Microdose Lithium Protects against Pancreatic Islet Destruction and Renal Impairment in Streptozotocin-Elicited Diabetes

Psychiatric use of lithium has been associated with hypoglycemic effects, but its effect on type 1 diabetes mellitus (T1D) is unknown. In streptozotocin (STZ) induced murine models of T1D, microdose lithium therapy improved hyperglycemia, attenuated body weight loss and prevented early signs of diabetic kidney injury. This beneficial effect was associated with preservation of pancreatic islet histology and β-cell production of insulin as well as mitigated oxidative damage of islets. Mechanistically, lithium in islets cells induced inhibitory phosphorylation of glycogen synthase kinase 3β (GSK3β), the major molecular target of lithium that has been recently implicated in non-canonical regulation of Nrf2 activity. In turn, Nrf2 antioxidant response was potentiated in islets, marked by nuclear translocation of Nrf2 and augmented expression of its target antioxidant enzyme heme oxygenase 1 (HO-1). Conversely, cotreatment with trigonelline, a selective blockade of Nrf2, offset the lithium enhanced Nrf2 antioxidant response in islets, blunted the protective effect of lithium on pancreatic islets and β-cells, and abolished the hypoglycemic activity of lithium in STZ-injured mice. Collectively, our findings suggest that microdose lithium confers a protective effect on islet β-cells via targeting the GSK3β-regulated Nrf2 antioxidant response and thereby ameliorates T1D and its related kidney impairment.

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Antagonizing Effects of Clematis apiifolia DC. Extract against Benzo[a]pyrene-Induced Damage to Human Keratinocytes

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/2386163 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Seung Eun Lee ◽

See-Hyoung Park ◽

Ju Ah Yoo ◽

Kitae Kwon ◽

Ji Woong Kim ◽

...

Keyword(s):

Nuclear Translocation ◽

Human Keratinocytes ◽

Antioxidant Response ◽

Luciferase Reporter ◽

Heme Oxygenase 1 ◽

Protective Effects ◽

Cytochrome P450 1A1 ◽

Independent Manner ◽

Reporter Activity ◽

Aryl Hydrocarbon

Background. Benzo[a]pyrene (B[a]P), a polycyclic aromatic hydrocarbon present in the atmosphere, has cytotoxic and carcinogenic effects. There have been no reports to demonstrate involvement of Clematis apiifolia DC. extract (CAE) in B[a]P-induced effects. This study was conducted to investigate the effect of CAE on B[a]P-induced effects and to elucidate its mechanism of action in HaCaT human keratinocytes. CAE inhibited aryl hydrocarbon receptor (AhR) signaling by decreasing both XRE reporter activity and expression of cytochrome P450 1A1 (CYP1A1) induced by B[a]P treatment in HaCaT cells. We also found that B[a]P-induced nuclear translocation of AhR and production of reactive oxygen species (ROS) and proinflammatory cytokines were attenuated by CAE treatment. CAE treatment suppressed B[a]P-induced phosphorylation of Src (Tyr416). In addition, dasatinib, a Src inhibitor, also inhibited B[a]P-induced nuclear translocation of AhR, similar to CAE treatment. In addition, CAE activated antioxidant response element (ARE) signaling by increasing ARE luciferase reporter activity and expression of ARE-dependent genes such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2), NAD(P)H dehydrogenase [quinone] 1 (NQO1), and heme oxygenase-1 (HO-1). Nuclear translocation of Nrf2 by CAE was demonstrated by Western blot analysis and immunocytochemistry. The effects of CAE on ARE signaling were attenuated by knockdown of the Nrf2 gene. Inhibition of AhR signaling and activation of antioxidant activity by CAE operated in a reciprocally independent manner as evidenced by AhR and Nrf2 siRNA experiments. These findings indicate that CAE exerts protective effects against B[a]P by inhibiting AhR signaling and activating Nrf2-mediated signaling, suggesting its potential in protection from harmful B[a]P-containing pollutants.

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l-carnitine protects human hepatocytes from oxidative stress-induced toxicity through Akt-mediated activation of Nrf2 signaling pathway

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2015-0305 ◽

2016 ◽

Vol 94 (5) ◽

pp. 517-525 ◽

Cited By ~ 9

Author(s):

Jinlian Li ◽

Yanli Zhang ◽

Haiyun Luan ◽

Xuehong Chen ◽

Yantao Han ◽

...

