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12 pages, 1300 KiB

Open AccessArticle

Beta-Carotene Affects the Effects of Heme Oxygenase-1 in Isolated, Ischemic/Reperfused Rat Hearts: Potential Role of the Iron

by Evelin Csepanyi, Alexandra Gyongyosi, Istvan Lekli, Arpad Tosaki and Istvan Bak

Molecules 2022, 27(9), 3039; https://doi.org/10.3390/molecules27093039 - 9 May 2022

Cited by 2 | Viewed by 1883

Abstract

Beta-carotene (BC) is a well-known antioxidant. However, increasing evidence shows that under severe oxidative conditions, BC can become pro-oxidant, an effect that may be enhanced in the presence of iron (II). In our earlier studies, we observed that despite increasing heme oxygenase-1 (HO-1) [...] Read more.

Beta-carotene (BC) is a well-known antioxidant. However, increasing evidence shows that under severe oxidative conditions, BC can become pro-oxidant, an effect that may be enhanced in the presence of iron (II). In our earlier studies, we observed that despite increasing heme oxygenase-1 (HO-1) levels in the heart, the protective effects of BC have been lost when it was used at a high concentration. Since iron releases from heme as a consequence of HO-1 activity, we hypothesized that the application of an iron-chelator (IC) would reverse the lost cardiac protection associated with an elevated HO-1 level. Thus, in the present study, we investigated the effects of desferrioxiamine (DFO) in isolated, ischemic/reperfused rat hearts after long-term treatment with vehicle or high-dose (HD) BC. Vehicle or 150 mg/bw kg daily doses of BC were administered to the rats for 4 weeks, and then their hearts were removed and subjected to 30 min of global ischemia (ISA) followed by 120 min of reperfusion (REP). During the experiments, cardiac function was registered, and at the end of the REP period, infarct size (IS) and HO-1 expression were measured. The results show that DFO treatment alone during REP significantly ameliorated postischemic cardiac function and decreased IS, although HO-1 expression was not increased significantly. In hearts isolated from BC-treated rats, no cardioprotective effects, despite an elevated HO-1 level, were observed, while DFO administration after ISA resulted in a mild improvement in heart function and IS. Our results suggest that iron could have a role whether BC exerts antioxidant or pro-oxidant effects in ISA/REP-injured hearts. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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17 pages, 2697 KiB

Open AccessArticle

Dysregulation of Catalase by a Sulphamoylated Estradiol Analogue Culminates in Antimitotic Activity and Cell Death Induction in Breast Cancer Cell Lines

by Maphuti T. Lebelo, Anna M. Joubert and Michelle H. Visagie

Molecules 2021, 26(3), 622; https://doi.org/10.3390/molecules26030622 - 25 Jan 2021

Cited by 2 | Viewed by 2067

Abstract

Recent findings revealed that 2-ethyl-17-oxoestra-1,3,5(10)-trien-3-yl sulfamate (ESE-one) induces antiproliferative activity and cell rounding dependent on the generation of superoxide anion, hydrogen peroxide and peroxyl radical. In the current study, the role of these reactive oxygen species was assessed in the activity exerted by [...] Read more.

Recent findings revealed that 2-ethyl-17-oxoestra-1,3,5(10)-trien-3-yl sulfamate (ESE-one) induces antiproliferative activity and cell rounding dependent on the generation of superoxide anion, hydrogen peroxide and peroxyl radical. In the current study, the role of these reactive oxygen species was assessed in the activity exerted by ESE-one on cell cycle progression, mitochondrial membrane potential and cell death induction in breast tumorigenic cells. The influence of ESE-one was also investigated on superoxide dismutase and catalase activity. ESE-one induced a time-dependent accumulation of cells in the G₁ phase and G₂/M phase that is partially impaired by tiron and trolox and N,N′-dimethylthiourea suggesting that superoxide anion, hydrogen peroxide and peroxyl radical are required for these effects exerted by ESE-one. Flow cytometry data in MCF-7 cells demonstrated that tiron decreased depolarization of the membrane potential in ESE-one exposed cells, indicating that superoxide anion plays a role in the depolarization effects induced by ESE-one. Spectrophotometry data showed that ESE-one decreased catalase activity in both cell lines. This study contributes towards pertinent information regarding the effects of an in silico-designed sulfamoylated compound on antioxidant enzymes leading to aberrant quantities of specific reactive oxygen species resulting in antimitotic activity culminating in the induction of cell death in breast cancer cell lines. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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14 pages, 2515 KiB

Open AccessArticle

Beneficial Regulation of Cellular Oxidative Stress Effects, and Expression of Inflammatory, Angiogenic, and the Extracellular Matrix Remodeling Proteins by 1α,25-Dihydroxyvitamin D3 in a Melanoma Cell Line

by Neena Philips, Philips Samuel, Thomas Keller, Asma Alharbi, Samar Alshalan and Sara-Ali Shamlan

Molecules 2020, 25(5), 1164; https://doi.org/10.3390/molecules25051164 - 5 Mar 2020

Cited by 8 | Viewed by 5369

Abstract

The causes of cancer include the cellular accumulation reactive oxygen species (ROS), which overrides the cellular antioxidants such as superoxide dismutase, from intrinsic aging, genetics, and exposure to environmental pollutants and ultraviolet (UV) radiation. The ROS damage biomolecules such as DNA (including p53 [...] Read more.

