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Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease

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

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 50300

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Special Issue Editors

Dr. Gianfranco Pintus

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Guest Editor

1. Professor of Biochemistry, Department of Medical Laboratory Sciences, University of Sharjah, P. O. Box 27272 Sharjah, United Arab Emirates
2. Department of Biomedical Sciences, University of Sassari, Sassari, Italy
Interests: vascular biology; natural antioxidants; tissue remodeling; oxidative stress; redox-regulated signaling; molecular toxicology

Dr. Panagiotis Paliogiannis

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Guest Editor

Department of Medical, Surgical and Experimental Sciences, University of Sassari, Viale San Pietro 43, 07100 Sassari, Italy
Interests: translational and precision medicine; biomarker research; oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

It is evident that redox-regulated signaling pathways play a primary role in modulating multiple cellular functions, ultimately controlling tissues and organs pathophysiology. Cancer, cardiovascular and metabolic diseases, inflammatory, autoimmune, and chronic degenerative diseases all appear to have an unbalance redox homeostasis in common due to either increased reacting oxygen species (ROS) production or defects in the body antioxidant response. Indeed, while the physiological levels of ROS act as signaling molecules maintaining healthy body functions, high levels of ROS aberrantly affect organs and system homeostasis, ultimately prompting disease onset and progression. Increased ROS production and subsequent oxidative stress are also being recognized as primary mechanisms of xenobiotic-associated toxicity. While low concentrations of exogenous compounds (e.g., antioxidants) may beneficially impact cell function by maintaining the redox homeostasis or preventing its rupture, high concentrations of these compounds can instead promote oxidative stress. Indeed, based on the body redox environment and their concentration many xenobiotics can aberrantly interact with organ redox-regulating machinery, ultimately promoting cell and tissue damage by oxidative stress. In this light, understanding the intricate machinery underpinning the control of the body redox homeostasis may pave the way toward better preventive and therapeutic approaches against diseases and xenobiotics associated threats.

This Special Issue on “Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease” welcomes original research articles that illustrate and stimulate the growing efforts to understand the implication of redox signaling in pathological conditions such as cancer, cardiovascular and metabolic diseases, inflammatory, autoimmune, and chronic degenerative diseases and potential redox-mediated therapeutic approaches to counteract or prevent these conditions. Research articles investigating and reporting new aspects of redox-regulated signaling phenomena triggered by the interaction of xenobiotics with the cell/organ/tissue/body redox-regulatory apparatus are also particularly welcome. We also appreciate the submission of review articles that critically assess and discuss the current state of the art concerning the highlighted topics

Prof. Dr. Gianfranco Pintus
Dr. Panagiotis Paliogiannis
Guest Editors

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

Oxidative stress
Redox signaling
Reactive oxygen species
Xenobiotics
Toxicology
Diseases
Translational and precision medicine
Biomarker
Signal transduction
Tissue damage
Cell damage

Published Papers (13 papers)

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13 pages, 1745 KiB

Open AccessArticle

Celastrol Prevents Oxidative Stress Effects on FSHR, PAPP, and CYP19A1 Gene Expression in Cultured Human Granulosa-Lutein Cells

by Rita Martín-Ramírez, Rebeca González-Fernández, Deborah Rotoli, Jairo Hernández, Pablo Martín-Vasallo, Angela Palumbo and Julio Ávila

Int. J. Mol. Sci. 2021, 22(7), 3596; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073596 - 30 Mar 2021