Keyword(s):

Protective Effect ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Cell Damage ◽

Binding Activity ◽

Akt Pathway ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Akt Inhibitor ◽

Nrf2 Signaling Pathway

In our previous study, l-carnitine was shown to have cytoprotective effect against hydrogen peroxide (H2O2)-induced injury in human normal HL7702 hepatocytes. The aim of this study was to investigate whether the protective effect of l-carnitine was associated with the nuclear factor erythroid 2 (NFE2)-related factor 2 (Nrf2) pathway. Our results showed that pretreatment with l-carnitine augmented Nrf2 nuclear translocation, DNA binding activity and heme oxygenase-1 (HO-1) expression in H2O2-treated HL7702 cells, although l-carnitine treatment alone had no effect on them. Analysis using Nrf2 siRNA demonstrated that Nrf2 activation was involved in l-carnitine-induced HO-1 expression. In addition, l-carnitine-mediated protection against H2O2 toxicity was abrogated by Nrf2 siRNA, indicating the important role of Nrf2 in l-carnitine-induced cytoprotection. Further experiments revealed that l-carnitine pretreatment enhanced the phosphorylation of Akt in H2O2-treated cells. Blocking Akt pathway with inhibitor partly abrogated the protective effect of l-carnitine. Moreover, our finding demonstrated that the induction of Nrf2 translocation and HO-1 expression by l-carnitine directly correlated with the Akt pathway because Akt inhibitor showed inhibitory effects on the Nrf2 translocation and HO-1 expression. Altogether, these results demonstrate that l-carnitine protects HL7702 cells against H2O2-induced cell damage through Akt-mediated activation of Nrf2 signaling pathway.

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Regulation of heme oxygenase-1 expression by demethoxy curcuminoids through Nrf2 by a PI3-kinase/Akt-mediated pathway in mouse β-cells

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00111.2007 ◽

2007 ◽

Vol 293 (3) ◽

pp. E645-E655 ◽

Cited By ~ 75

Author(s):

Subbiah Pugazhenthi ◽

Leonid Akhov ◽

Gopalan Selvaraj ◽

Maorong Wang ◽

Jawed Alam

Keyword(s):

Signaling Pathways ◽

Heme Oxygenase ◽

Nuclear Translocation ◽

Regulatory Subunit ◽

Luciferase Reporter ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Mrna Levels ◽

Phase 2 ◽

Β Cells

Curcumin (diferuloylmethane), a component of turmeric, has been shown to have therapeutic properties. Induction of phase 2 detoxifying enzymes is a potential mechanism through which some of the actions of curcumin could proceed. Heme oxygenase-1 (HO-1), an antioxidant phase 2 enzyme, has been reported to have cytoprotective effects in pancreatic β-cells. Curcumin on further purification yields demethoxy curcumin (DMC) and bisdemethoxy curcumin (BDMC). The objective of the present study was to determine the mechanism by which these purified curcuminoids induce HO-1 in MIN6 cells, a mouse β-cell line. Demethoxy curcuminoids induced HO-1 promoter linked to the luciferase reporter gene more effectively than curcumin. The induction was dependent on the presence of antioxidant response element (ARE) sites containing enhancer regions (E1 and E2) in HO-1 promoter and nuclear translocation of nuclear factor-E2-related factor (Nrf2), the transcription factor that binds to ARE. Curcuminoids stimulated multiple signaling pathways that are known to induce HO-1. Inhibition of specific signaling pathways with pharmacological inhibitors and cotransfection experiments suggested the involvement of phosphotidylinositol 3-kinase and Akt. Real-time quantitative RT-PCR analysis showed significant elevation in the mRNA levels of HO-1 and two other phase 2 enzymes, the regulatory subunit of glutamyl cysteine ligase, which is needed for the synthesis of glutathione, and NAD(P)H:quinone oxidoreductase, which detoxifies quinones. DMC and BDMC induced the expression of HO-1 and translocated Nrf2 to nucleus in β-cells of mouse islets. Our observations suggest that demethoxy curcuminoids could be used to induce a cellular defense mechanism in β-cells under conditions of stress as seen in diabetes.

