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Special Issue "Natural, Semi-Synthetic and Synthetic Compounds Acting on Heme Oxygenase System"

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

Deadline for manuscript submissions: closed (30 October 2020).

Special Issue Editors

Prof. Dr. Loredana Salerno
E-Mail Website
Guest Editor
Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy
Interests: leukemia; cml; heme oxygenase inhibitors; ho-!; ho-2; imidazole derivatives; imatinib
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Valeria Pittalà
E-Mail Website
Guest Editor
Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy
Interests: heme oxygenase; HO-1 inducers; enzyme inhibitors; serotonergic receptors; medicinal chemistry

Special Issue Information

Dear Colleagues,

Heme oxygenases (HOs) are a family of enzymes responsible for the regioselective catabolism of the pro-oxidant heme into carbon monoxide, biliverdin, and bilirubin. Between the isoforms identified so far, HO-1 is a highly inducible, stress-responsive protein, well-known for its cyto-protective effects. In addition, the migration of HO-1 into the nucleus exerts important non-enzymatic protective signaling functions. The induction of HO-1 expression represents a powerful tool in the management of all those diseases in which oxidative stress plays a role. Several natural compounds, acting as HO-1 inducers, possess a number of pharmacological effects, as evidenced by the growing number of papers. However, HO-1 also exerts its cytoprotective role in tumor cells, and the aberrant overexpression of HO-1 has been observed in several cancers and in some neurodegenerative diseases. Particularly, the expression of HO-1 increases in response to anticancer treatments, and it seems to be involved at the onset of drug resistance. Therefore, it is conceivable that HO-1 inhibitors can be regarded as potential antitumor agents and cancer treatment enhancers under regimens of chemotherapy, radiotherapy, or photodynamic therapy.

This Special Issue will encompass a selection of original research papers and reviews aimed to highlight the beneficial effects of HO induction or inhibition through natural, synthetic and semi-syntetic agents.

Prof. Dr. Loredana Salerno
Prof. Dr. Valeria Pittalà
Guest Editors

Manuscript Submission Information

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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.

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Keywords

  • Heme oxygenase-1
  • Heme oxygenase-2
  • Carbon monoxide
  • Biliverdin
  • Bilirubin
  • Inducers
  • Inhibitors
  • Natural compounds
  • Imidazole
  • Cancer.

Published Papers (9 papers)

