Therapeutic Potential of Pegylated Hemin for Reactive Oxygen Species-Related Diseases via Induction of Heme Oxygenase-1: Results from a Rat Hepatic Ischemia/Reperfusion Injury Model

Fang, Jun; Qin, Haibo; Seki, Takahiro; Nakamura, Hideaki; Tsukigawa, Kenji; Shin, Takashi; Maeda, Hiroshi

doi:10.1124/jpet.111.185348

Cited by 43 publications

(38 citation statements)

References 37 publications

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“…more than 80%) in the mammalian system, and the roles of CO include, similarly to NO, regulating vascular tone (vasorelaxant), participating in antiapoptosis, serving an antioxidative, anti-inflammatory function and inhibiting the activation of monocytes/macrophages, inducing angiogenesis and others [24]. The vasorelaxant effect of CO will further enhance the permeability of blood vessels and thus increase blood flow; this was verified in our recent study showing that injection of HO-1 protein into the skin of mice enhanced the permeability of blood vessels remarkably, and the blood flow of liver and tumor tissue was significantly improved after administration of CO or HO-1 inducer pegylated hemin, in a rat liver I/R model and a murine solid tumor model, respectively [35,36]. In agreement with these findings, in our present experiment, we found the CO concentration in circulation increased after glutamine treatment ( fig.…”

Section: Discussionmentioning

confidence: 56%

Tissue-Protective Effect of Glutamine on Hepatic Ischemia-Reperfusion Injury via Induction of Heme Oxygenase-1

Zhang¹,

Shi²,

Yu³

et al. 2013

Pharmacology

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Background/Aims: Glutamine showed cytoprotective activity in vitro on anoxia-reoxygenation injury via induction of heme oxygenase-1 (HO-1). We thus investigated its in vivo tissue-protective effect in a rat liver ischemia-reperfusion (I/R) model. Methods: Before the I/R procedure, animals were treated with glutamine. Liver injury was evaluated by serum liver enzymes, histological examination and apoptosis detection by transferase-mediated uridine nick end labeling staining. Meanwhile, expression and activities of HO-1 were measured by Western blot and a biochemical method. Liver blood flow was measured by using a laser Doppler flowmeter, and oxidative injury was investigated by the thiobarbituric acid-reactive substance (TBARS) assay. The inflammatory cytokine monocyte chemotactic protein (MCP)-1 was quantified by ELISA. Results: I/R caused a large increase in levels of liver enzymes, remarkably inducing the necrosis and apoptosis of liver tissue, which was markedly inhibited by glutamine, during which HO-1 was upregulated significantly, and the HO-1 inhibitor zinc protoporphyrin nullified the effect of glutamine. Liver blood flow was greatly reduced after I/R; however, it was significantly improved by glutamine. Lipid peroxidation (TBARS) in liver tissue was largely induced which was significantly lowered by glutamine. Similar results were also observed for the production of MCP-1. Conclusion: Glutamine protected tissue against oxidative injury during rat hepatic I/R, by induction of HO-1 to fulfill antioxidative and antiapoptotic effects.

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Section: Discussionmentioning

confidence: 56%

Tissue-Protective Effect of Glutamine on Hepatic Ischemia-Reperfusion Injury via Induction of Heme Oxygenase-1

Zhang¹,

Shi²,

Yu³

et al. 2013

Pharmacology

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“…We developed PEG-hemin, a water-soluble pegylated HO-1 inducer, in our laboratory. (30) It behaves as a macromolecular micelle with a molecular mass of 126 kDa, and so may accumulate selectively in solid tumors based on the EPR effect. Accordingly, to investigate the role of HO-1 in the permeability of the tumor vasculature, we used PEG-hemin to induce HO-1 in S180 solid tumors.…”

