scholarly journals DPHC From Alpinia officinarum Ameliorates Oxidative Stress and Insulin Resistance via Activation of Nrf2/ARE Pathway in db/db Mice and High Glucose-Treated HepG2 Cells

2022 ◽  
Vol 12 ◽  
Author(s):  
Xuguang Zhang ◽  
Yuxin Zhang ◽  
Mingyan Zhou ◽  
Yiqiang Xie ◽  
Xiujuan Dong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
High Glucose ◽  
Hepg2 Cells ◽  
Fasting Blood Glucose ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Alpinia Officinarum

(R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC) from the natural plant Alpinia officinarum has been reported to have antioxidation and antidiabetic effects. In this study, the therapeutic effect and molecular mechanism of DPHC on type 2 diabetes mellitus (T2DM) were investigated based on the regulation of oxidative stress and insulin resistance (IR) in vivo and in vitro. In vivo, the fasting blood glucose (FBG) level of db/db mice was significantly reduced with improved glucose tolerance and insulin sensitivity after 8 weeks of treatment with DPHC. In vitro, DPHC ameliorated IR because of its increasing glucose consumption and glucose uptake of IR-HepG2 cells induced by high glucose. In addition, in vitro and in vivo experiments showed that DPHC could regulate the antioxidant enzyme levels including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), thereby reducing the occurrence of oxidative stress and improving insulin resistance. Western blotting and polymerase chain reaction results showed that DPHC could promote the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), the heme oxygenase-1 (HO-1), protein kinase B (AKT), and glucose transporter type 4 (GLUT4), and reduced the phosphorylation levels of c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 (IRS-1) on Ser307 both in vivo and in vitro. These findings verified that DPHC has the potential to relieve oxidative stress and IR to cure T2DM by activating Nrf2/ARE signaling pathway in db/db mice and IR-HepG2 cells.

Salvia miltiorrhiza Lipophilic Fraction Attenuates Oxidative Stress in Diabetic Nephropathy through Activation of Nuclear Factor Erythroid 2-Related Factor 2

2017 ◽  
Vol 45 (07) ◽  
pp. 1441-1457 ◽  
Author(s):  
Lin An ◽  
Mei Zhou ◽  
Faiz M. M. T. Marikar ◽  
Xue-Wen Hu ◽  
Qiu-Yun Miao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Diabetic Nephropathy ◽  
High Glucose ◽  
Mesangial Cells ◽  
Salvia Miltiorrhiza ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor

Diabetic nephropathy (DN) is a common cause of chronic kidney disease and end-stage renal disease, which can be triggered by oxidative stress. In this study, we investigated the renoprotective effect of the ethyl acetate extract of Salvia miltiorrhiza (EASM) on DN and examined the underlying molecular mechanism. We observed that EASM treatment attenuated metabolic abnormalities associated with hyperglycemic conditions in the experimental DN model. In streptozotocin (STZ)-induced mice, EASM treatment reduced albuminuria, improved renal function and alleviated the pathological alterations within the glomerulus. To mimic the hyperglycemic conditions in DN patients, we used high glucose (25[Formula: see text]mmol/L) media to stimulate mouse mesangial cells (MMCs), and EASM inhibited high glucose-induced reactive oxygen species. We also observed that EASM enhanced the expression of nuclear factor erythroid-2-related factor 2 (Nrf2), which mediated the anti-oxidant response, and its downstream gene heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1) with concomitant decrease of expression of kelch-like ECH-associated protein 1 (keap1) both in vitro and in vivo. Taken together, these results suggest that EASM alleviates the progression of DN and this might be associated with activation of Nrf2.

scholarly journals Identification of MicroRNA-92a-3p as an Essential Regulator of Tubular Epithelial Cell Pyroptosis by Targeting Nrf1 via HO-1

2021 ◽  
Vol 11 ◽  
Author(s):  
Renhe Wang ◽  
Haijun Zhao ◽  
Yingyu Zhang ◽  
Hai Zhu ◽  
Qiuju Su ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Epithelial Cell ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Tubular Epithelial Cell ◽  
Heme Oxygenase 1 ◽  
Related Factor

Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and has no effective treatment. Exploring the molecular mechanisms of renal IRI is critical for the prevention of AKI and its evolution to chronic kidney disease and end-stage renal disease. The aim of the present study was to determine the biological function and molecular mechanism of action of miR-92a-3p in tubular epithelial cell (TEC) pyroptosis. We investigated the relationship between nuclear factor-erythroid 2-related factor 1 (Nrf1) and TEC pyroptosis induced by ischemia–reperfusion in vivo and oxygen–glucose deprivation/reoxygenation (OGD/R) in vitro. MicroRNAs (miRNAs) are regulators of gene expression and play a role in the progression of renal IRI. Nrf1 was confirmed as a potential target for miRNA miR-92a-3p. In addition, the inhibition of miR-92a-3p alleviated oxidative stress in vitro and decreased the expression levels of NLRP3, caspase-1, GSDMD-N, IL-1β, and IL-18 in vitro and in vivo. Moreover, Zn-protoporphyrin-IX, an inhibitor of heme oxygenase-1, reduced the protective effect of Nrf1 overexpression on OGD/R-induced TEC oxidative stress and pyroptosis. The results of this study suggest that the inhibition of miR-92a-3p can alleviate TEC oxidative stress and pyroptosis by targeting Nrf1 in renal IRI.

scholarly journals Psoralea corylifolia L. Seed Extract Attenuates Methylglyoxal-Induced Insulin Resistance by Inhibition of Advanced Glycation End Product Formation

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Cao-Sang Truong ◽  
Eunhui Seo ◽  
Hee-Sook Jun
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Hepg2 Cells ◽  
Product Formation ◽  
The Body ◽  
Psoralea Corylifolia ◽  
Advanced Glycation ◽  
Metabolic Conditions

Accumulation of advanced glycation end products (AGEs) in the body has been implicated in the pathogenesis of metabolic conditions, such as diabetes mellitus. Methylglyoxal (MGO), a major precursor of AGEs, has been reported to induce insulin resistance in both in vitro and in vivo studies. Psoralea corylifolia seeds (PCS) have been used as a traditional medicine for several diseases, but their potential application in treating insulin resistance has not yet been evaluated. This study is aimed at investigating whether PCS extract could attenuate insulin resistance induced by MGO. Male C57BL/6N mice (6 weeks old) were administered 1% MGO in their drinking water for 18 weeks, and the PCS extract (200 or 500 mg/kg) was orally administered daily from the first day of the MGO administration. We observed that both 200 and 500 mg/kg PCS extract treatment significantly improved glucose tolerance and insulin sensitivity and markedly restored p-Akt and p-IRS1/2 expression in the livers of the MGO-administered mice. Additionally, the PCS extract significantly increased the phosphorylation of Akt and IRS-1/2 and glucose uptake in MGO-treated HepG2 cells. Further studies showed that the PCS extract inhibited MGO-induced AGE formation in the HepG2 cells and in the sera of MGO-administered mice. PCS extract also increased the expression of glyoxalase 1 (GLO1) in the liver tissue of MGO-administered mice. The PCS extract significantly decreased the phosphorylation of ERK, p38, and NF-κB and suppressed the mRNA expression of proinflammatory molecules including TNF-α and IL-1β and iNOS in MGO-administered mice. Additionally, we demonstrated that the PCS extract attenuated oxidative stress, as evidenced by the reduced ROS production in the MGO-treated cells and the enhanced expression of antioxidant enzymes in the liver of MGO-administered mice. Thus, PCS extract ameliorated the MGO-induced insulin resistance in HepG2 cells and in mice by reducing oxidative stress via the inhibition of AGE formation. These findings suggest the potential of PCS extract as a candidate for the prevention and treatment of insulin resistance.

scholarly journals Activation of Nrf2/HO-1 Pathway and Human Atherosclerotic Plaque Vulnerability:an In Vitro and In Vivo Study

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 356 ◽  
Author(s):  
Fiorelli ◽  
Porro ◽  
Cosentino ◽  
Di Minno ◽  
Manega ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Healthy Subjects ◽  
Defense Mechanism ◽  
Thrombus Formation ◽  
Coronary Plaque ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Oxidative Stress Status