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Research

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Communication
Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure
Int. J. Mol. Sci. 2020, 21(24), 9541; https://doi.org/10.3390/ijms21249541 - 15 Dec 2020
Cited by 1 | Viewed by 580
Abstract
Novel heme oxygenase-1 (HO-1) inducers based on dimethyl fumarate (DMF) structure are reported in this paper. These compounds are obtained by modification of the DMF backbone. Particularly, maintaining the α, β-unsaturated dicarbonyl function as the central chain crucial for HO-1 induction, different substituted [...] Read more.
Novel heme oxygenase-1 (HO-1) inducers based on dimethyl fumarate (DMF) structure are reported in this paper. These compounds are obtained by modification of the DMF backbone. Particularly, maintaining the α, β-unsaturated dicarbonyl function as the central chain crucial for HO-1 induction, different substituted or unsubstituted phenyl rings are introduced by means of an ester or amide linkage. Symmetric and asymmetric derivatives are synthesized. All compounds are tested on a human hepatic stellate cell line LX-2 to assay their capacity for modifying HO-1 expression. Compounds 1b, 1l and 1m stand out for their potency as HO-1 inducers, being 2–3 fold more active than DMF, and for their ability to reverse reactive oxygen species (ROS) production mediated using palmitic acid (PA). These properties, coupled with a low toxicity toward LX-2 cell lines, make these compounds potentially useful for treatment of diseases in which HO-1 overexpression may counteract inflammation, such as hepatic fibrosis. Docking studies show a correlation between predicted binding free energy and experimental HO-1 expression data. These preliminary results may support the development of new approaches in the management of liver fibrosis. Full article
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Article
A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women, Menopause, and “Medical Cannabinoids”
Int. J. Mol. Sci. 2020, 21(22), 8801; https://doi.org/10.3390/ijms21228801 - 20 Nov 2020
Viewed by 750
Abstract
Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in [...] Read more.
Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in an estrogen-depleted rat model. Sham-operated (SO) and surgically induced estrogen-deficient (OVX) female Wistar rats were used. During a two-week period, a group of OVX rats received 0.1 mg/kg estrogen (E2) per os, while AEA-induced alterations were analyzed after two weeks of AEA treatment at the dose of 1.0 mg/kg. At the end of the experiment, cardiac activity and expression of HO and NOS enzymes, content of cannabinoid 1 receptor, as well as concentrations of transient potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) were measured. Our results show that estrogen withdrawal caused a significant decrease in both NOS and HO systems, and a similar tendency was observed regarding the TRPV1/CGRP pathway. Two weeks of either AEA or E2 treatment restored the adverse changes; however, the combined administration of these two molecules did not result in a further improvement. In light of the potential relationship between AEA and HO/NOS systems, AEA-induced upregulation of HO/NOS enzymes may be a therapeutic strategy in estrogen-deficient conditions. Full article
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Article
The Extent of Intracellular Accumulation of Bilirubin Determines Its Anti- or Pro-Oxidant Effect
Int. J. Mol. Sci. 2020, 21(21), 8101; https://doi.org/10.3390/ijms21218101 - 30 Oct 2020
Cited by 4 | Viewed by 711
Abstract
Background: Severe hyperbilirubinemia can cause permanent neurological damage in particular in neonates, whereas mildly elevated serum bilirubin protects from various oxidative stress-mediated diseases. The present work aimed to establish the intracellular unconjugated bilirubin concentrations (iUCB) thresholds differentiating between anti- and pro-oxidant effects. Methods: [...] Read more.
Background: Severe hyperbilirubinemia can cause permanent neurological damage in particular in neonates, whereas mildly elevated serum bilirubin protects from various oxidative stress-mediated diseases. The present work aimed to establish the intracellular unconjugated bilirubin concentrations (iUCB) thresholds differentiating between anti- and pro-oxidant effects. Methods: Hepatic (HepG2), heart endothelial (H5V), kidney tubular (HK2) and neuronal (SH-SY5Y) cell lines were exposed to increasing concentration of bilirubin. iUCB, cytotoxicity, intracellular reactive oxygen species (ROS) concentrations, and antioxidant capacity (50% efficacy concentration (EC50)) were determined. Results: Exposure of SH-SY5Y to UCB concentration > 3.6 µM (iUCB of 25 ng/mg) and >15 µM in H5V and HK2 cells (iUCB of 40 ng/mg) increased intracellular ROS production (p < 0.05). EC50 of the antioxidant activity was 21 µM (iUCB between 5.4 and 21 ng/mg) in HepG2 cells, 0.68 µM (iUCB between 3.3 and 7.5 ng/mg) in SH-SY5Y cells, 2.4 µM (iUCB between 3 and 6.7 ng/mg) in HK2 cells, and 4 µM (iUCB between 4.7 and 7.5 ng/mg) in H5V cells. Conclusions: In all the cell lines studied, iUCB of around 7 ng/mg protein had antioxidant activities, while iUCB > 25 ng/mg protein resulted in a prooxidant and cytotoxic effects. UCB metabolism was found to be cell-specific resulting in different iUCB. Full article
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Article
Cold Press Pomegranate Seed Oil Attenuates Dietary-Obesity Induced Hepatic Steatosis and Fibrosis through Antioxidant and Mitochondrial Pathways in Obese Mice
Int. J. Mol. Sci. 2020, 21(15), 5469; https://doi.org/10.3390/ijms21155469 - 31 Jul 2020