Section: Resultsmentioning

confidence: 99%

“…The synthesis, purification, and characterization of PEG-hemin were as described previously. (30) Determination of the effect of HO-1, HO-1 inhibitors, and CO on vascular permeability in normal mouse skin. The ddY mice were anesthetized with sodium pentobarbital (83 mg ⁄ kg, i.p.).…”

Section: Methodsmentioning

confidence: 99%

Carbon monoxide, generated by heme oxygenase‐1, mediates the enhanced permeability and retention effect in solid tumors

et al. 2012

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The enhanced permeability and retention (EPR) effect is a unique pathophysiological phenomenon of solid tumors that sees biocompatible macromolecules (>40 kDa) accumulate selectively in the tumor. Various factors have been implicated in this effect. Herein, we report that heme oxygenase-1 (HO-1; also known as heat shock protein 32) significantly increases vascular permeability and thus macromolecular drug accumulation in tumors. Intradermal injection of recombinant HO-1 in mice, followed by i.v. administration of a macromolecular Evans blue-albumin complex, resulted in dose-dependent extravasation of Evans blue-albumin at the HO-1 injection site. Almost no extravasation was detected when inactivated HO-1 or a carbon monoxide (CO) scavenger was injected instead. Because HO-1 generates CO, these data imply that CO plays a key role in vascular leakage. This is supported by results obtained after intratumoral administration of a CO-releasing agent (tricarbonyldichlororuthenium(II) dimer) in the same experimental setting, specifically dose-dependent increases in vascular permeability plus augmented tumor blood flow. In addition, induction of HO-1 in tumors by the water-soluble macromolecular HO-1 inducer pegylated hemin significantly increased tumor blood flow and Evans blue-albumin accumulation in tumors. These findings suggest that HO-1 and ⁄ or CO are important mediators of the EPR effect. Thus, anticancer chemotherapy using macromolecular drugs may be improved by combination with an HO-1 inducer, such as pegylated hemin, via an enhanced EPR effect. (Cancer Sci 2012; 103: 535-541) C onventional chemotherapy with small molecule drugs has been used for many types of cancer for decades. However, the therapeutic efficacy remains less than optimal, mostly because of a lack of tumor selectivity, which results in severe adverse side effects and prevents the use of high drug doses.(1)The development of tumor-targeted chemotherapy is critically important for more successful treatment.During investigations of targeting drugs to tumors, Matsumura and Maeda (2) found that macromolecular agents larger than 40 kDa selectively accumulate and remain in tumor tissues for long periods. This unique phenomenon in the blood vasculature of solid tumor tissues is quite different from that in normal tissues and was attributed to the unique anatomic and pathophysiologic characteristics of solid tumors. These features include: (i) extensive angiogenesis and hence high vascular density; (3,4) (ii) extensive extravasation (vascular permeability) induced by various vascular mediators, including bradykinin, (5-7) nitric oxide (NO), (7,8) vascular endothelial growth factor (VEGF), (9,10) prostaglandins produced via cyclo-oxygenases,and matrix metalloproteinases;(11) (iii) defective vascular architecture, such as the lack of a smooth muscle layer and large gaps between vascular endothelial cells; (12,13) and (iv) impaired lymphatic clearance from the tumor interstitial space. (14)(15)(16) The increased vascular permeability and defective vas...

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“…6A). When cells were treated with varying concentrations of BCE (10,20,40, 60 and 80 µg/ml), while keeping the treatment time constant at 0.5 h, Nrf-2 nuclear accumulation was induced by BCE in a dose-dependent manner (Fig. 6B).…”

Section: Effects Of Bce On the Accumulation And Transactivation Functmentioning

confidence: 99%

“…However, treatment with 10-80 µg/ml of BCE improved the viability of glutamate-stimulated cells gradually, in a dose-dependent manner. Due to the unstable nature of ROS, their overproduction may cause neuronal cell toxicity (20). Therefore, we investigated whether glutamate-induced ROS production was reduced by BCE in hippocampal HT22 cells.…”

