Hesperidin protects against stress induced gastric ulcer through regulation of peroxisome proliferator activator receptor gamma in diabetic rats
Elshazly SM, Abd El Motteleb DM and Ibrahim IAAE
Stress induced gastric ulcer is a serious health problem in diabetic patients. Some studies reported that hesperidin (HDN), a citrus bioflavonoid, can bind to and stimulate peroxisome proliferator-activator receptor-gamma (PPAR-γ) which may mediate its antidiabetic, anti-inflammatory and anti-oxidant effects. This work aims to study the possible protective effect of HDN against stress induced gastric ulcer in diabetic rats as well as the possible involvement of PPARγ in this effect. Type 2 diabetes was induced using streptozotocin and nicotinamide. Diabetic rats received either HDN (100 mg/kg/day, orally) & omeprazole (20 mg/kg/day, orally) or HDN (100 mg/kg/day, orally) + GW9662, PPARγ antagonist, (1 mg/kg/day, i.p.) for 8 weeks then acute gastric injury was induced by cold restraint stress technique. Glycemic controls and gastroprotective effects were evaluated by measuring serum levels of glucose and insulin, gastric free and total acidity and gastric ulcer indices. Histopathological examination of gastric mucosa was also performed. To determine the underlying mechanism of action, gastric mucosal expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hemeoxygenase-1 (HO-1), cluster of differentiation 45 (CD45), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NFκB) and inducible nitric oxide synthase (iNOS), gastric contents of reduced glutathione (GSH), malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α) and nitric oxide (NO); as well as superoxide dismutase (SOD) and catalase activities were measured. HDN significantly improved glycemic level; it also reduced gastric acidity and gastric ulcer index and histopathological changes comparable to that produced by omeprazole. Moreover, HDN reduced lipid peroxidation and inflammatory markers levels and enhanced antioxidant capacity. The use of GW9662 significantly abrogated the gastric protective effect of HDN as well as reduced the antioxidant and anti-inflammatory effects. Our work showed, for the first time that, HDN has promising protective effect against stress induced gastric ulcer in diabetic rats through activation of PPARγ.
Molecular mechanism of the role of carbamyl erythropoietin in treating diabetic retinopathy rats
Xu X, Cai Y and Yu Y
The aim of the present study was to investigate the therapeutic effects of carbamyl erythropoietin (CEPO) and safflor yellow (SY) in the treatment of rats with diabetic retinopathy (DR) as well as exploring the mechanism of action. Male SD rats were used to establish a diabetes model and streptozotocin-induced retinopathy was also performed in rats. A total of 126 rats with DR were obtained, and model rats were randomly divided into the model (n=42), experimental (n=42) and control (n=42) groups. The rats in the model group were injected with saline, the rats in the experimental group were treated with CEPO, and the rats in the control group were treated with SY. After treatment for 2 weeks, the retinas were harvested for quantitative analysis of the mRNA expression levels of angiogenesis-promoting and -inhibiting molecules, apoptosis-promoting and -inhibiting molecules, and oxidative stress pathway-related factors by Reverse transcription-quantitative PCR (RT-qPCR). No significant differences in expression levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), angiopoietin (Ang-1), tissue kallikrein (TKLK) and pigment epithelium-derived factor (PEDF) were observed between the experimental and model groups (P>0.05). The expression levels of apoptosis-promoting molecules Bcl-2 related X protein (Bax) and cysteine aspartate specific protease (caspase-3) mRNA in the retina of the experimental group was significantly lower than those in the control group (P<0.05). The expression levels of Bcl-2 and survivin mRNA were significantly higher in the experimental group than in the control group (P<0.05). The expression levels of the oxidative stress pathway nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) mRNA were significantly higher in the experimental group than in the control group. Therefore, the therapeutic effects of CEPO in treating DR are better than those of SY. As a result, CEPO may inhibit apoptosis and oxidative stress damage of retinal tissue cells in DR rats without affecting angiogenesis.