Cited by 5 | Viewed by 2346

Abstract

Regulation of oxidative stress (OS) is important to prevent damage to female reproductive physiology. While normal OS levels may have a regulatory role, high OS levels may negatively affect vital processes such as folliculogenesis or embryogenesis. The aim of this work was to study OS induced by glucose, a reactive oxygen species generator, or peroxynitrite, a reactive nitrogen species generator, in cultured human granulosa-lutein (hGL) cells from oocyte donors, analyzing expression of genes involved in oocyte maturation (FSHR, PAPP, and CYP19A1) and OS damage response (ALDH3A2). We also evaluated the effect of celastrol as an antioxidant. Our results showed that although both glucose and peroxynitrite produce OS increments in hGL cells, only peroxynitrite treatment increases ALDH3A2 and PAPP gene expression levels and decreases FSHR gene expression levels. Celastrol pre-treatment prevents this effect of peroxynitrite. Interestingly, when celastrol alone was added, we observed a reduction of the expression of all genes studied, which was independent of both OS inductors. In conclusion, regulation of OS imbalance by antioxidant substances such as celastrol may prevent negative effects of OS in female fertility. In addition to the antioxidant activity, celastrol may well have an independent role on regulation of gene expression in hGL cells. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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10 pages, 1675 KiB

Open AccessArticle

The Effects of Spirulina Supplementation on Redox Status and Performance Following a Muscle Damaging Protocol

by Aggelos Pappas, Athanasios Tsiokanos, Ioannis G. Fatouros, Athanasios Poulios, Dimitris Kouretas, Nikos Goutzourelas, Giannis Giakas and Athanasios Z. Jamurtas

Int. J. Mol. Sci. 2021, 22(7), 3559; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073559 - 30 Mar 2021

Cited by 17 | Viewed by 3089

Abstract

Spirulina plantensis is a popular supplement which has been shown to have antioxidant and performance enhancing properties. The purpose of this study was to evaluate the effects of spirulina supplementation on (a) redox status (b) muscle performance and (c) muscle damage following an eccentric bout of exercise that would induce muscle damage. Twenty-four healthy, recreationally trained males participated in the study and were randomly separated into two groups: a spirulina supplementation (6 g per day) and a placebo group. Both groups performed an eccentric bout of exercise consisting of 5 sets and 15 maximum reps per set. Blood was collected at 24, 48, 72 and 96 h after the bout and total antioxidant capacity (TAC) and protein carbonyls (PC) were assessed in plasma. Delayed onset muscle soreness (DOMS) was also assessed at the same aforementioned time points. Eccentric peak torque (EPT) was evaluated immediately after exercise, as well as at 24, 48, 72 and 96 h post exercise. Redox status indices (TAC and PC) did not change significantly at any time point post exercise. DOMS increased significantly 24 h post exercise and remained elevated until 72 h and 96 h post exercise for the placebo and spirulina group, respectively. EPT decreased significantly and immediately post exercise and remained significantly lower compared to baseline until 72 h post exercise. No significant differences between groups were found for DOMS and EPT. These results indicate that spirulina supplementation following a muscle damaging protocol does not confer beneficial effects on redox status, muscle performance or damage. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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21 pages, 3648 KiB

Open AccessArticle

Minocycline Impact on Redox Homeostasis of Normal Human Melanocytes HEMn-LP Exposed to UVA Radiation and Hydrogen Peroxide

by Jakub Rok, Zuzanna Rzepka, Mateusz Maszczyk, Artur Beberok and Dorota Wrześniok

Int. J. Mol. Sci. 2021, 22(4), 1642; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041642 - 06 Feb 2021

Cited by 7 | Viewed by 2887

Abstract

Minocycline is a semisynthetic tetracycline antibiotic. In addition to its antibacterial activity, minocycline shows many non-antibiotic, beneficial effects, including antioxidative action. The property is responsible, e.g., for anti-inflammatory, neuroprotective, and cardioprotective effects of the drug. However, long-term pharmacotherapy with minocycline may lead to hyperpigmentation of the skin. The reasons for the pigmentation disorders include the deposition of the drug and its metabolites in melanin-containing cells and the stimulation of melanogenesis. The adverse drug reaction raises a question about the influence of the drug on melanocyte homeostasis. The study aimed to assess the effect of minocycline on redox balance in human normal melanocytes HEMn-LP exposed to hydrogen peroxide and UVA radiation. The obtained results indicate that minocycline induced oxidative stress in epidermal human melanocytes. The drug inhibited cell proliferation, decreased the level of reduced thiols, and stimulated the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). The described changes were accompanied by an increase in the intracellular level of ROS. On the other hand, pretreatment with minocycline at the same concentrations increased cell viability and significantly attenuated the oxidative stress in melanocytes exposed to hydrogen peroxide and UVA radiation. Moreover, the molecular docking analysis revealed that the different influence of minocycline and other tetracyclines on CAT activity can be related to the location of the binding site. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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21 pages, 3182 KiB

