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Antioxidants
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Pharmacological and Clinical Significance of Heme Oxygenase-1 2022
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Pharmacological and Clinical Significance of Heme Oxygenase-1 2022

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 32300

Special Issue Editor

Dr. David E. Stec

E-Mail Website
Guest Editor
Center for Excellence in Cardiovascular-Renal Research, Department of Physiology & Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 392161, USA
Interests: obesity; diabetes; hypertension; cardiovascular disease; heme oxygenase; bilirubin; biliverdin reductase; antioxidants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The Special Issue will continue to focus on the most up-to-date knowledge concerning the pharmacology and clinical applications of the enzyme heme oxygenase-1 (HO-1) that plays a critical role in the catabolism of heme to the bile pigment bilirubin, generating carbon monoxide (CO) and releasing iron, which is sequestered by ferritin.

This Special Issue will highlight the wealth of research on the hereditary and acquired disorders of heme metabolism and the role of dietary regulation of heme-containing proteins via hormonal and chemical actions as well as on the genetic and acquired disorders associated with such diseases as neonatal jaundice and hemochromatosis.

In recent years, the discovery of non-heme-containing inducers of HO-1 has resulted in new discoveries regarding the metabolic and cardiovascular effects of the upregulation of HO activity. This is especially relevant to a wide variety of natural product HO-1 inducers, which have the potential for important pharmaceutical and clinical applications, all of which will be highlighted in this Special Issue.

The HO-1 system plays an important role in cellular defense in the context of several diseases or physiological processes, including cardiovascular disease, diabetes, obesity, inflammation, neurodegeneration and ageing, and transplantation, among many others. The HO-derived metabolites CO and bilirubin also play an important physiological role and could be a source of clinical therapeutics for several diseases. CO-releasing molecules have potential therapeutic uses for vascular disease as well as obesity. Bilirubin has recently been discovered to have hormone-like functions that could be very beneficial for cardiovascular and metabolic diseases. The importance of the heme degradation pathway to pharmacology and clinical medicine has increased significantly over the past several years, with over 35,000 manuscripts published in this area.

This Special Issue will continue to highlight the diverse role that HO-1 and its metabolites play in numerous physiological functions and how this system can offer potential therapeutics for several diseases. We welcome submissions from a broad range of disciplines, which may highlight a novel function or therapeutic application of this important pathway.

Dr. David E. Stec
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. Antioxidants is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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.

