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Protective and Detrimental Role of Heme Oxygenase-1: 2021
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Protective and Detrimental Role of Heme Oxygenase-1: 2021

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 16068

Special Issue Editor

Prof. Dr. Valeria Sorrenti

E-Mail Website
Guest Editor
Department of Drug Sciences, Universita degli Studi di Catania, Catania, Italy
Interests: the HO-1/HO-2 system and DDAH/NOS pathway in different biological systems and physiopathological conditions; evaluation of the biological activity of natural and newly synthesized molecules capable of interfering with the activity of various enzymes such as dihydrofolate reductase, nitric oxide synthetase (nNOS, eNOS, iNOS), heme oxygenase (HO-1, HO-2); identification of the biochemical mechanisms involved in the beneficial effect of nutraceuticals
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Special Issue Information

Dear Colleagues,

Heme oxygenase (HO) is the enzyme that catalyzes the regioselective oxidative catabolism of heme, with the simultaneous release of carbon monoxide (CO), ferrous iron (Fe2+), and biliverdin, which is then reduced to bilirubin. The first consequence of this enzymatic activity is a cyto-protective effect in various stress-related conditions. Two main isoforms of heme oxygenase are present in humans: HO-1, inducible, and HO-2, constitutive. HO-1 may be induced in many organs and tissues by a variety of stimuli, such as the same substrate heme, heat shock, ROS and stressful conditions. Therefore, its critical role is cell protection against such insults. HO-1 may be both up- and down-regulated. During the past decade, a large number of studies have been carried out to delineate the diverse roles of HO-1 in inflammatory, neurodegenerative and other stress conditions. Due to its cyto-protective effects, HO-1 up-regulation may be useful in many stress-related diseases. On the contrary, HO-1 over-expression may contribute to tissue injury under certain unfavorable conditions such as neurodegeneration and carcinogenesis. Therefore, HO-1 inhibition mediated by natural or synthetic compounds may be useful.

The Special Issue, “Protective and detrimental role of heme oxygenase-1”, of the International Journal of Molecular Sciences will include a selection of original research papers and reviews aimed to understanding the dual role (protective and detrimental) of HO-1 and the signaling pathway involved. Moreover, original research papers and reviews aimed at the identification of natural molecules or new synthetic compounds able to modulate HO-1 activity/expression will help make HO-1 a potential therapeutic target for the amelioration of various diseases.

Prof. Valeria Sorrenti
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • HO-1
  • oxidative stress
  • natural compounds
  • HO-1 inducers
  • HO-1 inhibitors

Published Papers (6 papers)

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Editorial

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3 pages, 184 KiB  
Editorial
Editorial of Special Issue “Protective and Detrimental Role of Heme Oxygenase-1”: 2021
by Valeria Sorrenti
Int. J. Mol. Sci. 2023, 24(5), 4386; https://doi.org/10.3390/ijms24054386 - 23 Feb 2023
Viewed by 795
Abstract
The Special Issue “Protective and detrimental role of heme oxygenase-1”(2021), in the International Journal of Molecular Sciences, includes original research papers and reviews aiming to understand the protective or detrimental role of HO-1 and the signaling pathway involved [...] Full article
(This article belongs to the Special Issue Protective and Detrimental Role of Heme Oxygenase-1: 2021)

