. The level of lipid peroxidation and SOD expression were determined by MDA and SOD assay. The findings indicated that miR-187 may be a possible regulator in the protective effect of H/R-induced cardiomyocyte apoptosis, cellular oxidative stress and leaded to DYRK2 suppression at a posttranscriptional level. Moreover, the improvement of miR-187 on H/R-induced cardiomyocyte injury contributed to the obstruction of DYRK2 expression. In addition, these results identified DYRK2 as the functional downstream target of miR-187 regulated myocardial infarction and oxidative stress.These present work provided the first insight into the function of miR-187 in successfully protect cardiomyocyte both in vivo and in vitro, and such a protective effect were mediated through the regulation of DYRK2 expression.

Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat

2019 ◽  
Vol 133 (1) ◽  
pp. 117-134 ◽  
Author(s):  
Pamela L. Martín ◽  
Paula Ceccatto ◽  
María V. Razori ◽  
Daniel E.A. Francés ◽  
Sandra M.M. Arriaga ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Bile Flow ◽  
Driving Forces ◽  
Membrane Lipids ◽  
Ex Vivo ◽  
Heme Oxygenase 1 ◽  
Canalicular Transporters

Abstract We previously demonstrated in in vitro and ex vivo models that physiological concentrations of unconjugated bilirubin (BR) prevent oxidative stress (OS)-induced hepatocanalicular dysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether a similar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction that consequently elevates endogenous BR levels. This was achieved through the administration of hemin, an inducer of HO-1, the rate-limiting step in BR generation. We found that BR peaked between 6 and 8 h after hemin administration. During this time period, HO-1 induction fully prevented the pro-oxidant tert-butylhydroperoxide (tBuOOH)-induced drop in bile flow, and in the biliary excretion of bile salts and glutathione, the two main driving forces of bile flow; this was associated with preservation of the membrane localization of their respective canalicular transporters, bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2), which are otherwise endocytosed by OS. HO-1 induction counteracted the oxidation of intracellular proteins and membrane lipids induced by tBuOOH, and fully prevented the increase in the oxidized-to-total glutathione (GSHt) ratio, a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) were also prevented. We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thus preventing consequent cholestasis. This reveals an important role for the induction of HO-1 and the consequently elevated levels of BR in preserving biliary secretory function under OS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury that bears an oxidative background.

scholarly journals Detecting Validated Intracellular ROS Generation with 18F-dihydroethidine-Based PET

2021 ◽  
Author(s):  
Edward C. T. Waters ◽  
Friedrich Baark ◽  
Zilin Yu ◽  
Filipa Mota ◽  
Thomas R. Eykyn ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Contractile Function ◽  
Ex Vivo ◽  
Glutathione Depletion ◽  
Ros Generation ◽  
Cardiac Contractile ◽  
Rat Hearts ◽  
Intracellular Ros ◽  
Cardiac Contractile Dysfunction

Abstract Purpose To determine the sensitivity of the 18F-radiolabelled dihydroethidine analogue ([18F]DHE) to ROS in a validated ex vivo model of tissue oxidative stress. Procedures The sensitivity of [18F]DHE to various ROS-generating systems was first established in vitro. Then, isolated rat hearts were perfused under constant flow, with contractile function monitored by intraventricular balloon. Cardiac uptake of infused [18F]DHE (50–150 kBq.min−1) was monitored by γ-detection, while ROS generation was invoked by menadione infusion (0, 10, or 50 μm), validated by parallel measures of cardiac oxidative stress. Results [18F]DHE was most sensitive to oxidation by superoxide and hydroxyl radicals. Normalised [18F]DHE uptake was significantly greater in menadione-treated hearts (1.44 ± 0.27) versus control (0.81 ± 0.07) (p < 0.05, n = 4/group), associated with concomitant cardiac contractile dysfunction, glutathione depletion, and PKG1α dimerisation. Conclusion [18F]DHE reports on ROS in a validated model of oxidative stress where perfusion (and tracer delivery) is unlikely to impact its pharmacokinetics.

