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Experimental and Therapeutic Targeting of Heme Oxygenase

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A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Antioxidant Enzyme Systems".

Deadline for manuscript submissions: closed (30 May 2024) | Viewed by 21407

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Dr. J. Catharina Duvigneau

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Department for Biomedical Sciences, Institute for Medical Biochemistry, University of Veterinary Medicine, 1210 Vienna, Austria
Interests: heme oxygenase in cell and organ dysfunction; heme oxygenase and biliverdin reductase activity; ferroptosis; oxidative stress response
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Dear Colleagues,

Heme oxygenase (HO) is an integral part of antioxidative cellular defense. HO catalyzes the rate-limiting step of heme degradation, yielding carbon monoxide (CO), ferrous iron (Fe²⁺), and biliverdin, which is further reduced to bilirubin in mammalians. Mammalian heme oxygenase exists in two catalytically active isoforms: the inducible isoform HO-1, and the constitutively expressed isoform HO-2. Both enzymes contribute to a different extent to the overall HO activity, which is capable of exerting cytoprotection via two synergistic effects: the removal of pro-oxidative heme and the generation of HO products, CO and biliverdin/bilirubin with antioxidative, antiapoptotic, and anti-inflammatory properties. However, the third product released in the HO reaction, ferrous iron, may act as pro-oxidative compound when not sufficiently sequestered. In general, HO induction provides protection to stressed cells and thereby helps to restore the physiologic function of tissues. HO also provides cytoprotection to malignant cells, which exploit the upregulation of HO activity to enhance their resistance against oxidative stressors. In order to selectively target cancer, new therapeutics have been developed that kill cells by means of ferroptosis, a form of cell death involving iron. However, for this type of cell death, both a protective and detrimental role of HO in ferroptosis have been described.

It is the aim of this follow-up Special Issue to collect contributions focusing on HO as a therapeutic target for treating sepsis, hypoxia, and ischemia/reperfusion on the one hand, and cancer cells on the other. Experimental studies using appropriate animal models, in vitro studies, and reviews highlighting so far underrated functions of HO are invited. Studies that investigate the role of HO as a signaling molecule are equally well-suited contributions. Additionally, contributions describing new methodological approaches for determining HO activity are also welcome.

Dr. J. Catharina Duvigneau
Guest Editor

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Keywords

cytoprotection
ferroptosis
ferrous iron
heme degradation
enzyme activity

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Published Papers (9 papers)

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12 pages, 1917 KiB

Open AccessArticle

Enhancement of Heme-Oxygenase 1 in the Injured Peripheral Nerve Following Sulforaphane Administration Fosters Regeneration via Proliferation and Maintenance of Repair Schwann Cells

by Fabian Szepanowski, Jaqueline Zipfel, Rebecca D. Szepanowski, Bianca Eggert, Nail-Mert Güner, Leon-Phillip Szepanowski, Christoph Kleinschnitz, Anne K. Mausberg and Mark Stettner

Antioxidants 2024, 13(9), 1038; https://doi.org/10.3390/antiox13091038 - 27 Aug 2024

Viewed by 1362

Abstract

Nuclear erythroid 2-related factor 2 (Nrf2) and its downstream effector heme oxygenase 1 (HO-1) are commonly activated in response to cellular stresses. The elevated expression of HO-1 has been associated with markedly accelerated peripheral nerve regeneration. This study aimed to evaluate the impact of a naturally occurring dietary Nrf2/HO-1 activator—sulforaphane (SFN)—on regeneration in a murine sciatic nerve crush model. The beneficial safety profile of SFN has been thoroughly investigated and confirmed several times. Here, SFN was administered daily, starting immediately after C57BL/6 mice were subjected to sciatic nerve crush injury. Injured sciatic nerves were excised at various time points post injury for molecular, immunohistochemical and morphometric analyses. Moreover, functional assessment was performed by grip strength analysis and electrophysiology. Following SFN treatment, the early response to injury includes a modulation of autophagic pathways and marked upregulation of Nrf2/HO-1 expression. This enhancement of HO-1 expression was maintained throughout the regeneration phase and accompanied by a significant increase in repair Schwann cells. In these cells, elevated proliferation rates were observed. Significant improvements in grip strength test performance, nerve conduction velocity and remyelination were also noted following SFN treatment. Collectively, SFN modulates cytoprotective and autophagic pathways in the injured nerve, increasing the number of repair Schwann cells and contributing to effective nerve regeneration. Given the availability of SFN as a nutritional supplement, this compound might constitute a novel regenerative approach with broad patient accessibility and further studies on this topic are warranted. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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19 pages, 7891 KiB