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Curcumin Pretreatment Induces Nrf2 and an Antioxidant Response and Prevents Hemin-Induced Toxicity in Primary Cultures of Cerebellar Granule Neurons of Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/801418 ◽

2013 ◽

Vol 2013 ◽

pp. 1-14 ◽

Cited By ~ 88

Author(s):

Susana González-Reyes ◽

Silvia Guzmán-Beltrán ◽

Omar Noel Medina-Campos ◽

José Pedraza-Chaverri

Keyword(s):

Protective Effect ◽

Heme Oxygenase ◽

Curcuma Longa ◽

Primary Cultures ◽

Buthionine Sulfoximine ◽

Antioxidant Response ◽

Cerebellar Granule Neurons ◽

Heme Oxygenase 1 ◽

Granule Neurons ◽

Cerebellar Granule

Curcumin is a bifunctional antioxidant derived fromCurcuma longa. This study identifies curcumin as a neuroprotectant against hemin-induced damage in primary cultures of cerebellar granule neurons (CGNs) of rats. Hemin, the oxidized form of heme, is a highly reactive compound that induces cellular injury. Pretreatment of CGNs with 5–30 μM curcumin effectively increased by 2.3–4.9 fold heme oxygenase-1 (HO-1) expression and by 5.6–14.3-fold glutathione (GSH) levels. Moreover, 15 μM curcumin attenuated by 55% the increase in reactive oxygen species (ROS) production, by 94% the reduction of GSH/glutathione disulfide (GSSG) ratio, and by 49% the cell death induced by hemin. The inhibition of heme oxygenase system or GSH synthesis with tin mesoporphyrin and buthionine sulfoximine, respectively, suppressed the protective effect of curcumin against hemin-induced toxicity. These data strongly suggest that HO-1 and GSH play a major role in the protective effect of curcumin. Furthermore, it was found that 24 h of incubation with curcumin increases by 1.4-, 2.3-, and 5.2-fold the activity of glutathione reductase, glutathione S-transferase and superoxide dismutase, respectively. Additionally, it was found that curcumin was capable of inducing nuclear factor (erythroid-derived 2)-like 2 (Nrf2) translocation into the nucleus. These data suggest that the pretreatment with curcumin induces Nrf2 and an antioxidant response that may play an important role in the protective effect of this antioxidant against hemin-induced neuronal death.

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The B55α-containing PP2A holoenzyme dephosphorylates FOXO1 in islet β-cells under oxidative stress

Biochemical Journal ◽

10.1042/bj20111606 ◽

2012 ◽

Vol 444 (2) ◽

pp. 239-247 ◽

Cited By ~ 20

Author(s):

Ling Yan ◽

Shuangli Guo ◽

Marie Brault ◽

Jamie Harmon ◽

R. Paul Robertson ◽

...

Keyword(s):

Oxidative Stress ◽

Type 2 Diabetes ◽

Cell Death ◽

Pancreatic Islet ◽

Transcriptional Activation ◽

Nuclear Import ◽

Nuclear Translocation ◽

Regulatory Subunit ◽

Β Cells

The FOXO1 (forkhead box O1) transcription factor influences many key cellular processes, including those important in metabolism, proliferation and cell death. Reversible phosphorylation of FOXO1 at Thr24 and Ser256 regulates its subcellular localization, with phosphorylation promoting cytoplasmic localization, whereas dephosphorylation triggers nuclear import and transcriptional activation. In the present study, we used biochemical and molecular approaches to isolate and link the serine/threonine PP2A (protein phosphatase 2A) holoenzyme containing the B55α regulatory subunit, with nuclear import of FOXO1 in pancreatic islet β-cells under oxidative stress, a condition associated with cellular dysfunction in Type 2 diabetes. The mechanism of FOXO1 dephosphorylation and nuclear translocation was investigated in pancreatic islet INS-1 and βTC-3 cell lines subjected to oxidative stress. A combined chemical cross-linking and MS strategy revealed the association of FOXO1 with a PP2A holoenzyme composed of the catalytic C, structural A and B55α regulatory subunits. Knockdown of B55α in INS-1 cells reduced FOXO1 dephosphorylation, inhibited FOXO1 nuclear translocation and attenuated oxidative stress-induced cell death. Furthermore, both B55α and nuclear FOXO1 levels were increased under hyperglycaemic conditions in db/db mouse islets, an animal model of Type 2 diabetes. We conclude that B55α-containing PP2A is a key regulator of FOXO1 activity in vivo.

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Induction of HO-1 by Mevastatin Mediated via a Nox/ROS-Dependent c-Src/PDGFRα/PI3K/Akt/Nrf2/ARE Cascade Suppresses TNF-α-Induced Lung Inflammation

Journal of Clinical Medicine ◽

10.3390/jcm9010226 ◽

2020 ◽

Vol 9 (1) ◽

pp. 226 ◽

Cited By ~ 5

Author(s):

Chih-Chung Lin ◽

Wei-Ning Lin ◽

Rou-Ling Cho ◽

Chien-Chung Yang ◽

Yi-Cheng Yeh ◽

...