Commiphora molmol protects against methotrexate-induced nephrotoxicity by up-regulating Nrf2/ARE/HO-1 signaling
Mahmoud AM, Germoush MO, Al-Anazi KM, Mahmoud AH, Farah MA and Allam AA
Commiphora molmol possesses multiple therapeutic benefits against various diseases; however, its protective role against methotrexate (MTX) renal toxicity has not been previously investigated. MTX is a dihydrofolate reductase inhibitor that can induce acute kidney injury (AKI). This study evaluated the in vitro antioxidant activity and the protective effect of C. molmol resin extract against MTX-induced oxidative stress, inflammation and renal injury. Male Wistar rats received 125 and 250 mg/kg C. molmol resin extract for 15 days and a single injection of MTX at day 16. C. molmol showed a radical scavenging activity against DPPH, superoxide and nitric oxide (NO) radicals. Rats received MTX showed renal injury evidenced by the significantly elevated serum creatinine and urea, and the histological alterations. The kidney of MTX-induced rats exhibited increased lipid peroxidation, NO, NF-κB and pro-inflammatory cytokines. Pre-treatment with C. molmol prevented MTX-induced kidney injury and attenuated oxidative stress and inflammation. C. molmol down-regulated Bax and enhanced the activity and expression of the antioxidant defenses. Furthermore, the expression of Bcl-2, Nrf2, NQO-1 and HO-1 was down-regulated in the kidney of MTX-induced rats. Pre-treatment with C. molmol resin up-regulated Bcl-2 and activated Nrf2/HO-1 signaling in the kidney of MTX-induced rats. In conclusion, C. molmol resin provided protection against MTX-induced AKI via activation of Nrf2 signaling and mitigation of oxidative stress.
Activation of the Nrf2-ARE Pathway Ameliorates Hyperglycemia-Mediated Mitochondrial Dysfunction in Podocytes Partly Through Sirt1
Zhang Q, Deng Q, Zhang J, Ke J, Zhu Y, Wen RW, Ye Z, Peng H, Su ZZ, Wang C and Lou T
Previously we have shown that activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element (ARE) attenuated hyperglycemia-induced damage in podocytes, but the molecular mechanism remains unknown.
Protective effects of flavonoids from Coreopsis tinctoria Nutt. on experimental acute pancreatitis via Nrf-2/ARE-mediated antioxidant pathways
Du D, Yao L, Zhang R, Shi N, Shen Y, Yang X, Zhang X, Jin T, Liu T, Hu L, Xing Z, Criddle DN, Xia Q, Huang W and Sutton R
Oxidative stress is a prominent feature of clinical acute pancreatitis (AP). Coreopsis tinctoria has been used traditionally to treat pancreas disorders like diabetes mellitus in China and Portugal and its flavonoid-rich fraction contain the main phytochemicals that have antioxidant and anti-inflammatory activities.
Effects of CeO2 nanoparticles on the HO-1, NQO1 and GCLC expression in the testes of diabetic rats
Hasanvand D, Amiri I, Soleimani Asl S, Saidijam M, Shabab N and Artimani T
CeO2 nanoparticles (CNPs) as effective ROS scavengers exhibit potent antioxidant activity. In this study the effect of CNPs investigated was on HO-1, NQO1 and GCLC expression in the streptozotocin (STZ) induced diabetic rats. Twenty-four male Wistar rats divided into four groups: Controls did not receive any treatment, diabetic rats received STZ (60mg/kg/daily), CNPs group received CNPs 30mg/kg/daily/2 weeks, rats in STZ+CNPs group following STZ injection, received CNPs 30mg/kg/2 weeks. Oxidative stress evaluated by measurement of TAC and TOS levels. HO-1, NQO1 and GCLC expression measured using quantitative real-time PCR. Following STZ injection, significant lower levels of TAC and higher levels of TOS were observed. CNPs could alleviate deleterious effects of diabetes through the enhancement of TAC levels and a significant decline in TOS levels. HO-1, NQO1 and GCLC expression in the diabetic rats were lower than controls. HO-1, NQO1 and GCLC upregulated in the diabetic rates treated with CNPs. There were significant correlations between NQO1 and GCLC, NQO1 and HO-1 and between HO-1 and GCLC expression. Moreover, Nrf2 was associated with NQO1, GCLC and HO-1 expression. CNPs as Nrf2 up-regulator confers protection against oxidative stress in the testes of STZ-induced diabetic rats by upregulating HO-1, GCLC and NQO1 cyto-protective genes.