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18 pages, 2749 KiB  
Article
Hyperforin Enhances Heme Oxygenase-1 Expression Triggering Lipid Peroxidation in BRAF-Mutated Melanoma Cells and Hampers the Expression of Pro-Metastatic Markers
by Alessia Cardile, Carlotta Passarini, Valentina Zanrè, Alessandra Fiore and Marta Menegazzi
Antioxidants 2023, 12(7), 1369; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12071369 - 30 Jun 2023
Cited by 1 | Viewed by 1712
Abstract
Hyperforin (HPF) is an acylphloroglucinol compound found abundantly in Hypericum perforatum extract which exhibits antidepressant, anti-inflammatory, antimicrobial, and antitumor activities. Our recent study revealed a potent antimelanoma effect of HPF, which hinders melanoma cell proliferation, motility, colony formation, and induces apoptosis. Furthermore, we [...] Read more.
Hyperforin (HPF) is an acylphloroglucinol compound found abundantly in Hypericum perforatum extract which exhibits antidepressant, anti-inflammatory, antimicrobial, and antitumor activities. Our recent study revealed a potent antimelanoma effect of HPF, which hinders melanoma cell proliferation, motility, colony formation, and induces apoptosis. Furthermore, we have identified glutathione peroxidase-4 (GPX-4), a key enzyme involved in cellular protection against iron-induced lipid peroxidation, as one of the molecular targets of HPF. Thus, in three BRAF-mutated melanoma cell lines, we investigated whether iron unbalance and lipid peroxidation may be a part of the molecular mechanisms underlying the antimelanoma activity of HPF. Initially, we focused on heme oxygenase-1 (HO-1), which catalyzes the heme group into CO, biliverdin, and free iron, and observed that HPF treatment triggered the expression of this inducible enzyme. In order to investigate the mechanism involved in HO-1 induction, we verified that HPF downregulates the BTB and CNC homology 1 (BACH-1) transcription factor, an inhibitor of the heme oxygenase 1 (HMOX-1) gene transcription. Remarkably, we observed a partial recovery of cell viability and an increase in the expression of the phosphorylated and active form of retinoblastoma protein when we suppressed the HMOX-1 gene using HMOX-1 siRNA while HPF was present. This suggests that the HO-1 pathway is involved in the cytostatic effect of HPF in melanoma cells. To explore whether lipid peroxidation is induced, we conducted cytofluorimetric analysis and observed a significant increase in the fluorescence of the BODIPY C-11 probe 48 h after HPF administration in all tested melanoma cell lines. To discover the mechanism by which HPF triggers lipid peroxidation, along with the induction of HO-1, we examined the expression of additional proteins associated with iron homeostasis and lipid peroxidation. After HPF administration, we confirmed the downregulation of GPX-4 and observed low expression levels of SLC7A11, a cystine transporter crucial for the glutathione production, and ferritin, able to sequester free iron. A decreased expression level of these proteins can sensitize cells to lipid peroxidation. On the other hand, HPF treatment resulted in increased expression levels of transferrin, which facilitates iron uptake, and LC3B proteins, a molecular marker of autophagy induction. Indeed, ferritin and GPX-4 have been reported to be digested during autophagy. Altogether, these findings suggest that HPF induced lipid peroxidation likely through iron overloading and decreasing the expression of proteins that protect cells from lipid peroxidation. Finally, we examined the expression levels of proteins associated with melanoma cell invasion and metastatic potential. We observed the decreased expression of CD133, octamer-4, tyrosine-kinase receptor AXL, urokinase plasminogen activator receptor, and metalloproteinase-2 following HPF treatment. These findings provide further support for our previous observations, demonstrating the inhibitory effects of HPF on cell motility and colony formation in soft agar, which are both metastasis-related processes in tumor cells. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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14 pages, 2059 KiB  
Article
High Heme and Low Heme Oxygenase-1 Are Associated with Mast Cell Activation/Degranulation in HIV-Induced Chronic Widespread Pain
by Tanima Chatterjee, Itika Arora, Lilly Underwood, Anastasiia Gryshyna, Terry L. Lewis, Juan Xavier Masjoan Juncos, Burel R. Goodin, Sonya Heath and Saurabh Aggarwal
Antioxidants 2023, 12(6), 1213; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12061213 - 03 Jun 2023
Cited by 1 | Viewed by 1636
Abstract
An overwhelming number of people with HIV (PWH) experience chronic widespread pain (CWP) throughout their lifetimes. Previously, we demonstrated that PWH with CWP have increased hemolysis and attenuated heme oxygenase 1 (HO-1) levels. HO-1 degrades reactive, cell-free heme into antioxidants like biliverdin and [...] Read more.