Open AccessArticle

The Combination of Molecular Hydrogen and Heme Oxygenase 1 Effectively Inhibits Neuropathy Caused by Paclitaxel in Mice

by Ignacio Martínez-Martel, Xue Bai, Rebecca Kordikowski, Christie R. A. Leite-Panissi and Olga Pol

Antioxidants 2024, 13(7), 856; https://doi.org/10.3390/antiox13070856 - 17 Jul 2024

Cited by 1 | Viewed by 1837

Abstract

Chemotherapy-provoked peripheral neuropathy and its associated affective disorders are important adverse effects in cancer patients, and its treatment is not completely resolved. A recent study reveals a positive interaction between molecular hydrogen (H₂) and a heme oxygenase (HO-1) enzyme inducer, cobalt protoporphyrin IX (CoPP), in the inhibition of neuropathic pain provoked by nerve injury. Nevertheless, the efficacy of CoPP co-administered with hydrogen-rich water (HRW) on the allodynia and emotional disorders related to paclitaxel (PTX) administration has not yet been assessed. Using male C57BL/6 mice injected with PTX, we examined the effects of the co-administration of low doses of CoPP and HRW on mechanical and thermal allodynia and anxiodepressive-like behaviors triggered by PTX. Moreover, the impact of this combined treatment on the oxidative stress and inflammation caused by PTX in the amygdala (AMG) and dorsal root ganglia (DRG) were studied. Our results indicated that the antiallodynic actions of the co-administration of CoPP plus HRW are more rapid and higher than those given by each of them when independently administered. This combination inhibited anxiodepressive-like behaviors, the up-regulation of the inflammasome NLRP3 and 4-hydroxynonenal, as well as the high mRNA levels of some inflammatory mediators. This combination also increased the expression of NRF2, HO-1, superoxide dismutase 1, glutathione S-transferase mu 1, and/or the glutamate-cysteine ligase modifier subunit and decreased the protein levels of BACH1 in the DRG and/or AMG. Thus, it shows a positive interaction among HO-1 and H₂ systems in controlling PTX-induced neuropathy by modulating inflammation and activating the antioxidant system. This study recommends the co-administration of CoPP plus HRW as an effective treatment for PTX-provoked neuropathy and its linked emotive deficits. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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14 pages, 2484 KiB

Open AccessArticle

Antioxidant Activity of Bilirubin in Micellar and Liposomal Systems Is pH-Dependent

by Paweł Przybylski, Michał Żebrowski, Wojciech Witkowski, Martyna Cybularczyk-Cecotka and Grzegorz Litwinienko

Antioxidants 2024, 13(4), 426; https://doi.org/10.3390/antiox13040426 - 30 Mar 2024

Cited by 1 | Viewed by 1985

Abstract

Bilirubin (BR), a product of heme catabolism, plays a critical role in biological systems. Although increased levels of BR result in hyperbilirubinemia or jaundice, there is increasing evidence that lower concentrations substantially decrease the risk of oxidative stress-mediated diseases due to antioxidant functions of BR. We studied the radical-trapping ability of BR in two model systems, micellar and liposomal, at a broad pH range. At pH < 6.0, BR behaves as a retardant; however, at pH ≥ 6.0, BR becomes strong radical trapping antioxidant, with rate constants for reaction with lipidperoxyl radicals (k_inh) within the range from 1.2 × 10⁴ M⁻¹ s⁻¹ to 3.5 × 10⁴ M⁻¹ s⁻¹, and in liposomal system, the activity of BR is comparable to α-tocopherol. This transition is likely facilitated by the ionization of carboxyl groups, leading to a conformational shift in BR and improved solubility/localization at the water/lipid interface. This is the first experimental evidence of the role of pH on the antioxidant activity of bilirubin, and the observed pH-dependent radical-trapping ability of BR holds practical significance, particularly in jaundice treatment where light therapy targets the skin’s weakly acidic surface. Minor adjustments toward neutral or alkaline pH can enhance radical-trapping action of BR, thereby mitigating oxidative stress induced with blue or violet light exposure. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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16 pages, 8146 KiB