Cited by 13 | Viewed by 1585
Abstract
Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial [...] Read more.
Aim: Obesity is associated with metabolic syndrome, hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes. In this study, we investigated whether the dietary supplementation of pomegranate seed oil (PSO) exerted a protective effect on liver lipid uptake, fibrosis, and mitochondrial function in a mouse model of obesity and insulin resistance. Method: In this in vivo study, eight-week-old C57BL/6J male mice were fed with a high fat diet (HFD) for 24 weeks and then were divided into three groups as follows: group (1) Lean; group (n = 6) (2) HF diet; group (n = 6) (3) HF diet treated with PSO (40 mL/kg food) (n = 6) for eight additional weeks starting at 24 weeks. Physiological parameters, lipid droplet accumulation, inflammatory biomarkers, antioxidant biomarkers, mitochondrial biogenesis, insulin sensitivity, and hepatic fibrosis were determined to examine whether PSO intervention prevents obesity-associated metabolic syndrome. Results: The PSO group displayed an increase in oxygen consumption, as well as a decrease in fasting glucose and blood pressure (p < 0.05) when compared to the HFD-fed mice group. PSO increased both the activity and expression of hepatic HO-1, downregulated inflammatory adipokines, and decreased hepatic fibrosis. PSO increased the levels of thermogenic genes, mitochondrial signaling, and lipid metabolism through increases in Mfn2, OPA-1, PRDM 16, and PGC1α. Furthermore, PSO upregulated obesity-mediated hepatic insulin receptor phosphorylation Tyr-972, p-IRB tyr1146, and pAMPK, thereby decreasing insulin resistance. Conclusions: These results indicated that PSO decreased obesity-mediated insulin resistance and the progression of hepatic fibrosis through an improved liver signaling, as manifested by increased insulin receptor phosphorylation and thermogenic genes. Furthermore, our findings indicate a potential therapeutic role for PSO in the prevention of obesity-associated NAFLD, NASH, and other metabolic disorders. Full article
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Article
Neuroprotective and Anti-Inflammatory Effects of Kuwanon C from Cudrania tricuspidata Are Mediated by Heme Oxygenase-1 in HT22 Hippocampal Cells, RAW264.7 Macrophage, and BV2 Microglia
Int. J. Mol. Sci. 2020, 21(14), 4839; https://doi.org/10.3390/ijms21144839 - 08 Jul 2020
Cited by 7 | Viewed by 1179
Abstract
Heme oxygenase (HO)-1 is a detoxifying phase II enzyme that plays a role in both inflammatory and oxidative stress responses. Curdrania tricuspidata is widespread throughout East Asia and is used as a therapeutic agent in traditional medicine. We investigated whether treatment with sixteen [...] Read more.
Heme oxygenase (HO)-1 is a detoxifying phase II enzyme that plays a role in both inflammatory and oxidative stress responses. Curdrania tricuspidata is widespread throughout East Asia and is used as a therapeutic agent in traditional medicine. We investigated whether treatment with sixteen flavonoid or xanthone compounds from C. tricuspidata could induce HO-1 expression in HT22 hippocampal cells, RAW264.7 macrophage, and BV2 microglia. In these compounds, kuwanon C showed the most remarkable HO-1 expression effects. In addition, treatment with kuwanon C reduced cytoplasmic nuclear erythroid 2-related factor (Nrf2) expression and increased Nrf2 expression in the nucleus. Significant inhibition of glutamate-induced oxidative injury and induction of reactive oxygen species (ROS) occurred when HT22 hippocampal cells were pretreated with kuwanon C. The levels of inflammatory mediator and cytokine, which increased following lipopolysaccharide (LPS) stimulation, were suppressed in RAW264.7 macrophage and BV2 microglia after kuwanon C pretreatment. Kuwanon C also attenuated p65 DNA binding and translocation into the nucleus in LPS-induced RAW264.7 and BV2 cells. The anti-inflammatory, anti-neuroinflammatory, and neuroprotective effects of kuwanon C were reversed when co-treatment with HO-1 inhibitor of tin protoporphyrin-IX (SnPP). These results suggest that the neuroprotective and anti-inflammatory effects of kuwanon C are regulated by HO-1 expression. Full article
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Article
New Arylethanolimidazole Derivatives as HO-1 Inhibitors with Cytotoxicity against MCF-7 Breast Cancer Cells
Int. J. Mol. Sci. 2020, 21(6), 1923; https://doi.org/10.3390/ijms21061923 - 11 Mar 2020
Cited by 12 | Viewed by 1122
Abstract
In this paper, a novel series of imidazole-based heme oxygenase-1 (HO-1) inhibitors is reported. These compounds were obtained by modifications of previously described high potent and selective arylethanolimidazoles. In particular, simplification of the central linker and repositioning of the hydrophobic portion were carried [...] Read more.
In this paper, a novel series of imidazole-based heme oxygenase-1 (HO-1) inhibitors is reported. These compounds were obtained by modifications of previously described high potent and selective arylethanolimidazoles. In particular, simplification of the central linker and repositioning of the hydrophobic portion were carried out. Results indicate that a hydroxyl group in the central region is crucial for the potency as well as the spatial distribution of the hydrophobic portion. Docking studies revealed a similar interaction of the classical HO-1 inhibitors with the active site of the protein. The most potent and selective compound (5a) was tested for its potential cytotoxic activity against hormone-sensitive and hormone-resistant breast cancer cell lines (MCF-7 and MDA-MB-231). Full article
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Review