An overwhelming number of people with HIV (PWH) experience chronic widespread pain (CWP) throughout their lifetimes. Previously, we demonstrated that PWH with CWP have increased hemolysis and attenuated heme oxygenase 1 (HO-1) levels. HO-1 degrades reactive, cell-free heme into antioxidants like biliverdin and carbon monoxide (CO). We found that high heme or low HO-1 caused hyperalgesia in animals, likely through multiple mechanisms. In this study, we hypothesized that high heme or low HO-1 caused mast cell activation/degranulation, resulting in the release of pain mediators like histamine and bradykinin. PWH who self-report CWP were recruited from the University of Alabama at Birmingham HIV clinic. Animal models included HO-1−/− mice and hemolytic mice, where C57BL/6 mice were injected intraperitoneally with phenylhydrazine hydrochloride (PHZ). Results demonstrated that plasma histamine and bradykinin were elevated in PWH with CWP. These pain mediators were also high in HO-1−/− mice and in hemolytic mice. Both in vivo and in vitro (RBL-2H3 mast cells), heme-induced mast cell degranulation was inhibited by treatment with CORM-A1, a CO donor. CORM-A1 also attenuated mechanical and thermal (cold) allodynia in hemolytic mice. Together, the data suggest that mast cell activation secondary to high heme or low HO-1 seen in cells and animals correlates with elevated plasma levels of heme, histamine, and bradykinin in PWH with CWP. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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13 pages, 2168 KiB  
Article
Bilirubin Levels Are Negatively Correlated with Adiposity in Obese Men and Women, and Its Catabolized Product, Urobilin, Is Positively Associated with Insulin Resistance
by Zachary A. Kipp, Mei Xu, Evelyn A. Bates, Wang-Hsin Lee, Philip A. Kern and Terry D. Hinds, Jr.
Antioxidants 2023, 12(1), 170; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12010170 - 11 Jan 2023
Cited by 15 | Viewed by 5017
Abstract
Bilirubin levels in obese humans and rodents have been shown to be lower than in their lean counterparts. Some studies have proposed that the glucuronyl UGT1A1 enzyme that clears bilirubin from the blood increases in the liver with obesity. UGT1A1 clearance of bilirubin [...] Read more.
Bilirubin levels in obese humans and rodents have been shown to be lower than in their lean counterparts. Some studies have proposed that the glucuronyl UGT1A1 enzyme that clears bilirubin from the blood increases in the liver with obesity. UGT1A1 clearance of bilirubin allows more conjugated bilirubin to enter the intestine, where it is catabolized into urobilin, which can be then absorbed via the hepatic portal vein. We hypothesized that when bilirubin levels are decreased, the urobilin increases in the plasma of obese humans, as compared to lean humans. To test this, we measured plasma levels of bilirubin and urobilin, body mass index (BMI), adiposity, blood glucose and insulin, and HOMA IR in a small cohort of obese and lean men and women. We found that bilirubin levels negatively correlated with BMI and adiposity in obese men and women, as compared to their lean counterparts. Contrarily, urobilin levels were positively associated with adiposity and BMI. Only obese women were found to be insulin resistant based on significantly higher HOMA IR, as compared to lean women. The urobilin levels were positively associated with HOMA IR in both groups, but women had a stronger linear correlation. These studies indicate that plasma urobilin levels are associated with obesity and its comorbidities, such as insulin resistance. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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14 pages, 1220 KiB  
Article
Serum Bilirubin and Markers of Oxidative Stress and Inflammation in a Healthy Population and in Patients with Various Forms of Atherosclerosis
by Libor Vítek, Alena Jirásková, Ivana Malíková, Gabriela Dostálová, Lenka Eremiášová, Vilém Danzig, Aleš Linhart and Martin Haluzík
Antioxidants 2022, 11(11), 2118; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11112118 - 27 Oct 2022
Cited by 7 | Viewed by 1874
Abstract
Oxidative stress and inflammation contribute significantly to atherogenesis. We and others have demonstrated that mildly elevated serum bilirubin levels protect against coronary and peripheral atherosclerosis, most likely due to the antioxidant and anti-inflammatory activities of bilirubin. The aim of the present study was [...] Read more.
Oxidative stress and inflammation contribute significantly to atherogenesis. We and others have demonstrated that mildly elevated serum bilirubin levels protect against coronary and peripheral atherosclerosis, most likely due to the antioxidant and anti-inflammatory activities of bilirubin. The aim of the present study was to assess serum bilirubin and the markers of oxidative stress and inflammation in both healthy subjects and patients with various forms of atherosclerosis. The study was performed in patients with premature myocardial infarction (n = 129), chronic ischemic heart disease (n = 43), peripheral artery disease (PAD, n = 69), and healthy subjects (n = 225). In all subjects, standard serum biochemistry, UGT1A1 genotypes, total antioxidant status (TAS), and concentrations of various pro- and anti-inflammatory chemokines were determined. Compared to controls, all atherosclerotic groups had significantly lower serum bilirubin and TAS, while having much higher serum high-sensitivity C-reactive protein (hsCRP) and most of the analyzed proinflammatory cytokines (p < 0.05 for all comparisons). Surprisingly, the highest inflammation, and the lowest antioxidant status, together with the lowest serum bilirubin, was observed in PAD patients, and not in premature atherosclerosis. In conclusion, elevated serum bilirubin is positively correlated with TAS, and negatively related to inflammatory markers. Compared to healthy subjects, patients with atherosclerosis have a much higher degree of oxidative stress and inflammation. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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16 pages, 2975 KiB  
Article
Hemoxygenase-1 Promotes Head and Neck Cancer Cell Viability
by Marilina Mascaró, Exequiel G. Alonso, Karen Schweitzer, Martín E. Rabassa, Jessica A. Carballido, Agustina Ibarra, Eliana N. Alonso, Vicente Bermúdez, Lucía Fernández Chavez, Georgina P. Coló, María Julia Ferronato, Pamela Pichel, Sergio Recio, Valentina Clemente, Maria Eugenia Fermento, María Marta Facchinetti and Alejandro C. Curino