Nrf2 protects against diabetic dysfunction of endothelial progenitor cells via regulating cell senescence
Wang RY, Liu LH, Liu H, Wu KF, An J, Wang Q, Liu Y, Bai LJ, Qi BM, Qi BL and Zhang L
Diabetes is associated with an increased risk of cardiovascular disease. A decrease in the number and functionality of endothelial progenitor cells (EPCs) leads to reduced endothelial repair and the development of cardiovascular disease. The aim of the present study was to explore the effect and underlying mechanisms of nuclear factor erythroid 2‑related factor 2 (Nrf2) on EPC dysfunction caused by diabetic mellitus. The biological functions of EPCs in streptozotocin‑induced diabetic mice were evaluated, including migration, proliferation, angiogenesis and the secretion of vascular endothelial growth factor (VEGF), stromal‑derived growth factor (SDF) and nitric oxide (NO). Oxidative stress levels in diabetic EPCs were also assessed by detecting intracellular reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). EPC senescence was evaluated by measuring p16 and b‑gal expression and observing the senescence‑associated secretory phenotype. In addition, the function of EPCs and level of oxidative stress were assessed following Nrf2 silencing or activation. Nrf2 silencing resulted in a decrease of EPC biological functions, accelerated cell senescence and increased oxidative stress, as indicated by ROS and MDA upregulation accompanied with decreased SOD activity. Furthermore, Nrf2 silencing inhibited migration, proliferation and secretion in EPCs, while it increased oxidative stress and cell senescence. Nrf2 activation protected diabetic EPCs against the effects of oxidative stress and cell senescence, ameliorating the biological dysfunction of EPCs derived from mice with diabetes. In conclusion, Nrf2 overexpression protected against oxidative stress‑induced functional damage in EPCs derived from diabetic mice by regulating cell senescence.
Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype
Tarantini S, Valcarcel-Ares MN, Yabluchanskiy A, Tucsek Z, Hertelendy P, Kiss T, Gautam T, Zhang XA, Sonntag WE, de Cabo R, Farkas E, Elliott MH, Kinter MT, Deak F, Ungvari Z and Csiszar A
Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.
Neochlorogenic acid inhibits against LPS-activated inflammatory responses through up-regulation of Nrf2/HO-1 and involving AMPK pathway
Park SY, Jin ML, Yi EH, Kim Y and Park G
Acute and chronic inflammatory diseases are associated with excessive inflammation due to the accumulation of pro-inflammatory mediators and cytokines produced by macrophages. In the present study, we investigated the anti-inflammatory properties of neochlorogenic acid (nCGA) from Lonicera japonica on lipopolysaccharide (LPS)-activated inflammation in macrophages and participation of the AMPK/Nrf2 pathway. nCGA pretreatment significantly reduced the production of nitric oxide, prostaglandin E, TNF-α, reactive oxygen species, IL-1β, and IL-6 by LPS-activated macrophages. Moreover, both transcript and protein levels of inducible nitric oxide synthase and cyclooxygenase-2 were reduced by nCGA in LPS-activated macrophages. nCGA inhibited NF-κB activation by attenuating IKKα/β and IκBα phosphorylation in LPS-stimulated macrophages. Moreover, nCGA attenuated LPS-elevated JAK-1, STAT-1, and MAPK phosphorylation. We further evaluated the possible role of nCGA in the induction of AMPK/Nrf2 signal pathways required for the protein expression of HO-1 and NQO-1. nCGA induced AMPK activation via phosphorylation of LKB1 and CaMKII and by the inhibitory phosphorylation of GSK3β. It stimulated the overexpression of Nrf2/ARE-regulated downstream proteins, such as NQO-1 and HO-1. Furthermore, the anti-inflammatory effects of nCGA were attenuated in macrophages subjected to siRNAs specific for HO-1, NQO-1, Nrf2, and AMPK. Accordingly, these results indicate that nCGA, as an AMPK/Nrf2 signal activator, prevents excessive macrophage-mediated responses associated with acute and chronic inflammatory disorders.