Research

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13 pages, 2058 KiB  
Article
Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells
by Valeria Consoli, Valeria Sorrenti, Valeria Pittalà, Khaled Greish, Agata Grazia D’Amico, Giuseppe Romeo, Sebastiano Intagliata, Loredana Salerno and Luca Vanella
Int. J. Mol. Sci. 2022, 23(10), 5709; https://doi.org/10.3390/ijms23105709 - 20 May 2022
Cited by 21 | Viewed by 2875
Abstract
The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among [...] Read more.
The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among the BC subtypes, triple negative breast cancer (TNBC) is considered the most aggressive, and conventional drugs fail to provide long-term efficacy. In this context, our study’s purpose was to investigate the mechanism of ferroptosis in breast cancer cell lines and reveal the significance of heme oxygenase (HO) modulation in the process, providing new biochemical approaches. HO’s effect on BC was evaluated by MTT tests, gene silencing, Western blot analysis, and measurement of reactive oxygen species (ROS), glutathione (GSH) and lipid hydroperoxide (LOOH) levels. In order to assess HO’s implication, different approaches were exploited, using two distinct HO-1 inducers (hemin and curcumin), a well-known HO inhibitor (SnMP) and a selective HO-2 inhibitor. The data obtained showed HO’s contribution to the onset of ferroptosis; in particular, HO-1 induction seemed to accelerate the process. Moreover, our results suggest a potential role of HO-2 in erastin-induced ferroptosis. In view of the above, HO modulation in ferroptosis can offer a novel approach for breast cancer treatment. Full article
(This article belongs to the Special Issue Protective and Detrimental Role of Heme Oxygenase-1: 2021)
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14 pages, 2955 KiB  
Article
Spiro-Oxindole Skeleton Compounds Are Efficient Inhibitors for Indoleamine 2,3-Dioxygenase 1: An Attractive Target for Tumor Immunotherapy
by Daojing Yan, Jiakun Xu, Xiang Wang, Jiaxing Zhang, Gang Zhao, Yingwu Lin and Xiangshi Tan
Int. J. Mol. Sci. 2022, 23(9), 4668; https://doi.org/10.3390/ijms23094668 - 23 Apr 2022
Cited by 3 | Viewed by 2057
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable [...] Read more.
Indoleamine 2,3-dioxygenase 1 (IDO1) is an attractive heme enzyme for its significant function in cancer immunotherapy. Potent IDO1 inhibitors have been discovered for decades, whereas no clinical drugs are used for cancer treatment up to now. With the goal of developing medically valuable IDO inhibitors, we performed a systematic study of SAR405838 analogs with a spiro-oxindole skeleton in this study. Based on the expression and purification of human IDO1, the inhibitory activity of spiro-oxindole skeleton compounds to IDO1 was evaluated by IC50 and Ki values. The results demonstrated that inhibitor 3 exhibited the highest IDO1 inhibitory activity with IC50 at 7.9 μM among all inhibitors, which is ~six-fold of the positive control (4−PI). Moreover, inhibitor 3 was found to have the most effective inhibition of IDO1 in MCF-7 cancer cells without toxic effects. Molecular docking analysis revealed that the hydrophobic interaction stabilized the binding of inhibitor 3 to the IDO1 active site and made an explanation for the uncompetitive mode of inhibitors. Therefore, this study provides valuable insights into the screen of more potent IDO1 inhibitors for cancer immunotherapy. Full article
(This article belongs to the Special Issue Protective and Detrimental Role of Heme Oxygenase-1: 2021)
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14 pages, 4477 KiB  
Article
Heme Oxygenase-1 Induction by Cobalt Protoporphyrin Ameliorates Cholestatic Liver Disease in a Xenobiotic-Induced Murine Model
by Jung-Yeon Kim, Yongmin Choi, Jaechan Leem and Jeong Eun Song
Int. J. Mol. Sci. 2021, 22(15), 8253; https://doi.org/10.3390/ijms22158253 - 31 Jul 2021
Cited by 13 | Viewed by 2001
Abstract
Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that [...] Read more.
Cholestatic liver diseases can progress to end-stage liver disease and reduce patients’ quality of life. Although their underlying mechanisms are still incompletely elucidated, oxidative stress is considered to be a key contributor to these diseases. Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that displays antioxidant action. It has been found that this enzyme plays a protective role against various inflammatory diseases. However, the role of HO-1 in cholestatic liver diseases has not yet been investigated. Here, we examined whether pharmacological induction of HO-1 by cobalt protoporphyrin (CoPP) ameliorates cholestatic liver injury. To this end, a murine model of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet feeding was used. Administration of CoPP ameliorated liver damage and cholestasis with HO-1 upregulation in DDC diet-fed mice. Induction of HO-1 by CoPP suppressed the DDC diet-induced oxidative stress and hepatocyte apoptosis. In addition, CoPP attenuated cytokine production and inflammatory cell infiltration. Furthermore, deposition of the extracellular matrix and expression of fibrosis-related genes after DDC feeding were also decreased by CoPP. HO-1 induction decreased the number of myofibroblasts and inhibited the transforming growth factor-β pathway. Altogether, these data suggest that the pharmacological induction of HO-1 ameliorates cholestatic liver disease by suppressing oxidative stress, hepatocyte apoptosis, and inflammation. Full article
(This article belongs to the Special Issue Protective and Detrimental Role of Heme Oxygenase-1: 2021)
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Review