Open AccessArticle

The Inhibition of Neuropathic Pain Incited by Nerve Injury and Accompanying Mood Disorders by New Heme Oxygenase-1 Inducers: Mechanisms Implicated

by Irene Suárez-Rojas, Montse Pérez-Fernández, Xue Bai, Ignacio Martínez-Martel, Sebastiano Intagliata, Valeria Pittalà, Loredana Salerno and Olga Pol

Antioxidants 2023, 12(10), 1859; https://doi.org/10.3390/antiox12101859 - 13 Oct 2023

Cited by 7 | Viewed by 1931

Abstract

Neuropathic pain is a type of pain that persists for a long time and becomes pathological. Additionally, the anxiodepressive disorders derived from neuropathic pain are difficult to palliate with the current treatments and need to be resolved. Then, using male mice with neuropathic pain provoked by chronic constriction of the sciatic nerve (CCI), we analyzed and compared the analgesic actions produced by three new heme oxygenase 1 (HO-1) inducers, 1m, 1b, and 1a, with those performed by dimethyl fumarate (DMF). Their impact on the anxiety- and depressive-like comportments and the expression of the inflammasome NLRP3, Nrf2, and some antioxidant enzymes in the dorsal root ganglia (DRG) and amygdala (AMG) were also investigated. Results revealed that the administration of 1m, 1b, and DMF given orally for four days inhibited the allodynia and hyperalgesia caused by CCI, while 1a merely reduced the mechanical allodynia. However, in the first two days of treatment, the antiallodynic effects produced by 1m were higher than those of 1a and DMF, and its antihyperalgesic actions were greater than those produced by 1b, 1a, and DMF, revealing that 1m was the most effective compound. At four days of treatment, all drugs exerted anxiolytic and antidepressant effects, decreased the NLRP3 levels, and increased/normalized the Nrf2, HO-1, and superoxide dismutase 1 levels in DRG and AMG. Data indicated that the dual modulation of the antioxidant and inflammatory pathways produced by these compounds, especially 1m, is a new promising therapeutic approach for neuropathic pain and related emotional illnesses. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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16 pages, 2468 KiB

Open AccessArticle

Novel Heme Oxygenase-1 Inducers Palliate Inflammatory Pain and Emotional Disorders by Regulating NLRP3 Inflammasome and Activating the Antioxidant Pathway

by Montse Pérez-Fernández, Irene Suárez-Rojas, Xue Bai, Ignacio Martínez-Martel, Valeria Ciaffaglione, Valeria Pittalà, Loredana Salerno and Olga Pol

Antioxidants 2023, 12(10), 1794; https://doi.org/10.3390/antiox12101794 - 23 Sep 2023

Cited by 1 | Viewed by 2162

Abstract

Chronic pain caused by persistent inflammation is current in multiple diseases and has a strong negative impact on society. It is commonly associated with several mental illnesses, which can exert a negative influence on pain perception, and needs to be eradicated. Nevertheless, actual therapies are not sufficiently safe and effective. Recent reports demonstrate that the induction of heme oxygenase-1 (HO-1) enzyme produces analgesic effects in animals with osteoarthritis pain and reverses the grip strength loss caused by sciatic nerve crush. In this research, we evaluated the potential use of three new HO-1 inducers, 1m, 1a, and 1b, as well as dimethyl fumarate (DMF), for treating persistent inflammatory pain induced by the subplantar injection of complete Freud’s adjuvant and the functional deficits and emotional sickness associated. The modulator role of these treatments on the inflammatory and antioxidant pathways were also assessed. Our findings revealed that repeated treatment, for four days, with 1m, 1a, 1b, or DMF inhibited inflammatory pain, reversed grip strength deficits, and reversed the linked anxious- and depressive-like behaviors, with 1m being the most effective. These treatments also suppressed the up-regulation of the inflammasome NLRP3 and activated the expression of the Nrf2 transcription factor and the HO-1 and superoxide dismutase 1 enzymes in the paw and/or amygdala, thus revealing the anti-inflammatory and antioxidant capacity of these compounds during inflammatory pain. Results suggest the use of 1m, 1a, 1b, and DMF, particularly 1m, as promising therapies for inflammatory pain and the accompanying functional disabilities and emotional diseases. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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18 pages, 5162 KiB