Keyword(s):

Protein Kinase ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Growth Factor Receptor ◽

Antioxidant Response ◽

Alveolar Epithelial Cells ◽

Intercellular Adhesion Molecule ◽

Ros Generation ◽

Heme Oxygenase 1 ◽

Tnf Α

Background: Mevastatin (MVS), a 3-hydroxy-3-methylglutaryl coenzyme, a reductase (HMG-CoA) inhibitor, has anti-inflammatory effects potentially via up-regulation of heme oxygenase-1 (HO-1). However, the mechanisms underlying MVS-induced HO-1 expression remain largely unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). Methods: HO-1 and intercellular adhesion molecule (ICAM)-1 expression were determined using real-time PCR, Western blotting, and promoter reporter analyses. The signaling components were investigated using pharmacological inhibitors or specific small interfering RNA (siRNA)s. Interaction between Nrf2 and the antioxidant response element (ARE) binding site for the HO-1 promoter was determined by chromatin immunoprecipitation (ChIP) assay. Results: Upregulation of HO-1 by MVS attenuated the tumor necrosis factor (TNF)-α-stimulated ICAM-1 expression associated with THP-1 adhesion to HPAEpiCs. These inhibitory effects of HO-1 were reversed by tin protoporphyrin (SnPP)IX or by transfection with HO-1 siRNA. MVS-induced HO-1 expression was mediated via NADPH oxidase (Nox)-derived reactive oxygen species (ROS) generation. Activation of Nox2/ROS further stimulated the phosphorylation of p47phox, proto-oncogene tyrosine-protein kinase (c-Src), platelet-derived growth factor receptor (PDFGR)α, protein kinase B (Akt), and Nrf2, which were inhibited by siRNAs. Pretreatment with pharmacological inhibitors, including diphenyleneiodonium (DPI), apocynin (APO), N-acetyl-L-cysteine (NAC), PP1, AG1296, or LY294002, reduced the MVS-activated Nrf2 nuclear-translocation binding to the ARE on the HO-1 promoter. Conclusions: MVS-induced HO-1 is, at least in part, mediated through a p47phox/Nox2/ROS-dependent activation of c-Src/PDGFRα/PI3K/Akt-regulated Nrf2/ARE axis and suppresses the TNF-α-mediated inflammatory responses in HPAEpiCs.

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Heme Oxygenase 1-Induced Resistance to Imatinib In Chronic Myelogenous Leukemia Cells

Blood ◽

10.1182/blood.v118.21.4410.4410 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4410-4410

Author(s):

Daniele Tibullo ◽

Ignazio Barbagallo ◽

Antonio Branca ◽

Cesarina Giallongo ◽

Piera La Cava ◽

...

Keyword(s):

Protective Effect ◽

Heme Oxygenase ◽

Nuclear Translocation ◽

K562 Cells ◽

Inhibitory Effect ◽

Myelogenous Leukemia ◽

Heme Oxygenase 1 ◽

Potent Inducer ◽

Cellular Reactive Oxygen Species ◽

Mitogenic Signals

Abstract Abstract 4410 Heme oxygenase 1 (HO-1) is the rate-limiting enzyme in heme degradation leading to the generation of free iron, biliverdin and carbon monoxide (CO). In this study, K562 cells were incubated for 24 h with imatinib (1 μM) alone or in combination with: 1) cobalt protoporphyrin (CoPP, 10 μM), a potent inducer of HO-1; or 2) tin mesoporphyrin (SnMP, 10 μM), an inhibitor of HO activity. CoPP was able to overcome the inhibitory effect of imatinib while SnMPP restored the cytotoxicity. Interestingly, neither bilirubin nor CO (using the CO-releasing agent CORM-3) were able to protect K562 cells from imatinib-induced toxicity. The protective effect of CoPP was mitigated by addition of a protease inhibitor (Ed64), which was able to stop HO-1 nuclear translocation. We also analyzed 96 kinase genes and found that addition of CoPP in combination with imatinib leads to at least seven kinases being significantly increased while the expression of these genes was reduced in cells treated with imatinib alone or in the presence of SnMP. All of them are able to activate mitogenic signals. We also found that 1 μM imatinib was able to increase the formation of cellular reactive oxygen species and this effect was inhibited by CoPP and restored in presence of SnMP. In conclusion, the protective effect of HO-1 on imatinib-induced cytotoxicity does not involve the action of its catabolites, but rather a translocation of HO-1 to the nucleus after proteolytic cleavage. Migration to the nucleus activates several kinases able to induce mitogenic signals thus enabling HO-1 to reduce oxidative stress induced by imatinib. Disclosures: Di Raimondo: celgene: Honoraria.