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19 pages, 1072 KiB  
Review
Beneficial and Detrimental Roles of Heme Oxygenase-1 in the Neurovascular System
by Yoon Kyung Choi and Young-Myeong Kim
Int. J. Mol. Sci. 2022, 23(13), 7041; https://doi.org/10.3390/ijms23137041 - 24 Jun 2022
Cited by 19 | Viewed by 3564
Abstract
Heme oxygenase (HO) has both beneficial and detrimental effects via its metabolites, including carbon monoxide (CO), biliverdin or bilirubin, and ferrous iron. HO-1 is an inducible form of HO that is upregulated by oxidative stress, nitric oxide, CO, and hypoxia, whereas HO-2 is [...] Read more.
Heme oxygenase (HO) has both beneficial and detrimental effects via its metabolites, including carbon monoxide (CO), biliverdin or bilirubin, and ferrous iron. HO-1 is an inducible form of HO that is upregulated by oxidative stress, nitric oxide, CO, and hypoxia, whereas HO-2 is a constitutive form that regulates vascular tone and homeostasis. In brains injured by trauma, ischemia-reperfusion, or Alzheimer’s disease (AD), the long-term expression of HO-1 can be detected, which can lead to cytotoxic ferroptosis via iron accumulation. In contrast, the transient induction of HO-1 in the peri-injured region may have regenerative potential (e.g., angiogenesis, neurogenesis, and mitochondrial biogenesis) and neurovascular protective effects through the CO-mediated signaling pathway, the antioxidant properties of bilirubin, and the iron-mediated ferritin synthesis. In this review, we discuss the dual roles of HO-1 and its metabolites in various neurovascular diseases, including age-related macular degeneration, ischemia-reperfusion injury, traumatic brain injury, Gilbert’s syndrome, and AD. Full article
(This article belongs to the Special Issue Protective and Detrimental Role of Heme Oxygenase-1: 2021)
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25 pages, 4636 KiB  
Review
Properties and Mechanisms of Flavin-Dependent Monooxygenases and Their Applications in Natural Product Synthesis
by Yaming Deng, Quan Zhou, Yuzhou Wu, Xi Chen and Fangrui Zhong
Int. J. Mol. Sci. 2022, 23(5), 2622; https://doi.org/10.3390/ijms23052622 - 27 Feb 2022
Cited by 13 | Viewed by 3768
Abstract
Natural products are usually highly complicated organic molecules with special scaffolds, and they are an important resource in medicine. Natural products with complicated structures are produced by enzymes, and this is still a challenging research field, its mechanisms requiring detailed methods for elucidation. [...] Read more.
Natural products are usually highly complicated organic molecules with special scaffolds, and they are an important resource in medicine. Natural products with complicated structures are produced by enzymes, and this is still a challenging research field, its mechanisms requiring detailed methods for elucidation. Flavin adenine dinucleotide (FAD)-dependent monooxygenases (FMOs) catalyze many oxidation reactions with chemo-, regio-, and stereo-selectivity, and they are involved in the synthesis of many natural products. In this review, we introduce the mechanisms for different FMOs, with the classical FAD (C4a)-hydroperoxide as the major oxidant. We also summarize the difference between FMOs and cytochrome P450 (CYP450) monooxygenases emphasizing the advantages of FMOs and their specificity for substrates. Finally, we present examples of FMO-catalyzed synthesis of natural products. Based on these explanations, this review will expand our knowledge of FMOs as powerful enzymes, as well as implementation of the FMOs as effective tools for biosynthesis. Full article
(This article belongs to the Special Issue Protective and Detrimental Role of Heme Oxygenase-1: 2021)
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