Open AccessArticle

Veronica persica Ethanol Extract Ameliorates Dinitrochlorobenzene-Induced Atopic Dermatitis-like Skin Inflammation in Mice, Likely by Inducing Nrf2/HO-1 Signaling

by Ki-Shuk Shim, Musun Park, Won-Kyung Yang, Hanbyeol Lee, Seung-Hyung Kim, Byung-Kil Choo, Sungwook Chae, Ho-Kyoung Kim, Taesoo Kim and Ki-Mo Kim

Antioxidants 2023, 12(6), 1267; https://doi.org/10.3390/antiox12061267 - 13 Jun 2023

Cited by 8 | Viewed by 2596

Abstract

Atopic dermatitis (AD) is chronic allergic contact dermatitis with immune dysregulation. Veronica persica has pharmacological activity that prevents asthmatic inflammation by ameliorating inflammatory cell activation. However, the potential effects of the ethanol extract of V. persica (EEVP) on AD remain elusive. This study evaluated the activity and underlying molecular pathway of EEVP in two AD models: dinitrochlorobenzene (DNCB)-induced mice and interferon (IFN)-γ/tumor necrosis factor (TNF)-α-stimulated human HaCaT keratinocytes. EEVP attenuated the DNCB-induced increase in serum immunoglobulin E and histamine levels, mast cell counts in toluidine-blue-stained dorsal skin, inflammatory cytokine (IFN-γ, interleukin [IL]-4, IL-5, and IL-13) levels in cultured splenocytes, and the mRNA expression of IL6, IL13, IL31 receptor, CCR-3, and TNFα in dorsal tissue. Additionally, EEVP inhibited the IFN-γ/TNF-α-induced mRNA expression of IL6, IL13, and CXCL10 in HaCaT cells. Furthermore, EEVP restored the IFN-γ/TNF-α-induced downregulation of heme oxygenase (HO)-1 in HaCaT cells by inducing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. A molecular docking analysis demonstrated that EEVP components have a strong affinity to the Kelch-like ECH-associated protein 1 Kelch domain. In summary, EEVP inhibits inflammatory AD by attenuating immune cell activation and inducing the Nrf2/HO-1 signaling pathway in skin keratinocytes. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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25 pages, 8079 KiB

Open AccessArticle

Microglial Hemoxygenase-1 Deletion Reduces Inflammation in the Retina of Old Mice with Tauopathy

by José A. Fernández-Albarral, Elena Salobrar-García, José A. Matamoros, Cristina Fernández-Mendívil, Eric del Sastre, Lejing Chen, Rosa de Hoz, Inés López-Cuenca, Lidia Sánchez-Puebla, José M. Ramírez, Juan J. Salazar, Manuela G. Lopez and Ana I. Ramírez

Antioxidants 2022, 11(11), 2151; https://doi.org/10.3390/antiox11112151 - 30 Oct 2022