scholarly journals Loss of Sirt3 accelerates arterial thrombosis by increasing formation of neutrophil extracellular traps and plasma tissue factor activity

2018 ◽  
Vol 114 (8) ◽  
pp. 1178-1188 ◽  
Author(s):  
Daniel S Gaul ◽  
Julien Weber ◽  
Lambertus J van Tits ◽  
Susanna Sluka ◽  
Lisa Pasterk ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Myocardial Infarction ◽  
Bone Marrow ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Neutrophil Extracellular Traps ◽  
Wild Type ◽  
Rotational Thromboelastometry ◽  
Extracellular Traps

AbstractAimsSirtuin 3 (Sirt3) is a mitochondrial, nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase that reduces oxidative stress by activation of superoxide dismutase 2 (SOD2). Oxidative stress enhances arterial thrombosis. This study investigated the effects of genetic Sirt3 deletion on arterial thrombosis in mice in an inflammatory setting and assessed the clinical relevance of these findings in patients with ST-elevation myocardial infarction (STEMI).Methods and resultsUsing a laser-induced carotid thrombosis model with lipopolysaccharide (LPS) challenge, in vivo time to thrombotic occlusion in Sirt3−/− mice (n = 6) was reduced by half compared to Sirt3+/+ wild-type (n = 8, P < 0.01) controls. Ex vivo analyses of whole blood using rotational thromboelastometry revealed accelerated clot formation and increased clot stability in Sirt3−/− compared to wild-type blood. rotational thromboelastometry of cell-depleted plasma showed accelerated clotting initiation in Sirt3−/− mice, whereas overall clot formation and firmness remained unaffected. Ex vivo LPS-induced neutrophil extracellular trap formation was increased in Sirt3−/− bone marrow-derived neutrophils. Plasma tissue factor (TF) levels and activity were elevated in Sirt3−/− mice, whereas plasma levels of other coagulation factors and TF expression in arterial walls remained unchanged. SOD2 expression in bone marrow -derived Sirt3−/− neutrophils was reduced. In STEMI patients, transcriptional levels of Sirt3 and its target SOD2 were lower in CD14+ leukocytes compared with healthy donors (n = 10 each, P < 0.01).ConclusionsSirt3 loss-of-function enhances experimental thrombosis in vivo via an increase of neutrophil extracellular traps and elevation of TF suggesting thrombo-protective effects of endogenous Sirt3. Acute coronary thrombosis in STEMI patients is associated with lower expression levels of SIRT3 and SOD2 in CD14+ leukocytes. Therefore, enhancing SIRT3 activity by pan-sirtuin activating NAD+-boosters may provide a novel therapeutic target to prevent or treat thrombotic arterial occlusion in myocardial infarction or stroke.

scholarly journals Tetrahydrocurcumin Ameliorates Diabetic Cardiomyopathy by Attenuating High Glucose-Induced Oxidative Stress and Fibrosis via Activating the SIRT1 Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Kaifeng Li ◽  
Mengen Zhai ◽  
Liqing Jiang ◽  
Fan Song ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Diabetic Cardiomyopathy ◽  
High Glucose ◽  
Therapeutic Potential ◽  
Ros Generation ◽  
Protective Effects ◽  
Collagen Iii

Hyperglycemia-induced oxidative stress and fibrosis play a crucial role in the development of diabetic cardiomyopathy (DCM). Tetrahydrocurcumin (THC), a major bioactive metabolite of natural antioxidant curcumin, is reported to exert even more effective antioxidative and superior antifibrotic properties as well as anti-inflammatory and antidiabetic abilities. This study was designed to investigate the potential protective effects of THC on experimental DCM and its underlying mechanisms, pointing to the role of high glucose-induced oxidative stress and interrelated fibrosis. In STZ-induced diabetic mice, oral administration of THC (120 mg/kg/d) for 12 weeks significantly improved the cardiac function and ameliorated myocardial fibrosis and cardiac hypertrophy, accompanied by reduced reactive oxygen species (ROS) generation. Mechanically, THC administration remarkably increased the expression of the SIRT1 signaling pathway both in vitro and in vivo, further evidenced by decreased downstream molecule Ac-SOD2 and enhanced deacetylated production SOD2, which finally strengthened antioxidative stress capacity proven by repaired activities of SOD and GSH-Px and reduced MDA production. Additionally, THC treatment accomplished its antifibrotic effect by depressing the ROS-induced TGFβ1/Smad3 signaling pathway followed by reduced expression of cardiac fibrotic markers α-SMA, collagen I, and collagen III. Collectively, these finds demonstrated the therapeutic potential of THC treatment to alleviate DCM mainly by attenuating hyperglycemia-induced oxidative stress and fibrosis via activating the SIRT1 pathway.