Reactive oxygen species (ROS) induce nuclear factor erythroid 2–related factor 2 (Nrf2) activation as an adaptive defense mechanism, determining the synthesis of antioxidant molecules, including heme-oxygenase-1 (HO-1). HO-1 protects cells against oxidative injury, degrading free heme and inhibiting ROS production. HO-1 is highly expressed in macrophages during plaque growth. Macrophages are morpho-functionally heterogeneous, and the prevalence of a specific phenotype may influence the plaque fate. This heterogeneity has also been observed in monocyte-derived macrophages (MDMs), a model of macrophages infiltrating tissue. The study aims to assess oxidative stress status and Nrf2/HO-1 axis in MDM morphotypes obtained from healthy subjects and coronary artery disease (CAD) patients, in relation to coronary plaque features evaluated in vivo by optical coherence tomography (OCT). We found that MDMs of healthy subjects exhibited a lower oxidative stress status, lower Nrf2 and HO-1 levels as compared to CAD patients. High HO-1 levels in MDMs were associated with the presence of a higher macrophage content, a thinner fibrous cap, and a ruptured plaque with thrombus formation, detected by OCT analysis. These findings suggest the presence of a relationship between in vivo plaque characteristics and in vitro MDM profile, and may help to identify patients with rupture-prone coronary plaque.

scholarly journals The Ethanol Extract of Licorice (Glycyrrhiza uralensis) Protects against Triptolide-Induced Oxidative Stress through Activation of Nrf2

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Ling-Juan Cao ◽  
Zhen-Yan Hou ◽  
Huan-De Li ◽  
Bi-Kui Zhang ◽  
Ping-Fei Fang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hepg2 Cells ◽  
Ethanol Extract ◽  
Treated Group ◽  
Related Factor ◽  
Mrna Levels ◽  
Icr Mice ◽  
Mice Liver

To investigate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2) in licorice ethanol extract (LEE) against triptolide- (TP-) induced hepatotoxicity, HepG2 cells were exposed to LEE (30, 60, and 90 mg·L−1) for 12 h and then treated with TP (50 nM) for 24 h. Besides, an acute liver injury model was established in ICR mice by a single dose of TP (1.0 mg·kg−1, i.p.). Relevant oxidant and antioxidant mediators were analyzed. TP led to an obvious oxidative stress as evidenced by increasing levels of ROS and decreasing GSH contents in HepG2 cells. In vitro results were likely to hold true in in vivo experiments. LEE protected against TP-induced oxidative stress in both in vitro and in vivo conditions. Furthermore, the decreased level of Nrf2 in the TP-treated group was observed. The mRNA levels of downstream genes decreased as well in ICR mice liver, whereas they increased in HepG2 cells. In contrast, LEE pretreatment significantly increased the level of Nrf2 and its downstream genes. LEE protects against TP-induced oxidative stress partly via the activation of Nrf2 pathway.

scholarly journals Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway

2018 ◽  
Vol 49 (5) ◽  
pp. 1943-1958 ◽  
Author(s):  
Xiaoye Fan ◽  
Lidong Wang ◽  
Jingbo Huang ◽  
Hongming Lv ◽  
Xuming Deng ◽  
...  
Keyword(s):  
Liver Injury ◽  
Hepg2 Cells ◽  
Glycogen Synthase ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Protective Effects ◽  
Cytochrome C Release ◽  
Underlying Mechanisms

Background/Aims: Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo. Methods: C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay. Results: In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H2O2) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3β (GSK3β) in HepG2 cells. Moreover, Pts protect against APAP or H2O2-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice. Conclusion: Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway.

scholarly journals Heme Oxygenase-1 Deficiency and Oxidative Stress: A Review of 9 Independent Human Cases and Animal Models

2021 ◽  
Vol 22 (4) ◽  
pp. 1514 ◽  
Author(s):  
Akihiro Yachie
Keyword(s):  
Oxidative Stress ◽  
Animal Models ◽  
Heme Oxygenase ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Pharmacological Intervention ◽  
Heme Oxygenase 1 ◽  
Inflammatory Reactions