Cited by 2 | Viewed by 2734

Abstract

Tauopathies such as Alzheimer’s disease are characterized by the accumulation of neurotoxic aggregates of tau protein. With aging and, especially, in Alzheimer’s patients, the inducible enzyme heme oxygenase 1 (HO-1) progressively increases in microglia, causing iron accumulation, neuroinflammation, and neurodegeneration. The retina is an organ that can be readily accessed and can reflect changes that occur in the brain. In this context, we evaluated how the lack of microglial HO-1, using mice that do not express HO-1 in microglia (HMO-KO), impacts retinal macro and microgliosis of aged subjects (18 months old mice) subjected to tauopathy by intrahippocampal delivery of AAV-hTau^P301L (TAU). Our results show that although tauopathy, measured as anti-TAUY9 and anti-AT8 positive immunostaining, was not observed in the retina of WT-TAU or HMO-KO+TAU mice, a morphometric study of retinal microglia and macroglia showed significant retinal changes in the TAU group compared to the WT group, such as: (i) increased number of activated microglia, (ii) retraction of microglial processes, (iii) increased number of CD68+ microglia, and (iv) increased retinal area occupied by GFAP (AROA) and C3 (AROC3). This retinal inflammatory profile was reduced in HMO-KO+TAU mice. Conclusion: Reduction of microglial HO-1 could be beneficial to prevent tauopathy-induced neuroinflammation. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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15 pages, 2556 KiB

Open AccessArticle

Differential Effects of Arsenic in Drinking Water on Mouse Hepatic and Intestinal Heme Oxygenase-1 Expression

by Hui Li, Xiaoyu Fan, Xiangmeng Wu, Weiguo Han, Mary Kay Amistadi, Pengfei Liu, Donna Zhang, Jon Chorover, Xinxin Ding and Qing-Yu Zhang

Antioxidants 2022, 11(9), 1835; https://doi.org/10.3390/antiox11091835 - 18 Sep 2022

Cited by 1 | Viewed by 2442

Abstract

Arsenic exposure has been associated with the risks of various diseases, including cancers and metabolic diseases. The aim of this study was to examine the effects of arsenic exposure via drinking water on the expression of heme oxygenase-1 (HO-1), a major responsive gene to arsenic-induced oxidative stress, in mouse intestinal epithelial cells which is the first site of exposure for ingested arsenic, and the liver, a known target of arsenic toxicity. The expression of HO-1 was determined at mRNA, protein, or enzymic activity levels in mice exposed to sodium arsenite through drinking water, at various doses (0, 2.5, 10, 25, 100 ppm), and for various time periods (1, 3, 7, or 28 days). HO-1 was significantly induced in the intestine, but not liver, at arsenic doses of 25 ppm or lower. The intestinal HO-1 induction was seen in both males and females, plateaued within 1–3 days of exposure, and was accompanied by increases in microsomal HO activity. In mice exposed to 25-ppm of arsenite for 7 days, total arsenic and As(III) levels in intestinal epithelial cells were significantly higher than in the liver. These findings identify intestinal epithelial cells as likely preferential targets for arsenic toxicity and support further studies on the functional consequences of intestinal HO-1 induction. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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32 pages, 4185 KiB

Open AccessReview

Heme Oxygenase-1 and Its Role in Colorectal Cancer

by Jörg Fahrer, Simon Wittmann, Ann-Cathrin Wolf and Tina Kostka

Antioxidants 2023, 12(11), 1989; https://doi.org/10.3390/antiox12111989 - 10 Nov 2023

Cited by 16 | Viewed by 3218

Abstract

Heme oxygenase-1 (HO-1) is an enzyme located at the endoplasmic reticulum, which is responsible for the degradation of cellular heme into ferrous iron, carbon monoxide and biliverdin-IXa. In addition to this main function, the enzyme is involved in many other homeostatic, toxic and cancer-related mechanisms. In this review, we first summarize the importance of HO-1 in physiology and pathophysiology with a focus on the digestive system. We then detail its structure and function, followed by a section on the regulatory mechanisms that control HO-1 expression and activity. Moreover, HO-2 as important further HO isoform is discussed, highlighting the similarities and differences with regard to HO-1. Subsequently, we describe the direct and indirect cytoprotective functions of HO-1 and its breakdown products carbon monoxide and biliverdin-IXa, but also highlight possible pro-inflammatory effects. Finally, we address the role of HO-1 in cancer with a particular focus on colorectal cancer. Here, relevant pathways and mechanisms are presented, through which HO-1 impacts tumor induction and tumor progression. These include oxidative stress and DNA damage, ferroptosis, cell cycle progression and apoptosis as well as migration, proliferation, and epithelial-mesenchymal transition. Full article

(This article belongs to the Special Issue Experimental and Therapeutic Targeting of Heme Oxygenase)

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