Open AccessArticle

Arachidonic Acid Metabolites of CYP450 Enzymes and HIF-1α Modulate Endothelium-Dependent Vasorelaxation in Sprague-Dawley Rats under Acute and Intermittent Hyperbaric Oxygenation

by Zrinka Mihaljević, Anita Matić, Ana Stupin, Ruža Frkanec, Branka Tavčar, Vanja Kelava, Ivana Tartaro Bujak, Nikolina Kolobarić, Aleksandar Kibel and Ines Drenjančević

Int. J. Mol. Sci. 2020, 21(17), 6353; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176353 - 01 Sep 2020

Cited by 8 | Viewed by 2605

Abstract

Acetylcholine-induced vasorelaxation (AChIR) and responses to reduced pO₂ (hypoxia-induced relaxation (HIR), 0% O₂) were assessed in vitro in aortic rings of healthy male Sprague-Dawley rats (N = 252) under hyperbaric (HBO₂) protocols. The studied groups consisted of the CTRL group (untreated); the A-HBO₂ group (single HBO₂; 120 min of 100% O₂ at 2.0 bars); the 24H-HBO₂ group (examined 24 h after single exposure) and the 4D-HBO₂ group (four consecutive days of single HBO₂). AChIR, sensitivity to ACh and iNOS expression were decreased in the A-HBO₂ group. HIR was prostanoid- and epoxyeicosatrienoic acid (EET)-mediated. HIF-1α expression was increased in the 24H-HBO₂ and 4D-HBO₂ groups. LW6 (HIF-1α inhibitor) decreased HIR in the 24H-HBO₂ group. HBO₂ affected the expression of COX-1 and COX-2. CYP2c11 expression was elevated in the 24H-HBO₂ and 4D-HBO₂ groups. Concentrations of arachidonic acid (AA) metabolites 14(15)-DiHET, 11(12)-DiHET and 8(9)-DiHET were increased in A-HBO₂ and 24H-HBO_2. An increased concentration of 8(9)-EET was observed in the A-HBO₂ and 24h-HBO₂ groups vs. the CTRL and 4D-HBO₂ groups, and an increased concentration of 5(6)-DiHET was observed in the 24H-HBO₂ group vs. the 4D-HBO₂ group. The 20-HETE concentration was increased in the A-HBO₂ group. All were determined by LC-MS/MS of the aorta. The results show that AChIR in all groups is mostly NO-dependent. HIR is undoubtedly mediated by the CYP450 enzymes’ metabolites of AA, whereas HIF-1α contributes to restored HIR. Vasoconstrictor metabolites of CYP450 enzymes contribute to attenuated AChIR and HIR in A-HBO₂. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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20 pages, 5751 KiB

Open AccessArticle

VAS3947 Induces UPR-Mediated Apoptosis through Cysteine Thiol Alkylation in AML Cell Lines

by Maya El Dor, Hassan Dakik, Marion Polomski, Eloi Haudebourg, Marie Brachet, Fabrice Gouilleux, Gildas Prié, Kazem Zibara and Frédéric Mazurier

Int. J. Mol. Sci. 2020, 21(15), 5470; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21155470 - 31 Jul 2020