Role of Oxidative Stress in Diabetic Retinopathy and the Beneficial Effects of Flavonoids

2018 ◽  
Vol 24 (19) ◽  
pp. 2180-2187 ◽  
Author(s):  
Mohammad Shamsul Ola ◽  
Dalia Al-Dosari ◽  
Abdullah S. Alhomida
Keyword(s):  
Oxidative Stress ◽  
Diabetic Retinopathy ◽  
Experimental Studies ◽  
Developed Countries ◽  
Retinal Damage ◽  
Beneficial Effects ◽  
Diabetic Retina ◽  
Retinal Pathology ◽  
Dietary Flavonoids

Diabetic Retinopathy (DR) is one of the leading causes of decreased vision and blindness in developed countries. Diabetes-induced metabolic disorder is believed to increase oxidative stress in the retina. This results in deleterious change through dysregulation of cellular physiology that damages both neuronal and vascular cells. In this review, we first highlight the evidence of potential metabolic sources and pathways which increase oxidative stress that contribute to retinal pathology in diabetes. As oxidative stress is a central factor in the pathophysiology of DR, antioxidants therapy would be beneficial towards preventing the retinal damage. A number of experimental studies by our group and others showed that dietary flavonoids cause reduction in increased oxidative stress and other beneficial effects in diabetic retina. We then discuss the beneficial effects of the six major flavonoid families, such as flavanones, flavanols, flavonols, isoflavones, flavones and anthocyanins, which have been studied to improve retinal damage. Flavanoids, being known antioxidants, may ameliorate the retinal degenerative factors including apoptosis, inflammation and neurodegeneration in diabetes. Therefore, intake of potential dietary flavonoids would limit oxidative stress and thereby prevent the retinal damage, and subsequently the development of DR.

scholarly journals Molecular Probes for Evaluation of Oxidative Stress by In Vivo EPR Spectroscopy and Imaging: State-of-the-Art and Limitations

2019 ◽  
Vol 5 (1) ◽  
pp. 13 ◽  
Author(s):  
Nikola Babić ◽  
Fabienne Peyrot
Keyword(s):  
Oxidative Stress ◽  
Ex Vivo ◽  
Critical Factor ◽  
Molecular Probes ◽  
Antioxidant Defenses ◽  
Whole Body ◽  
Paramagnetic Resonance ◽  
The Status ◽  
Living Tissues

Oxidative stress, defined as a misbalance between the production of reactive oxygen species and the antioxidant defenses of the cell, appears as a critical factor either in the onset or in the etiology of many pathological conditions. Several methods of detection exist. However, they usually rely on ex vivo evaluation or reports on the status of living tissues only up to a few millimeters in depth, while a whole-body, real-time, non-invasive monitoring technique is required for early diagnosis or as an aid to therapy (to monitor the action of a drug). Methods based on electron paramagnetic resonance (EPR), in association with molecular probes based on aminoxyl radicals (nitroxides) or hydroxylamines especially, have emerged as very promising to meet these standards. The principles involve monitoring the rate of decrease or increase of the EPR signal in vivo after injection of the nitroxide or the hydroxylamine probe, respectively, in a pathological versus a control situation. There have been many successful applications in various rodent models. However, current limitations lie in both the field of the technical development of the spectrometers and the molecular probes. The scope of this review will mainly focus on the latter.