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Review
Immune Modulation by Inhibitors of the HO System
Int. J. Mol. Sci. 2021, 22(1), 294; https://doi.org/10.3390/ijms22010294 - 30 Dec 2020
Cited by 5 | Viewed by 1036
Abstract
The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely [...] Read more.
The heme oxygenase (HO) system involves three isoforms of this enzyme, HO-1, HO-2, and HO-3. The three of them display the same catalytic activity, oxidating the heme group to produce biliverdin, ferrous iron, and carbon monoxide (CO). HO-1 is the isoform most widely studied in proinflammatory diseases because treatments that overexpress this enzyme promote the generation of anti-inflammatory products. However, neonatal jaundice (hyperbilirubinemia) derived from HO overexpression led to the development of inhibitors, such as those based on metaloproto- and meso-porphyrins inhibitors with competitive activity. Further, non-competitive inhibitors have also been identified, such as synthetic and natural imidazole-dioxolane-based, small synthetic molecules, inhibitors of the enzyme regulation pathway, and genetic engineering using iRNA or CRISPR cas9. Despite most of the applications of the HO inhibitors being related to metabolic diseases, the beneficial effects of these molecules in immune-mediated diseases have also emerged. Different medical implications, including cancer, Alzheimer´s disease, and infections, are discussed in this article and as to how the selective inhibition of HO isoforms may contribute to the treatment of these ailments. Full article
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Review
Natural Product Heme Oxygenase Inducers as Treatment for Nonalcoholic Fatty Liver Disease
Int. J. Mol. Sci. 2020, 21(24), 9493; https://doi.org/10.3390/ijms21249493 - 14 Dec 2020
Cited by 7 | Viewed by 1096
Abstract
Heme oxygenase (HO) is a critical component of the defense mechanism to a wide variety of cellular stressors. HO induction affords cellular protection through the breakdown of toxic heme into metabolites, helping preserve cellular integrity. Nonalcoholic fatty liver disease (NAFLD) is a pathological [...] Read more.
Heme oxygenase (HO) is a critical component of the defense mechanism to a wide variety of cellular stressors. HO induction affords cellular protection through the breakdown of toxic heme into metabolites, helping preserve cellular integrity. Nonalcoholic fatty liver disease (NAFLD) is a pathological condition by which the liver accumulates fat. The incidence of NAFLD has reached all-time high levels driven primarily by the obesity epidemic. NALFD can progress to nonalcoholic steatohepatitis (NASH), advancing further to liver cirrhosis or cancer. NAFLD is also a contributing factor to cardiovascular and metabolic diseases. There are currently no drugs to specifically treat NAFLD, with most treatments focused on lifestyle modifications. One emerging area for NAFLD treatment is the use of dietary supplements such as curcumin, pomegranate seed oil, milk thistle oil, cold-pressed Nigella Satvia oil, and resveratrol, among others. Recent studies have demonstrated that several of these natural dietary supplements attenuate hepatic lipid accumulation and fibrosis in NAFLD animal models. The beneficial actions of several of these compounds are associated with the induction of heme oxygenase-1 (HO-1). Thus, targeting HO-1 through dietary-supplements may be a useful therapeutic for NAFLD either alone or with lifestyle modifications. Full article
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Review
Pathophysiology of Peripheral Arterial Disease (PAD): A Review on Oxidative Disorders
Int. J. Mol. Sci. 2020, 21(12), 4393; https://doi.org/10.3390/ijms21124393 - 20 Jun 2020
Cited by 5 | Viewed by 1049
Abstract
Peripheral arterial disease (PAD) is an atherosclerotic disease that affects a wide range of the world’s population, reaching up to 200 million individuals worldwide. PAD particularly affects elderly individuals (>65 years old). PAD is often underdiagnosed or underestimated, although specificity in diagnosis is [...] Read more.
Peripheral arterial disease (PAD) is an atherosclerotic disease that affects a wide range of the world’s population, reaching up to 200 million individuals worldwide. PAD particularly affects elderly individuals (>65 years old). PAD is often underdiagnosed or underestimated, although specificity in diagnosis is shown by an ankle/brachial approach, and the high cardiovascular event risk that affected the PAD patients. A number of pathophysiologic pathways operate in chronic arterial ischemia of lower limbs, giving the possibility to improve therapeutic strategies and the outcome of patients. This review aims to provide a well detailed description of such fundamental issues as physical exercise, biochemistry of physical exercise, skeletal muscle in PAD, heme oxygenase 1 (HO-1) in PAD, and antioxidants in PAD. These issues are closely related to the oxidative stress in PAD. We want to draw attention to the pathophysiologic pathways that are considered to be beneficial in order to achieve more effective options to treat PAD patients. Full article
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