Antioxidants 2022, 11(10), 2077; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11102077 - 21 Oct 2022
Cited by 1 | Viewed by 1648
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a remarkably heterogeneous disease with around 50% mortality, a fact that has prompted researchers to try new approaches to improve patient survival. Hemoxygenase-1 (HO-1) is the rate-limiting step for heme degradation into carbon monoxide, free [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is a remarkably heterogeneous disease with around 50% mortality, a fact that has prompted researchers to try new approaches to improve patient survival. Hemoxygenase-1 (HO-1) is the rate-limiting step for heme degradation into carbon monoxide, free iron and biliverdin. We have previously reported that HO-1 protein is upregulated in human HNSCC samples and that it is localized in the cytoplasmic and nuclear compartments; additionally, we have demonstrated that HO-1 nuclear localization is associated with malignant progression. In this work, by using pharmacological and genetic experimental approaches, we begin to elucidate the mechanisms through which HO-1 plays a role in HNSCC. We found that high HO-1 mRNA was associated with decreased patient survival in early stages of HNSCC. In vitro experiments have shown that full-length HO-1 localizes in the cytoplasm, and that, depending on its enzymatic activity, it increases cell viability and promotes cell cycle progression. Instead, HO-1 does not alter migration capacity. Furthermore, we show that C-terminal truncated HO-1 localizes into the nucleus, increases cell viability and promotes cell cycle progression. In conclusion, we herein demonstrate that HO-1 displays protumor activities in HNSCC that depend, at least in part, on the nuclear localization of HO-1. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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18 pages, 6366 KiB  
Article
Identification of Cytoprotective Small-Molecule Inducers of Heme-Oxygenase-1
by Gelare Ghajar-Rahimi, Amie M. Traylor, Bini Mathew, James R. Bostwick, N Miranda Nebane, Anna A. Zmijewska, Stephanie K. Esman, Saakshi Thukral, Ling Zhai, Vijaya Sambandam, Rita M. Cowell, Mark J. Suto, James F. George, Corinne E. Augelli-Szafran and Anupam Agarwal
Antioxidants 2022, 11(10), 1888; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11101888 - 23 Sep 2022
Viewed by 1747
Abstract
Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a [...] Read more.
Acute kidney injury (AKI) is a major public health concern with significant morbidity and mortality and no current treatments beyond supportive care and dialysis. Preclinical studies have suggested that heme-oxygenase-1 (HO-1), an enzyme that catalyzes the breakdown of heme, has promise as a potential therapeutic target for AKI. Clinical trials involving HO-1 products (biliverdin, carbon monoxide, and iron), however, have not progressed beyond the Phase ½ level. We identified small-molecule inducers of HO-1 that enable us to exploit the full therapeutic potential of HO-1, the combination of its products, and yet-undefined effects of the enzyme system. Through cell-based, high-throughput screens for induction of HO-1 driven by the human HO-1 promoter/enhancer, we identified two novel small molecules and broxaldine (an FDA-approved drug) for further consideration as candidate compounds exhibiting an Emax ≥70% of 5 µM hemin and EC50 <10 µM. RNA sequencing identified shared binding motifs to NRF2, a transcription factor known to regulate antioxidant genes, including HMOX1. In vitro, the cytoprotective function of the candidates was assessed against cisplatin-induced cytotoxicity and apoptosis. In vivo, delivery of a candidate compound induced HO-1 expression in the kidneys of mice. This study serves as the basis for further development of small-molecule HO-1 inducers as preventative or therapeutic interventions for a variety of pathologies, including AKI. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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13 pages, 1510 KiB  
Article
Pharmacotherapies and Aortic Heme Oxygenase-1 Expression in Patients with Abdominal Aortic Aneurysm
by Anja Hofmann, Bianca Hamann, Anna Klimova, Margarete Müglich, Steffen Wolk, Albert Busch, Frieda Frank, Pamela Sabarstinski, Marvin Kapalla, Josef Albin Nees, Coy Brunssen, David M. Poitz, Henning Morawietz and Christian Reeps
Antioxidants 2022, 11(9), 1753; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11091753 - 04 Sep 2022
Cited by 3 | Viewed by 1596
Abstract
Background: Treatment of cardiovascular risk factors slows the progression of small abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a stress- and hemin-induced enzyme providing cytoprotection against oxidative stress when overexpressed. However, nothing is known about the effects of cardiometabolic standard therapies on [...] Read more.