Cited by 6 | Viewed by 2837

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) involvement has been established in the oncogenic cell signaling of acute myeloid leukemia (AML) cells and in the crosstalk with their niche. We have shown an expression of NOX subunits in AML cell lines while NOX activity is lacking in the absence of exogenous stimulation. Here, we used AML cell lines as models to investigate the specificity of VAS3947, a current NOX inhibitor. Results demonstrated that VAS3947 induces apoptosis in AML cells independently of its anti-NOX activity. High-performance liquid chromatography (HPLC) and mass spectrometry analyses revealed that VAS3947 thiol alkylates cysteine residues of glutathione (GSH), while also interacting with proteins. Remarkably, VAS3947 decreased detectable GSH in the MV-4-11 cell line, thereby suggesting possible oxidative stress induction. However, a decrease in both cytoplasmic and mitochondrial reactive oxygen species (ROS) levels was observed by flow cytometry without disturbance of mitochondrial mass and membrane potential. Thus, assuming the consequences of VAS3947 treatment on protein structure, we examined its impact on endoplasmic reticulum (ER) stress. An acute unfolded protein response (UPR) was triggered shortly after VAS3947 exposure, through the activation of inositol-requiring enzyme 1α (IRE1α) and PKR-like endoplasmic reticulum kinase (PERK) pathways. Overall, VAS3947 induces apoptosis independently of anti-NOX activity, via UPR activation, mainly due to aggregation and misfolding of proteins. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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12 pages, 2398 KiB

Open AccessArticle

Oxidation of Erythrocytes Enhance the Production of Reactive Species in the Presence of Artemisinins

by Ioannis Tsamesidis, Pierre Pério, Antonella Pantaleo and Karine Reybier

Int. J. Mol. Sci. 2020, 21(13), 4799; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21134799 - 07 Jul 2020

Cited by 14 | Viewed by 2418

Abstract

In red blood cells, hemoglobin iron represents the most plausible candidate to catalyze artemisinin activation but the limited reactivity of iron bound to hemoglobin does not play in favor for its direct involvement. Denatured hemoglobin appears a more likely candidate for artemisinin redox activation because it is expected to contain reactive iron and it has been described to release free heme and/or iron in erythrocyte. The aim of our study is to investigate, using three different methods: fluorescence, electron paramagnetic resonance and liquid chromatography coupled to mass spectrometry, how increasing the level of accessible iron into the red blood cells can enhance the reactive oxygen species (ROS) production derived from artemisinin. The over-increase of iron was achieved using phenylhydrazine, a strong oxidant that causes oxidative stress within erythrocytes, resulting in oxidation of oxyhemoglobin and leading to the formation of methemoglobin, which is subsequently converted into irreversible hemichromes (iron (III) compounds). Our findings confirmed, using the iron III chelator, desferrioxamine, the indirect participation of iron (III) compounds in the activation process of artemisinins. Furthermore, in strong reducing conditions, the activation of artemisinin and the consequent production of ROS was enhanced. In conclusion, we demonstrate, through the measurement of intra-erythrocytic superoxide and hydrogen peroxide production using various methods, that artemisinin activation can be drastically enhanced by pre-oxidation of erythrocytes. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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13 pages, 756 KiB

Open AccessArticle

Biomarkers of Oxidative Stress and Inflammation in Chronic Airway Diseases

by Liliya Chamitava, Lucia Cazzoletti, Marcello Ferrari, Vanessa Garcia-Larsen, Aneza Jalil, Paolo Degan, Alessandro G. Fois, Elisabetta Zinellu, Sara S. Fois, Anna Maria Fratta Pasini, Morena Nicolis, Mario Olivieri, Angelo Corsico, Roberto Bono, Pietro Pirina and Maria Elisabetta Zanolin

Int. J. Mol. Sci. 2020, 21(12), 4339; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124339 - 18 Jun 2020