Section: Bce Protects Hippocampal Ht22 Cells Against Glutamateinducedmentioning

confidence: 99%

Bambusae Caulis in Taeniam modulates neuroprotective and anti-neuroinflammatory effects in hippocampal and microglial cells via HO-1- and Nrf-2-mediated pathways

Eom

Park

Kim

et al. 2012

International Journal of Molecular Medicine

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Abstract. Recent evidence indicates that microglial activation and hippocampal damage may play important roles in neurodegenerative diseases, including Alzheimer's disease. Bambusae Caulis in Taeniam has been used as a folk remedy for the treatment of hypertension and cardiovascular disease in China and Korea. In this study, the mechanism responsible for the neuroprotective and anti-neuroinflammatory effects of Bambusae Caulis in Taeniam ethyl acetate fraction (BCE) was investigated. Heme oxygenase-1 (HO-1) is an inducible enzyme expressed in response to various inflammatory stimuli. Due to its role in the anti-inflammatory signaling pathway, the expression and modulation of HO-1 are important. In this study, the neuroprotective and antineuroinflammatory effects of BCE were examined using the murine microglial BV2 and hippocampal HT22 cells. We demonstrated that the administration of BCE provided neuroprotective effects against glutamate-induced cytotoxicity in HT22 cells through the HO-1 and nuclear erythroid-2 related factor 2 (Nrf-2) signaling pathways. We also reported that BCE inhibited lipopolysaccharide (LPS)-induced pro-inflammatory cytokines and that the presence of selective inhibitors of HO-1 (SnPP) resulted in the inhibition of BCE-mediated anti-inflammatory activity in BV2 microglial cells. BCE was shown to induce HO-1 expression as well as the nuclear translocation of Nrf-2 in both microglial and hippocampal cells. These findings revealed the potential therapeutic mechanisms of BCE in neurodegenerative diseases, suggesting that HO-1 and Nrf-2 signaling may play important roles in the mediation of its neuroprotective and anti-neuroinflammatory effects. IntroductionAlzheimer's disease (AD) is the most common neurodegenerative disease causing adult dementia. The pathological feature of AD is progressive neuronal degeneration in separate areas of the forebrain, including the hippocampus and associated cortices (1). Oxidative stress has also been implicated in the pathophysiological mechanisms underlying AD (2). Thus, the regulation of oxidative stress is important in AD patients.Microglia are the primary immune cells of the brain and play an essential role in the regulation of the immune response triggered by damaged cells (3). Microglial cells are considered 'brain macrophages' because they scavenge dying cells in the brain. However, chronic activation of these cells leads to the production of many pro-inflammatory cytokines and inflammatory mediators, such as nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 (4). Therefore, the regulation of microglial activation has been regarded as an important therapeutic approach for the treatment of inflammatory neurodegenerative diseases. A number of studies have been conducted using BV2 cells, an immortalized murine microglial cell line. In addition to microglia, the hippocampus, an essential area for memory function, also has an important function pertinent in neurodegenerative diseases. Hippocampal HT22 cells are derived from t...

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Therapeutic Potential of Pegylated Hemin for Reactive Oxygen Species-Related Diseases via Induction of Heme Oxygenase-1: Results from a Rat Hepatic Ischemia/Reperfusion Injury Model

Cited by 43 publications

References 37 publications

Tissue-Protective Effect of Glutamine on Hepatic Ischemia-Reperfusion Injury via Induction of Heme Oxygenase-1

Tissue-Protective Effect of Glutamine on Hepatic Ischemia-Reperfusion Injury via Induction of Heme Oxygenase-1

Carbon monoxide, generated by heme oxygenase‐1, mediates the enhanced permeability and retention effect in solid tumors

Bambusae Caulis in Taeniam modulates neuroprotective and anti-neuroinflammatory effects in hippocampal and microglial cells via HO-1- and Nrf-2-mediated pathways

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