Background: Treatment of cardiovascular risk factors slows the progression of small abdominal aortic aneurysms (AAA). Heme oxygenase-1 (HO-1) is a stress- and hemin-induced enzyme providing cytoprotection against oxidative stress when overexpressed. However, nothing is known about the effects of cardiometabolic standard therapies on HO-1 expression in aortic walls in patients with end-stage AAA. Methods: The effects of statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers, diuretics, acetylsalicylic acid (ASA), and therapeutic anticoagulation on HO-1 mRNA and protein expressions were analyzed in AAA patients using multivariate logistic regression analysis and comparison of monotherapy. Results: Analysis of monotherapy revealed that HO-1 mRNA and protein expressions were higher in patients on diuretics and lower in patients on statin therapy. Tests on combinations of antihypertensive medications demonstrated that ACE inhibitors and diuretics, ARBs and diuretics, and beta-blockers and diuretics were associated with increase in HO-1 mRNA expression. ASA and therapeutic anticoagulation were not linked to HO-1 expression. Conclusion: Diuretics showed the strongest association with HO-1 expression, persisting even in combination with other antihypertensive medications. Hence, changes in aortic HO-1 expression in response to different medical therapies and their effects on vessel wall degeneration should be analyzed in future studies. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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17 pages, 5650 KiB  
Article
Induction of BVR-A Expression by Korean Red Ginseng in Murine Hippocampal Astrocytes: Role of Bilirubin in Mitochondrial Function via the LKB1–SIRT1–ERRα Axis
by Sunhong Moon, Chang-Hee Kim, Jinhong Park, Minsu Kim, Hui Su Jeon, Young-Myeong Kim and Yoon Kyung Choi
Antioxidants 2022, 11(9), 1742; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11091742 - 01 Sep 2022
Cited by 4 | Viewed by 2017
Abstract
The beneficial effects of Korean red ginseng extract (KRGE) on the central nervous system (CNS) have been reported. Among the CNS cells, astrocytes possess robust antioxidative properties and regenerative potential. Under physiological conditions, biliverdin reductase A (BVR-A) converts biliverdin (a heme oxygenase metabolite) [...] Read more.
The beneficial effects of Korean red ginseng extract (KRGE) on the central nervous system (CNS) have been reported. Among the CNS cells, astrocytes possess robust antioxidative properties and regenerative potential. Under physiological conditions, biliverdin reductase A (BVR-A) converts biliverdin (a heme oxygenase metabolite) into bilirubin, a major natural and potent antioxidant. We found that KRGE enhanced BVR-A in astrocytes in the fimbria region of the adult mouse hippocampus under physiological conditions. KRGE-induced BVR-A expression and subsequent bilirubin production were required for changes in mitochondrial membrane potential, mitochondrial mass, and oxidative phosphorylation through liver kinase B1 (LKB1), estrogen-related receptor α (ERRα), and sirtuin (SIRT1 and SIRT5) in astrocytes. However, BVR-A did not affect the KRGE-induced expression of AMP-activated protein kinase α (AMPKα). The KRGE-stimulated BVR-A–LKB1–SIRT1–ERRα pathway regulates the levels of mitochondria-localized proteins such as SIRT5, translocase of the outer mitochondrial membrane 20 (Tom20), Tom22, cytochrome c (Cyt c), and superoxide dismutase 2 (SOD2). Increased Tom20 expression in astrocytes of the hippocampal fimbria region was observed in KRGE-treated mice. KRGE-induced expression of Cyt c and SOD2 was associated with the Tom20/Tom22 complex. Taken together, KRGE-induced bilirubin production is required for enhanced astrocytic mitochondrial function in an LKB1-dependent and AMPKα-independent manner under physiological conditions. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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14 pages, 2481 KiB  
Article
HO-1 Limits the Efficacy of Vemurafenib/PLX4032 in BRAFV600E Mutated Melanoma Cells Adapted to Physiological Normoxia or Hypoxia
by Anna Lisa Furfaro, Giulia Loi, Caterina Ivaldo, Mario Passalacqua, Gabriella Pietra, Giovanni Enrico Mann and Mariapaola Nitti
Antioxidants 2022, 11(6), 1171; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11061171 - 14 Jun 2022
Cited by 1 | Viewed by 2285
Abstract
Induction of heme oxygenase 1 (HO-1) favors immune-escape in BRAFV600 melanoma cells treated with Vemurafenib/PLX4032 under standard cell culture conditions. However, the oxygen tension under standard culture conditions (~18 kPa O2) is significantly higher than the physiological oxygen levels encountered [...] Read more.
Induction of heme oxygenase 1 (HO-1) favors immune-escape in BRAFV600 melanoma cells treated with Vemurafenib/PLX4032 under standard cell culture conditions. However, the oxygen tension under standard culture conditions (~18 kPa O2) is significantly higher than the physiological oxygen levels encountered in vivo. In addition, cancer cells in vivo are often modified by hypoxia. In this study, MeOV-1 primary melanoma cells bearing the BRAFV600E mutation, were adapted to either 5 kPa O2 (physiological normoxia) or 1 kPa O2 (hypoxia) and then exposed to 10 μM PLX4032. PLX4032 abolished ERK phosphorylation, reduced Bach1 expression and increased HO-1 levels independent of pericellular O2 tension. Moreover, cell viability was significantly reduced further in cells exposed to PLX4032 plus Tin mesoporphyrin IX, a HO-1 inhibitor. Notably, our findings provide the first evidence that HO-1 inhibition in combination with PLX4032 under physiological oxygen tension and hypoxia restores and increases the expression of the NK ligands ULBP3 and B7H6 compared to cells exposed to PLX4032 alone. Interestingly, although silencing NRF2 prevented PLX4032 induction of HO-1, other NRF2 targeted genes were unaffected, highlighting a pivotal role of HO-1 in melanoma resistance and immune escape. The present findings may enhance translation and highlight the potential of the HO-1 inhibitors in the therapy of BRAFV600 melanomas. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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22 pages, 3227 KiB  
Article
Adipocyte-Specific Expression of PGC1α Promotes Adipocyte Browning and Alleviates Obesity-Induced Metabolic Dysfunction in an HO-1-Dependent Fashion