Cited by 32 | Viewed by 2706

Abstract

Introduction: The global burden of chronic airway diseases represents an important public health concern. The role of oxidative stress and inflammation in the pathogenesis of these diseases is well known. The aim of this study is to evaluate the behavior of both inflammatory and oxidative stress biomarkers in patients with chronic bronchitis, current asthma and past asthma in the frame of a population-based study. Methods: For this purpose, data collected from the Gene Environment Interactions in Respiratory Diseases (GEIRD) Study, an Italian multicentre, multicase-control study, was evaluated. Cases and controls were identified through a two-stage screening process of individuals aged 20-65 years from the general population. Out of 16,569 subjects selected from the general population in the first stage of the survey, 2259 participated in the clinical evaluation. Oxidative stress biomarkers such as 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), 8-isoprostane and glutathione and inflammatory biomarkers such as Fractional Exhaled Nitric Oxide (FENO) and white blood cells were evaluated in 1878 subjects. Results: Current asthmatics presented higher levels of FENO (23.05 ppm), leucocytes (6770 n/µL), basophils (30.75 n/µL) and eosinophils (177.80 n/µL), while subjects with chronic bronchitis showed higher levels of GSH (0.29 mg/mL) and lymphocytes (2101.6 n/µL). The multivariable multinomial logistic regression confirmed high levels of leucocytes (RRR = 1.33), basophils (RRR = 1.48), eosinophils (RRR = 2.39), lymphocytes (RRR = 1.26) and FENO (RRR = 1.42) in subjects with current asthma. Subjects with past asthma had a statistically significant higher level of eosinophils (RRR = 1.78) with respect to controls. Subjects with chronic bronchitis were characterized by increased levels of eosinophils (RRR = 2.15), lymphocytes (RRR = 1.58), GSH (RRR = 2.23) and 8-isoprostane (RRR = 1.23). Conclusion: In our study, current asthmatics show a greater expression of the inflammatory profile compared to subjects who have had asthma in the past and chronic bronchitis. On the other hand, chronic bronchitis subjects showed a higher rate of expression of oxidative stress biomarkers compared to asthmatic subjects. In particular, inflammatory markers such as circulating inflammatory cells and FENO seem to be more specific for current asthma, while oxidative stress biomarkers such as glutathione and 8-isoprostane appear to be more specific and applicable to patients with chronic bronchitis. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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17 pages, 2610 KiB

Open AccessArticle

Resveratrol Inhibits Oxidative Stress and Prevents Mitochondrial Damage Induced by Zinc Oxide Nanoparticles in Zebrafish (Danio rerio)

by Roberta Giordo, Gheyath K. Nasrallah, Ola Al-Jamal, Panagiotis Paliogiannis and Gianfranco Pintus

Int. J. Mol. Sci. 2020, 21(11), 3838; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21113838 - 28 May 2020

Cited by 49 | Viewed by 4524

Abstract

Despite their wide industrial use, Zinc oxide (ZnO) nanoparticles (NPs) exhibit a high toxic potential while concerns of their health-related risks are still present, urging additional in vivo clarification studies. Oxidative stress is recognized as the primary trigger of NP-associated toxicity, suggesting antioxidants as a promising counteractive approach. Here, we investigated the protective effect of the natural antioxidant resveratrol against ZnO NP-induced toxicity in vivo using the zebrafish model. Our findings demonstrate that resveratrol counteracts ZnO NP-induced zebrafish lethality preventing cardiac morphological and functional damage. NP-induced vascular structural abnormalities during embryonic fish development were significantly counteracted by resveratrol treatment. Mechanistically, we further showed that resveratrol inhibits ROS increase, prevents mitochondrial membrane potential dysfunction, and counteracts cell apoptosis/necrosis elicited by ZnO NP. Overall, our data provide further evidence demonstrating the primary role of oxidative stress in NP-induced damage, and highlight new insights concerning the protective mechanism of antioxidants against nanomaterial toxicity. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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Review

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18 pages, 647 KiB

Open AccessReview

Treatment of Oxidative Stress with Exosomes in Myocardial Ischemia

by Yun Liu, Mengxue Wang, Yin Liang, Chen Wang, Keiji Naruse and Ken Takahashi

Int. J. Mol. Sci. 2021, 22(4), 1729; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041729 - 09 Feb 2021