Liver-specific knockout of histone methyltransferase G9a impairs liver maturation and dysregulates inflammatory, cytoprotective, and drug-processing genes
Lu H, Lei X and Zhang Q
1. Methyltransferase G9a is essential for a key gene silencing mark, histone H3 dimethylation at lysine-9 (H3K9me2). Hepatic G9a expression is down-regulated by xenobiotics and diabetes. However, little is known about the role of G9a in liver. Thus, we generated mice with liver-specific knockout (Liv-KO) of G9a. 2. Adult G9a Liv-KO mice had marked loss of H3K9me2 proteins in liver, without overt liver injury or infiltration of inflammatory cells. However, G9a-null livers had ectopic induction of certain genes normally expressed in neural and immune systems. Additionally, G9a-null livers had moderate down-regulation of cytoprotective genes, markedly altered expression of certain important drug-processing genes, elevated endogenous reactive oxygen species, induction of ER stress marker Chop, but decreased glutathione and nuclear Nrf2. microRNA-383, a negative regulator of the PI3K/Akt pathway, was strongly induced in G9a Liv-KO mice. After LPS treatment, G9a Liv-KO mice had aggravated lipid peroxidation and proinflammatory response. 3. Taken together, the present study demonstrates that G9a regulates liver maturation by silencing neural and proinflammatory genes but maintaining/activating cytoprotective and drug-processing genes, in which the G9a/miR-383/PI3K/Akt/Nrf2(Chop) pathways may play important roles. G9a deficiency due to genetic polymorphism and/or environmental exposure may alter xenobiotic metabolism and aggravate inflammation and liver dysfunction.
Sodium butyrate attenuates diabetes-induced aortic endothelial dysfunction via P300-mediated transcriptional activation of Nrf2
Wu J, Jiang Z, Zhang H, Liang W, Huang W, Zhang H, Li Y, Wang Z, Wang J, Jia Y, Liu B and Wu H
Oxidative stress and inflammation are major contributors to diabetes-induced endothelial dysfunction which is the critical first step to the development of diabetic macrovascular complications. Nuclear factor erythroid 2-related factor 2 (NRF2) plays a key role in combating diabetes-induced oxidative stress and inflammation. Sodium butyrate (NaB) is an inhibitor of histone deacetylase (HDAC) and an activator of NRF2. However, NaB's effect on diabetes-induced aortic injury was unknown. It was also not known whether or to what extent NRF2 is required for both self-defense and NaB's protection in the diabetic aorta. Additionally, the mechanism by which NaB activates NRF2 was unclear. Therefore, C57BL/6 Nrf2 knockout (KO) and wild type (WT) mice were induced to diabetes by streptozotocin, and were treated in the presence or absence of NaB, for 20 weeks. The KO diabetic mice developed more severe aortic endothelial oxidative stress, inflammation and dysfunction, as compared with the WT diabetic mice. NaB significantly attenuated these effects in the WT, but not the KO, mice. In high glucose-treated aortic endothelial cells, NaB elevated Nrf2 mRNA and protein without facilitating NRF2 nuclear translocation, an effect distinct from that of sulforaphane. NaB inhibited HDAC activity, and increased occupancy of the transcription factor aryl hydrocarbon receptor and the co-activator P300 at the Nrf2 gene promoter. Further, the P300 inhibitor C646 completely abolished NaB's efficacies. Thus, NRF2 is required for both self-defense and NaB's protection against diabetes-induced aortic endothelial dysfunction. Other findings suggest that P300 mediates the transcriptional activation of Nrf2 by NaB.
HX-1171 attenuates pancreatic β-cell apoptosis and hyperglycemia-mediated oxidative stress via Nrf2 activation in streptozotocin-induced diabetic model
Kim J, Shin SH, Kang JK and Kim JW
Streptozotocin (STZ) acts specifically on pancreatic beta cells, inducing cell destruction and cell dysfunction, resulting in diabetes. Many studies have reported that nuclear factor-erythroid 2-related factor 2 (Nrf2), a main regulator of antioxidant expression, prevents and improves diabetes-related diseases. In this study, we investigated the antidiabetic effect of the newly discovered Nrf2 activator, HX-1171, in the STZ-induced diabetic mouse model. HX-1171 enhanced insulin secretion by reducing STZ-induced cell apoptosis, and decreased intracellular reactive oxygen species (ROS) generation by upregulating the expression of antioxidant enzymes through Nrf2 activation in INS-1 pancreatic beta cells. In STZ-induced diabetic mice, HX-1171 administration significantly lowered blood glucose levels and restored blood insulin levels. In the STZ-only injected mice, the pancreatic islets showed morphological changes and loss of function, whereas the HX-1171-treated group was similar to that of the control group. These results suggest that HX-1171 may be developed as a promising therapeutic agent for diabetes-related diseases.