by Shin-Hsueh Shen, Shailendra P. Singh, Marco Raffaele, Maayan Waldman, Edith Hochhauser, Juancarlos Ospino, Michael Arad and Stephen J. Peterson
Antioxidants 2022, 11(6), 1147; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11061147 - 10 Jun 2022
Cited by 9 | Viewed by 2535
Abstract
Recent studies suggest that PGC1-α plays a crucial role in mitochondrial and vascular function, yet the physiological significance of PGC1α and HO expression in adipose tissues in the context of obesity-linked vascular dysfunction remains unclear. We studied three groups of six-week-old C57BL/6J male [...] Read more.
Recent studies suggest that PGC1-α plays a crucial role in mitochondrial and vascular function, yet the physiological significance of PGC1α and HO expression in adipose tissues in the context of obesity-linked vascular dysfunction remains unclear. We studied three groups of six-week-old C57BL/6J male mice: (1) mice fed a normal chow diet; (2) mice fed a high-fat diet (H.F.D.) for 28 weeks, and (3) mice fed a high-fat diet (H.F.D.) for 28 weeks, treated with adipose-specific overexpression of PGC-1α (transgenic-adipocyte-PGC-1α) at week 20, and continued on H.F.D. for weeks 20–28. R.N.A. arrays examined 88 genes involved in adipocyte proliferation and maturation. Blood pressure, tissue fibrosis, fasting glucose, and oxygen consumption were measured, as well as liver steatosis, and the expression levels of metabolic and mitochondrial markers. Obese mice exhibited a marked reduction of PGC1α and developed adipocyte hypertrophy, fibrosis, hepatic steatosis, and decreased mitochondrial respiration. Mice with adipose-specific overexpression of PGC1-α exhibited improvement in HO-1, mitochondrial biogenesis and respiration, with a decrease in fasting glucose, reduced blood pressure and fibrosis, and increased oxygen consumption. PGC-1α led to the upregulated expression of processes associated with the browning of fat tissue, including UCP1, FGF21, and pAMPK signaling, with a reduction in inflammatory adipokines, NOV/CCN3 expression, and TGFβ. These changes required HO-1 expression. The R.N.A. array analysis identified subgroups of genes positively correlated with contributions to the browning of adipose tissue, all dependent on HO-1. Our observations reveal a positive impact of adipose-PGC1-α on distal organ systems, with beneficial effects on HO-1 levels, reversing obesity-linked cardiometabolic disturbances. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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26 pages, 6123 KiB  
Article
HO-1 Upregulation by Kaempferol via ROS-Dependent Nrf2-ARE Cascade Attenuates Lipopolysaccharide-Mediated Intercellular Cell Adhesion Molecule-1 Expression in Human Pulmonary Alveolar Epithelial Cells
by Chien-Chung Yang, Li-Der Hsiao, Chen-Yu Wang, Wei-Ning Lin, Ya-Fang Shih, Yi-Wen Chen, Rou-Ling Cho, Hui-Ching Tseng and Chuen-Mao Yang
Antioxidants 2022, 11(4), 782; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040782 - 14 Apr 2022
Cited by 10 | Viewed by 2532
Abstract
Lung inflammation is a pivotal event in the pathogenesis of acute lung injury. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme that could be induced by kaempferol (KPR) and exerts anti-inflammatory effects. However, the molecular mechanisms of KPR-mediated HO-1 expression and its effects [...] Read more.
Lung inflammation is a pivotal event in the pathogenesis of acute lung injury. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme that could be induced by kaempferol (KPR) and exerts anti-inflammatory effects. However, the molecular mechanisms of KPR-mediated HO-1 expression and its effects on inflammatory responses remain unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). This study aimed to verify the relationship between HO-1 expression and KPR treatment in both in vitro and in vivo models. HO-1 expression was determined by real time-PCR, Western blotting, and promoter reporter analyses. The signaling components were investigated by using pharmacological inhibitors or specific siRNAs. Chromatin immunoprecipitation (ChIP) assay was performed to investigate the interaction between nuclear factor erythroid-2-related factor (Nrf2) and antioxidant response elements (ARE) binding site of HO-1 promoter. The effect of KPR on monocytes (THP-1) binding to HPAEpiCs challenged with lipopolysaccharides (LPS) was determined by adhesion assay. We found that KPR-induced HO-1 level attenuated the LPS-induced intercellular cell adhesion protein 1 (ICAM-1) expression in HPAEpiCs. KPR-induced HO-1 mRNA and protein expression also attenuated ICAM-1 expression in mice. Tin protoporphyrin (SnPP)IX reversed the inhibitory effects of KPR in HPAEpiCs. In addition, in HPAEpiCs, KPR-induced HO-1 expression was abolished by both pretreating with the inhibitor of NADPH oxidase (NOX, apocynin (APO)), reactive oxygen species (ROS) (N-acetyl-L-cysteine (NAC)), Src (Src kinase inhibitor II (Srci II)), Pyk2 (PF431396), protein kinase C (PKC)α (Gö6976), p38 mitogen-activated protein kinase (MAPK) inhibitor (p38i) VIII, or c-Jun N-terminal kinases (JNK)1/2 (SP600125) and transfection with their respective siRNAs. The transcription of the homx1 gene was enhanced by Nrf2 activated by JNK1/2 and p38α MAPK. The binding activity between Nrf2 and HO-1 promoter was attenuated by APO, NAC, Srci II, PF431396, or Gö6983. KPR-mediated NOX/ROS/c-Src/Pyk2/PKCα/p38α MAPK and JNK1/2 activate Nrf2 to bind with ARE on the HO-1 promoter and induce HO-1 expression, which further suppresses the LPS-mediated inflammation in HPAEpiCs. Thus, KPR exerts a potential strategy to protect against pulmonary inflammation via upregulation of the HO-1. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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Graphical abstract