Cited by 24 | Viewed by 3851

Abstract

A thrombus in a coronary artery causes ischemia, which eventually leads to myocardial infarction (MI) if not removed. However, removal generates reactive oxygen species (ROS), which causes ischemia–reperfusion (I/R) injury that damages the tissue and exacerbates the resulting MI. The mechanism of I/R injury is currently extensively understood. However, supplementation of exogenous antioxidants is ineffective against oxidative stress (OS). Enhancing the ability of endogenous antioxidants may be a more effective way to treat OS, and exosomes may play a role as targeted carriers. Exosomes are nanosized vesicles wrapped in biofilms which contain various complex RNAs and proteins. They are important intermediate carriers of intercellular communication and material exchange. In recent years, diagnosis and treatment with exosomes in cardiovascular diseases have gained considerable attention. Herein, we review the new findings of exosomes in the regulation of OS in coronary heart disease, discuss the possibility of exosomes as carriers for the targeted regulation of endogenous ROS generation, and compare the advantages of exosome therapy with those of stem-cell therapy. Finally, we explore several miRNAs found in exosomes against OS. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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20 pages, 651 KiB

Open AccessReview

Cardiac Autonomic Neuropathy: A Progressive Consequence of Chronic Low-Grade Inflammation in Type 2 Diabetes and Related Metabolic Disorders

by Nour-Mounira Z. Bakkar, Haneen S. Dwaib, Souha Fares, Ali H. Eid, Yusra Al-Dhaheri and Ahmed F. El-Yazbi

Int. J. Mol. Sci. 2020, 21(23), 9005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21239005 - 27 Nov 2020

Cited by 23 | Viewed by 6158

Abstract

Cardiac autonomic neuropathy (CAN) is one of the earliest complications of type 2 diabetes (T2D), presenting a silent cause of cardiovascular morbidity and mortality. Recent research relates the pathogenesis of cardiovascular disease in T2D to an ensuing chronic, low-grade proinflammatory and pro-oxidative environment, being the hallmark of the metabolic syndrome. Metabolic inflammation emerges as adipose tissue inflammatory changes extending systemically, on the advent of hyperglycemia, to reach central regions of the brain. In light of changes in glucose and insulin homeostasis, dysbiosis or alteration of the gut microbiome (GM) emerges, further contributing to inflammatory processes through increased gut and blood–brain barrier permeability. Interestingly, studies reveal that the determinants of oxidative stress and inflammation progression exist at the crossroad of CAN manifestations, dictating their evolution along the natural course of T2D development. Indeed, sympathetic and parasympathetic deterioration was shown to correlate with markers of adipose, vascular, and systemic inflammation. Additionally, evidence points out that dysbiosis could promote a sympatho-excitatory state through differentially affecting the secretion of hormones and neuromodulators, such as norepinephrine, serotonin, and γ-aminobutyric acid, and acting along the renin–angiotensin–aldosterone axis. Emerging neuronal inflammation and concomitant autophagic defects in brainstem nuclei were described as possible underlying mechanisms of CAN in experimental models of metabolic syndrome and T2D. Drugs with anti-inflammatory characteristics provide potential avenues for targeting pathways involved in CAN initiation and progression. The aim of this review is to delineate the etiology of CAN in the context of a metabolic disorder characterized by elevated oxidative and inflammatory load. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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21 pages, 10558 KiB

Open AccessReview

Reactive Oxygen Species: Modulators of Phenotypic Switch of Vascular Smooth Muscle Cells

by Adnan Badran, Suzanne A. Nasser, Joelle Mesmar, Ahmed F. El-Yazbi, Alessandra Bitto, Manal M. Fardoun, Elias Baydoun and Ali H. Eid

Int. J. Mol. Sci. 2020, 21(22), 8764; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21228764 - 20 Nov 2020