scholarly journals Inhibition of Oxidative Neurotoxicity and Scopolamine-Induced Memory Impairment by γ-Mangostin: In Vitro and In Vivo Evidence

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Youngmun Lee ◽  
Sunyoung Kim ◽  
Yeonsoo Oh ◽  
Young-Mi Kim ◽  
Young-Won Chin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Memory Impairment ◽  
Neuronal Damage ◽  
Biological Activities ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ros Generation ◽  
Garcinia Mangostana

Among a series of xanthones identified from mangosteen, the fruit of Garcinia mangostana L. (Guttifereae), α- and γ-mangostins are known to be major constituents exhibiting diverse biological activities. However, the effects of γ-mangostin on oxidative neurotoxicity and impaired memory are yet to be elucidated. In the present study, the protective effect of γ-mangostin on oxidative stress-induced neuronal cell death and its underlying action mechanism(s) were investigated and compared to that of α-mangostin using primary cultured rat cortical cells. In addition, the effect of orally administered γ-mangostin on scopolamine-induced memory impairment was evaluated in mice. We found that γ-mangostin exhibited prominent protection against H2O2- or xanthine/xanthine oxidase-induced oxidative neuronal death and inhibited reactive oxygen species (ROS) generation triggered by these oxidative insults. In contrast, α-mangostin had no effects on the oxidative neuronal damage or associated ROS production. We also found that γ-mangostin, not α-mangostin, significantly inhibited H2O2-induced DNA fragmentation and activation of caspases 3 and 9, demonstrating its antiapoptotic action. In addition, only γ-mangostin was found to effectively inhibit lipid peroxidation and DPPH radical formation, while both mangostins inhibited β-secretase activity. Furthermore, we observed that the oral administration of γ-mangostin at dosages of 10 and 30 mg/kg markedly improved scopolamine-induced memory impairment in mice. Collectively, these results provide both in vitro and in vivo evidences for the neuroprotective and memory enhancing effects of γ-mangostin. Multiple mechanisms underlying this neuroprotective action were suggested in this study. Based on our findings, γ-mangostin could serve as a potentially preferable candidate over α-mangostin in combatting oxidative stress-associated neurodegenerative diseases including Alzheimer’s disease.

scholarly journals Probucol Prevents Diabetes-Induced Retinal Neuronal Degeneration through Upregulating Nrf2

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Heng-Wei Liu ◽  
Yong Luo ◽  
Yu-Fan Zhou ◽  
Zhong-Ping Chen
Keyword(s):  
Diabetic Retinopathy ◽  
Neuronal Degeneration ◽  
Fundus Photography ◽  
Control Group ◽  
Ros Generation ◽  
Fundus Fluorescein Angiography ◽  
Diabetic Retina ◽  
Nrf2 Signaling Pathway ◽  
Retinal Structure ◽  
Nrf2 Expression

Diabetic retinopathy (DR) is a sight-threatening complication of diabetes. This study investigated the therapeutic effect of probucol in a mouse model of diabetic retinopathy. C57BL/6 mice were rendered diabetic through Streptozotocin (STZ) intraperitoneal injection. Mice were treated with probucol (150 mg/kg, gavage administration) or vehicle (DMSO) for 12 weeks. Optical coherence tomography (OCT), fundus photography (FP), and fundus fluorescein angiography (FFA) were conducted to evaluate retinal structure and damage. Eyes were collected for histology, reactive oxygen species (ROS) assay, apoptotic cells count, and western blot. After STZ injection, all mice developed hyperglycemia. Compared with the retina of the control group, the retina of diabetic mice showed enhanced arterial reflex and beaded vein dilatation. Besides, reduced inner and middle retinal thickness and significantly fewer nuclei were found in diabetic retina. Moreover, the diabetic retina also presented increased ROS generation and more TUNEL-positive cells. Probucol treatment prevented diabetes-induced lesions. In addition, the treatment also upregulated Nrf2 expression in diabetic retina. It was suggested that probucol attenuated diabetes-induced retinal neuronal degeneration via upregulating the Nrf2 signaling pathway possibly. Probucol may be repurposed for DR management.

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