21 pages, 3696 KiB  
Article
Induction of Heme Oxygenase-1 by 15d-Prostaglandin J2 Mediated via a ROS-Dependent Sp1 and AP-1 Cascade Suppresses Lipopolysaccharide-Triggered Interleukin-6 Expression in Mouse Brain Microvascular Endothelial Cells
by Chien-Chung Yang, Li-Der Hsiao, Ya-Fang Shih, Ching-I Chang and Chuen-Mao Yang
Antioxidants 2022, 11(4), 719; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox11040719 - 06 Apr 2022
Cited by 4 | Viewed by 2203
Abstract
Heme oxygenase-1 (HO-1) has been shown to exert antioxidant, anti-inflammatory, and anti-apoptotic effects in various types of cells. Therefore, the induction of HO-1 is an excellent rationale for the development of protective drugs. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) can modulate [...] Read more.
Heme oxygenase-1 (HO-1) has been shown to exert antioxidant, anti-inflammatory, and anti-apoptotic effects in various types of cells. Therefore, the induction of HO-1 is an excellent rationale for the development of protective drugs. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) can modulate the expression of antioxidant defense proteins and be beneficial for neuroinflammation. Brain endothelial cells play an important role in the pathophysiology of brain disorders. Whether 15d-PGJ2 can induce HO-1 expression and protect against the inflammatory responses in mouse brain microvascular endothelial (bEnd.3) cells remains unclear. Here, we reveal that 15d-PGJ2 stimulated HO-1 protein and mRNA expression in a time- and concentration-dependent manner in bEnd.3 cells, which was attenuated by diphenyleneiodonium chloride (DPI) and MitoTempo. Thus, activation of NADPH oxidase (NOX)- and mitochondria-derived reactive oxygen species (ROS) mediated 15d-PGJ2-induced HO-1 expression. ROS generation could cause phosphorylation of protein kinase C (PKC)δ, leading to HO-1 expression, which was suppressed by Rottlerin (selective inhibitor PKCδ), DPI, and MitoTempo. We further demonstrated that phosphorylation of c-Jun N-terminal kinase (JNK)1/2 participated in 15d-PGJ2-upregulated HO-1 expression, which was blocked by SP600125 or Rottlerin. Moreover, 15d-PGJ2-induced HO-1 expression was mediated through the activation of c-Jun (a subunit of activator protein 1 (AP-1)) and specificity protein 1 (Sp1), leading to their interaction with the HO-1 promoter, revealed by chromatin immunoprecipitation assay, which was attenuated by SP600125, Mithramycin A, or Tanshinone II A. We further verified the anti-inflammatory effect of HO-1 expression. Our results showed that 15d-PGJ2-induced HO-1 could mitigate the lipopolysaccharide-triggered interleukin-6 expression and secretion, as measured by an ELISA assay kit. These results suggest that 15d-PGJ2-induced HO-1 expression is mediated through the activation of NOX- and mitochondria-derived ROS-dependent PKCδ/JNK1/2/Sp1 and the AP-1 signaling pathway and protects against inflammatory responses in bEnd.3 cells. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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Review