Cited by 58 | Viewed by 5176

Abstract

Reactive oxygen species (ROS) are natural byproducts of oxygen metabolism in the cell. At physiological levels, they play a vital role in cell signaling. However, high ROS levels cause oxidative stress, which is implicated in cardiovascular diseases (CVD) such as atherosclerosis, hypertension, and restenosis after angioplasty. Despite the great amount of research conducted to identify the role of ROS in CVD, the image is still far from being complete. A common event in CVD pathophysiology is the switch of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic phenotype. Interestingly, oxidative stress is a major contributor to this phenotypic switch. In this review, we focus on the effect of ROS on the hallmarks of VSMC phenotypic switch, particularly proliferation and migration. In addition, we speculate on the underlying molecular mechanisms of these cellular events. Along these lines, the impact of ROS on the expression of contractile markers of VSMCs is discussed in depth. We conclude by commenting on the efficiency of antioxidants as CVD therapies. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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24 pages, 4448 KiB

Open AccessReview

The Role of Epac in Cancer Progression

by Nadine Wehbe, Hasan Slika, Joelle Mesmar, Suzanne A. Nasser, Gianfranco Pintus, Serine Baydoun, Adnan Badran, Firas Kobeissy, Ali H. Eid and Elias Baydoun

Int. J. Mol. Sci. 2020, 21(18), 6489; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186489 - 05 Sep 2020

Cited by 25 | Viewed by 4731

Abstract

Cancer continues to be a prime contributor to global mortality. Despite tremendous research efforts and major advances in cancer therapy, much remains to be learned about the underlying molecular mechanisms of this debilitating disease. A better understanding of the key signaling events driving the malignant phenotype of cancer cells may help identify new pharmaco-targets. Cyclic adenosine 3′,5′-monophosphate (cAMP) modulates a plethora of biological processes, including those that are characteristic of malignant cells. Over the years, most cAMP-mediated actions were attributed to the activity of its effector protein kinase A (PKA). However, studies have revealed an important role for the exchange protein activated by cAMP (Epac) as another effector mediating the actions of cAMP. In cancer, Epac appears to have a dual role in regulating cellular processes that are essential for carcinogenesis. In addition, the development of Epac modulators offered new routes to further explore the role of this cAMP effector and its downstream pathways in cancer. In this review, the potentials of Epac as an attractive target in the fight against cancer are depicted. Additionally, the role of Epac in cancer progression, namely its effect on cancer cell proliferation, migration/metastasis, and apoptosis, with the possible interaction of reactive oxygen species (ROS) in these phenomena, is discussed with emphasis on the underlying mechanisms and pathways. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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14 pages, 2484 KiB

Open AccessReview

EPAC in Vascular Smooth Muscle Cells

by Nadine Wehbe, Suzanne Awni Nasser, Yusra Al-Dhaheri, Rabah Iratni, Alessandra Bitto, Ahmed F. El-Yazbi, Adnan Badran, Firas Kobeissy, Elias Baydoun and Ali H. Eid

Int. J. Mol. Sci. 2020, 21(14), 5160; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21145160 - 21 Jul 2020

Cited by 13 | Viewed by 6011

Abstract

Vascular smooth muscle cells (VSMCs) are major components of blood vessels. They regulate physiological functions, such as vascular tone and blood flow. Under pathological conditions, VSMCs undergo a remodeling process known as phenotypic switching. During this process, VSMCs lose their contractility and acquire a synthetic phenotype, where they over-proliferate and migrate from the tunica media to the tunica interna, contributing to the occlusion of blood vessels. Since their discovery as effector proteins of cyclic adenosine 3′,5′-monophosphate (cAMP), exchange proteins activated by cAMP (EPACs) have been shown to play vital roles in a plethora of pathways in different cell systems. While extensive research to identify the role of EPAC in the vasculature has been conducted, much remains to be explored to resolve the reported discordance in EPAC’s effects. In this paper, we review the role of EPAC in VSMCs, namely its regulation of the vascular tone and phenotypic switching, with the likely involvement of reactive oxygen species (ROS) in the interplay between EPAC and its targets/effectors. Full article

(This article belongs to the Special Issue Redox Homeostasis, Signaling, and Oxidative Stress in Health and Disease)

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