Since Yachie et al. reported the first description of human heme oxygenase (HO)-1 deficiency more than 20 years ago, few additional human cases have been reported in the literature. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs from oxidative stress and excessive inflammatory reactions, through the release of multiple molecules with anti-oxidative stress and anti-inflammatory functions. HO-1 production is induced in vivo within selected cell types, including renal tubular epithelium, hepatic Kupffer cells, vascular endothelium, and monocytes/macrophages, suggesting that HO-1 plays critical roles in these cells. In vivo and in vitro studies have indicated that impaired HO-1 production results in progressive monocyte dysfunction, unregulated macrophage activation and endothelial cell dysfunction, leading to catastrophic systemic inflammatory response syndrome. Data from reported human cases of HO-1 deficiency and numerous studies using animal models suggest that HO-1 plays critical roles in various clinical settings involving excessive oxidative stress and inflammation. In this regard, therapy to induce HO-1 production by pharmacological intervention represents a promising novel strategy to control inflammatory diseases.

Maltol inhibits the progression of osteoarthritis via the nuclear factor-erythroid 2-related factor-2/heme oxygenase-1 signal pathway in vitro and in vivo

2021 ◽  
Author(s):  
Ding-Chao Zhu ◽  
Yi-Han Wang ◽  
Jia-Hao Lin ◽  
Zhi-Min Miao ◽  
Jia-Jing Xu ◽  
...  
Keyword(s):  
Cartilage Degeneration ◽  
Degenerative Joint Disease ◽  
Signal Pathway ◽  
Joint Disease ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Articular Cartilage Degeneration

Osteoarthritis (OA) is a common degenerative joint disease characterized by articular cartilage degeneration and inflammation. Currently, there is hardly any effective treatment for OA due to its complicated pathology and...

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.

Abstract 6253: Increased Expression of Thioredoxin Interacting Protein Promotes Oxidative Stress and Contributes to the Pathogenesis Of Diabetic Cardiomyopathy

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Kim A Connelly ◽  
Darren J Kelly ◽  
Michael Zhang ◽  
Kerri Thai ◽  
Andrew Advani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mrna Expression ◽  
High Glucose ◽  
Diastolic Heart Failure ◽  
Transgenic Rat ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein ◽  
Neonatal Cardiomyocytes

Background: Alterations in the thioredoxin (TRX) antioxidant system have been implicated in the pathogenesis of cardiac injury, particularly in the diabetic setting. While constitutively present, TRX activity is reduced by the presence of its endogenous inhibitor, thioredoxin interacting protein (TxnIP). We hypothesized that by increasing TxnIP, diabetes may reduce TRX activity and contribute to oxidative stress. Methods: Cell culture studies were performed using the H9C2 rat cardiomyoblast cell line and neonatal cardiomyocytes isolated from 1 day old Sprague Dawley rat neonates. In-vivo studies were performed using a hemodynamically-validated rodent model of diabetic diastolic heart failure, the diabetic (mRen-2)27 transgenic rat (Ren-2). Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) was used as a measure of oxidative stress. Results: In- vitro, high glucose (25mmol/l) resulted in increased TxnIP mRNA expression in both neonatal cardiomyocytes as well as H92C cells (2.21 ± 0.6 v 1.00 ± 0.19, p<0.05 compared to normoglycaemic conditions) with a 45% reduction in TRX activity (0.11 ± 0.01 v 0.061± 0.003, p<0.01). In-vivo, diabetes led to a 250% rise in TxnIP mRNA expression compared to control (2.54 ± 0.5 v 1.00 ± 0.11, p<0.001) that was accompanied by a three fold rise in urinary 8-OHdG (680 ± 280 v 1395 ± 391 ng/ml, p<0.001). Conclusion: In both the in vitro and in vivo settings, high glucose leads to TxnIP over-expression associated with reduced TRX activity thereby increasing oxidative stress and implicating this system in the pathogenesis of the cardiac dysfunction that characterizes the diabetic state. Pharmacological manipulation of the TRX-TxnIP system may represent a novel target to reduce diabetic complications.

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