MicroRNA-146a: A Comprehensive Indicator of Inflammation and Oxidative Stress Status Induced in the Brain of Chronic T2DM Rats
Xie Y, Chu A, Feng Y, Chen L, Shao Y, Luo Q, Deng X, Wu M, Shi X and Chen Y
It was demonstrated that inflammation and oxidative stress induced by hyperglycemia were closely associated with alteration of miR-146a. Here, we investigated the role of miR-146a in mediating inflammation and oxidative stress in the brain of chronic T2DM rats. The chronic T2DM (cT2DM) models were induced by intraperitoneal administration of STZ (35 mg/kg) after being fed a high-fat, high-sugar diet for 6 weeks. H&E staining was conducted to observe the morphological impairment of the rat hippocampus. The expressions of inflammatory mediators (COX-2, TNF-α, IL-1β) and antioxidant proteins (Nrf2, HO-1) were measured by western blot. The levels of MDA and SOD were detected by the respective activity assay kit. The levels of p22phox and miR-146a were examined by quantitative real-time PCR (qRT-PCR). The expressions of IRAK1, TRAF6 and NF-κB p65 were measured by western blot and qRT-PCR. Pearson correlation analysis was performed to investigate the correlations between miR-146a and inflammatory mediators as well as oxidative stress indicators. The expression of miR-146a was negatively correlated with inflammation and oxidative stress status. In the brain tissues of cT2DM rats, it was observed that the expressions of inflammatory mediators (COX-2, TNF-α, IL-1β) and oxidative stress indicators including MDA and p22phox were elevated, which were negatively correlated with the expression of miR-146a. While, the antioxidant proteins (Nrf2, HO-1, SOD) levels decreased in the brain of cT2DM rats, which were positively correlated with the miR-146a level. The expressions of NF-κB p65 and its specific modulators (IRAK1&TRAF6) were elevated in the brain of cT2DM rats, which might be inhibited by miR-146a. Our results implied that increased inflammation and oxidative stress status were associated with brain impairment in cT2DM rats, which were negatively correlated with miR-146a expression. Thus, miR-146a may serve as a negative comprehensive indicator of inflammation and oxidative stress status in the brain of chronic T2DM rats.
Paeonol Ameliorates Diabetic Renal Fibrosis Through Promoting the Activation of the Nrf2/ARE Pathway via Up-Regulating Sirt1
Zhang L, Chen Z, Gong W, Zou Y, Xu F, Chen L and Huang H
Diabetic nephropathy (DN) is rapidly becoming the leading cause of end-stage renal disease worldwide and a major cause of morbidity and mortality in patients of diabetes. The main pathological change of DN is renal fibrosis. Paeonol (PA), a single phenolic compound extracted from the root bark of Cortex Moutan, has been demonstrated to have many potential pharmacological activities. However, the effects of PA on DN have not been fully elucidated. In this study, high glucose (HG)-treated glomerular mesangial cells (GMCs) and streptozotocin (STZ)-induced diabetic mice were analyzed in exploring the potential mechanisms of PA on DN. Results showed that: (1) PA inhibited HG-induced fibronectin (FN) and ICAM-1 overexpressions; (2) PA exerted renoprotective effect through activating the Nrf2/ARE pathway; (3) Sirt1 mediated the effects of PA on the activation of Nrf2/ARE pathway. What is more, in accordance with the results, significant elevated levels of Sirt1, Nrf2 and downstream proteins related to Nrf2 were observed in the kidneys of PA treatment group compared with model group. Taken together, our study shows that PA delays the progression of diabetic renal fibrosis, and the underlying mechanism is probably associated with regulating the Nrf2 pathway. The effect of PA on Nrf2 is at least partially dependent on Sirt1 activation.
Caenorhabditis elegans respond to high-glucose diets through a network of stress-responsive transcription factors
Alcántar-Fernández J, Navarro RE, Salazar-Martínez AM, Pérez-Andrade ME and Miranda-Ríos J
High-glycemic-index diets, as well as a sedentary lifestyle are considered as determinant factors for the development of obesity, type 2 diabetes, and cardiovascular diseases in humans. These diets have been shown to shorten the life span of C. elegans in a manner that is dependent on insulin signaling, but the participation of other signaling pathways have not been addressed. In this study, we have determined that worms fed with high-glucose diets show alterations in glucose content and uptake, triglyceride content, body size, number of eggs laid, egg-laying defects, and signs of oxidative stress and accelerated aging. Additionally, we analyzed the participation of different key regulators of carbohydrate and lipid metabolism, oxidative stress and longevity such as SKN-1/NRF2, HIF-1/HIF1α, SBP-1/SREBP, CRH-1/CREB, CEP-1/p53, and DAF-16/FOXO, in the reduction of lifespan in glucose-fed worms.

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