Jump to: Research, Other

25 pages, 1864 KiB  
Review
Heme: The Lord of the Iron Ring
by Vanessa Azevedo Voltarelli, Rodrigo W. Alves de Souza, Kenji Miyauchi, Carl J. Hauser and Leo Edmond Otterbein
Antioxidants 2023, 12(5), 1074; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12051074 - 10 May 2023
Cited by 5 | Viewed by 2911
Abstract
Heme is an iron-protoporphyrin complex with an essential physiologic function for all cells, especially for those in which heme is a key prosthetic group of proteins such as hemoglobin, myoglobin, and cytochromes of the mitochondria. However, it is also known that heme can [...] Read more.
Heme is an iron-protoporphyrin complex with an essential physiologic function for all cells, especially for those in which heme is a key prosthetic group of proteins such as hemoglobin, myoglobin, and cytochromes of the mitochondria. However, it is also known that heme can participate in pro-oxidant and pro-inflammatory responses, leading to cytotoxicity in various tissues and organs such as the kidney, brain, heart, liver, and in immune cells. Indeed, heme, released as a result of tissue damage, can stimulate local and remote inflammatory reactions. These can initiate innate immune responses that, if left uncontrolled, can compound primary injuries and promote organ failure. In contrast, a cadre of heme receptors are arrayed on the plasma membrane that is designed either for heme import into the cell, or for the purpose of activating specific signaling pathways. Thus, free heme can serve either as a deleterious molecule, or one that can traffic and initiate highly specific cellular responses that are teleologically important for survival. Herein, we review heme metabolism and signaling pathways, including heme synthesis, degradation, and scavenging. We will focus on trauma and inflammatory diseases, including traumatic brain injury, trauma-related sepsis, cancer, and cardiovascular diseases where current work suggests that heme may be most important. Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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Other

Jump to: Research, Review

8 pages, 873 KiB  
Opinion
Heme, Heme Oxygenase-1, Statins, and SARS-CoV-2
by David K. Stevenson, Hendrik J. Vreman and Ronald J. Wong
Antioxidants 2023, 12(3), 614; https://0-doi-org.brum.beds.ac.uk/10.3390/antiox12030614 - 02 Mar 2023
Viewed by 1247
Abstract
Heme, a metalloporphyrin, or more specifically, a tetrapyrrole containing ferrous iron, is an ancient molecule [...] Full article
(This article belongs to the Special Issue Pharmacological and Clinical Significance of Heme Oxygenase-1 2022)
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