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Protective Effect of An-Gong-Niu-Huang Wan Pre-treatment Against Experimental Cerebral Ischemia Injury via Regulating GSK-3β/HO-1 Pathway

Frontiers in Pharmacology ◽

10.3389/fphar.2021.640297 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shiqing Zhang ◽

Xiaoli Jiang ◽

Ying Wang ◽

Kaili Lin ◽

Zhang Zhang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Protective Effect ◽

Glycogen Synthase ◽

Functional Score ◽

Heme Oxygenase 1 ◽

Dependent Manner ◽

Protective Effects ◽

Infarct Area ◽

Pre Treatment ◽

Gsk 3Β

An-Gong-Niu-Huang Wan (AGNHW), a famous formula in traditional Chinese medicine, has been clinically used for centuries for treating cerebral diseases, but the protective effects of pre-treatment with AGNHW on cerebral ischemia have not yet been reported. The present study aimed to test such protective effects and elucidate the underlying mechanisms on cerebral ischemia in rats by phenotypic approaches (i.e. including the neurological functional score, cerebral infarct area, neuron apoptosis, and brain oxidative stress status) and target-based approaches (i.e. involving the GSK-3β/HO-1 pathway). AGNHW was administered orally at the doses of 386.26, 772.52, and 1545.04 mg/kg respectively for 7 days to male Sprague-Dawley rats and then cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 1.5 h. Pre-treatment with AGNHW significantly ameliorated ischemic damage to the brain in a dose-dependent manner, including reduction of the neurological deficit score and infarct area. AGNHW pre-treatment increased the number of Nissl+ cells, NeuN+ and DCX+ cells, and decreased the number of Tunel+ cells. Moreover, AGNHW reversed the up-regulation of ROS and MDA induced by cerebral ischemia. AGNHW pre-treatment increased the expression of p-GSK-3β(Ser9)/GSK-3β (glycogen synthase kinase-3β) ratio and heme oxygenase-1 (HO-1). These results firstly revealed that short-term pre-treatment of AGNHW could significantly protect the rats from injury caused by cerebral ischemia-reperfusion, which support further clinical studies for disease prevention. The in vivo protective effect of AGNWH pre-treatment could be associated with its antioxidant properties by the activation of GSK-3β-mediated HO-1 pathway.

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Ibudilast Attenuates Folic Acid–Induced Acute Kidney Injury by Blocking Pyroptosis Through TLR4-Mediated NF-κB and MAPK Signaling Pathways

Frontiers in Pharmacology ◽

10.3389/fphar.2021.650283 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xue Li ◽

Yu Zou ◽

Yuan-Yuan Fu ◽

Jia Xing ◽

Kai-Yue Wang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Folic Acid ◽

Protective Effect ◽

Signaling Pathways ◽

Nuclear Translocation ◽

Kidney Injury ◽

Mapk Signaling ◽

Inflammatory Factor ◽

Anti Inflammatory ◽

Mapk Signaling Pathways

Folic acid (FA)-induced renal tubule damage, which is characterized by extensive inflammation, is a common model of acute kidney injury (AKI). Pyroptosis, a pro-inflammatory form of cell death due to the activation of inflammatory caspases, is involved in AKI progression. Ibudilast, a TLR4 antagonist, has been used in the clinic to exert an anti-inflammatory effect on asthma. However, researchers have not explored whether ibudilast exerts a protective effect on AKI by inhibiting inflammation. In the present study, ibudilast reversed FA-induced AKI in mice, as indicated by the reduced serum creatinine and urea nitrogen levels, and improved renal pathology, as well as the downregulation of kidney injury marker-1. In addition, ibudilast significantly increased the production of the anti-inflammatory factor IL-10 while suppressing the secretion of the pro-inflammatory cytokine TNF-α and macrophage infiltration. Moreover, in the injured kidney, ibudilast reduced the levels of both inflammasome markers (NLRP3) and pyroptosis-related proteins (caspase-1, IL1-β, IL-18, and GSDMD cleavage), and decreased the number of TUNEL-positive cells. Further mechanistic studies showed that ibudilast administration inhibited the FA-induced upregulation of TLR4, blocked NF-κB nuclear translocation, and reduced the phosphorylation of NF-κB and IκBα, p38, ERK, and JNK. Thus, this study substantiates the protective effect of ibudilast on FA-induced AKI in mice and suggests that protection might be achieved by reducing pyroptosis and inflammation, likely through the inhibition of TLR4-mediated NF-κB and MAPK signaling pathways.

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