The causes of cancer include the cellular accumulation reactive oxygen species (ROS), which overrides the cellular antioxidants such as superoxide dismutase, from intrinsic aging, genetics, and exposure to environmental pollutants and ultraviolet (UV) radiation. The ROS damage biomolecules such as DNA (including p53 gene), RNA, and lipids, and activate inflammatory, angiogenic, and extracellular matrix (ECM) remodeling proteins; which collectively facilitate carcinogenesis. The 1α,25-dihydroxyvitamin D3 (Vitamin D) has anti-carcinogenic potential from its antioxidant, anti-inflammatory, and endocrine properties. We examined the anti-carcinogenic mechanism of vitamin D through the beneficial regulation of oxidative stress effects (oxidative DNA/RNA damage, superoxide dismutase expression, membrane damage, and p53 promoter activity), and expression (at the protein, mRNA and/or promoter levels) of inflammatory mediators (interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α)), angiogenic mediators (transforming growth factor-β (TGF-β), and vascular endothelial growth factor (VEGF)), and the ECM remodeling proteins (matrix metalloproteinases (MMP)-1 and MMP-2) by vitamin D in melanoma cells. Vitamin D inhibited oxidative DNA/RNA damage and membrane damage; and stimulated superoxide dismutase expression and p53 promoter activity in melanoma cells. It inhibited the expression of IL-1, TNF-α, TGF-β, VEGF, MMP-1 and MMP-2 by transcriptional or post-transcriptional mechanisms. We conclude that vitamin D is beneficial to melanoma cells through the inhibition of oxidative DNA/RNA damage, membrane damage, and the expression of inflammatory, angiogenic and ECM remodeling proteins; and the stimulation of superoxide dismutase expression and p53 promoter activity. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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15 pages, 1848 KiB

Open AccessArticle

The Neuroprotective Effects of Histamine H3 Receptor Antagonist E177 on Pilocarpine-Induced Status Epilepticus in Rats

by Alaa Alachkar, Sheikh Azimullah, Shreesh K. Ojha, Rami Beiram, Dorota Łażewska, Katarzyna Kieć-Kononowicz and Bassem Sadek

Molecules 2019, 24(22), 4106; https://doi.org/10.3390/molecules24224106 - 14 Nov 2019

Cited by 13 | Viewed by 3180

Abstract

Epilepsy is a multifaceted neurological disorder which severely affects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases [...] Read more.

Epilepsy is a multifaceted neurological disorder which severely affects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the effect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the effects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective effect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist R-(α)-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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Review

Jump to: Research

16 pages, 1447 KiB

Open AccessReview

Current Status of Endoplasmic Reticulum Stress in Type II Diabetes

by Sagir Mustapha, Mustapha Mohammed, Ahmad Khusairi Azemi, Abubakar Ibrahim Jatau, Aishatu Shehu, Lukman Mustapha, Ibrahim Muazzamu Aliyu, Rabi’u Nuhu Danraka, Abdulbasit Amin, Auwal Adam Bala, Wan Amir Nizam Wan Ahmad, Aida Hanum Ghulam Rasool, Mohd Rais Mustafa and Siti Safiah Mokhtar

Molecules 2021, 26(14), 4362; https://doi.org/10.3390/molecules26144362 - 19 Jul 2021

Cited by 29 | Viewed by 5253

Abstract

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The [...] Read more.

The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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21 pages, 835 KiB

Open AccessReview

Pathological and Pharmacological Roles of Mitochondrial Reactive Oxygen Species in Malignant Neoplasms: Therapies Involving Chemical Compounds, Natural Products, and Photosensitizers

by Yasuyoshi Miyata, Yuta Mukae, Junki Harada, Tsuyoshi Matsuda, Kensuke Mitsunari, Tomohiro Matsuo, Kojiro Ohba and Hideki Sakai

Molecules 2020, 25(22), 5252; https://doi.org/10.3390/molecules25225252 - 11 Nov 2020

Cited by 9 | Viewed by 2871

Abstract

Oxidative stress plays an important role in cellular processes. Consequently, oxidative stress also affects etiology, progression, and response to therapeutics in various pathological conditions including malignant tumors. Oxidative stress and associated outcomes are often brought about by excessive generation of reactive oxygen species [...] Read more.

Oxidative stress plays an important role in cellular processes. Consequently, oxidative stress also affects etiology, progression, and response to therapeutics in various pathological conditions including malignant tumors. Oxidative stress and associated outcomes are often brought about by excessive generation of reactive oxygen species (ROS). Accumulation of ROS occurs due to dysregulation of homeostasis in an otherwise strictly controlled physiological condition. In fact, intracellular ROS levels are closely associated with the pathological status and outcome of numerous diseases. Notably, mitochondria are recognized as the critical regulator and primary source of ROS. Damage to mitochondria increases mitochondrial ROS (mROS) production, which leads to an increased level of total intracellular ROS. However, intracellular ROS level may not always reflect mROS levels, as ROS is not only produced by mitochondria but also by other organelles such as endoplasmic reticulum and peroxisomes. Thus, an evaluation of mROS would help us to recognize the biological and pathological characteristics and predictive markers of malignant tumors and develop efficient treatment strategies. In this review, we describe the pathological significance of mROS in malignant neoplasms. In particular, we show the association of mROS-related signaling in the molecular mechanisms of chemically synthesized and natural chemotherapeutic agents and photodynamic therapy. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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17 pages, 1205 KiB

Open AccessFeature PaperReview

Targeting Oxidative Stress for Disease Prevention and Therapy: Where Do We Stand, and Where Do We Go from Here

by Cristina Vassalle, Maristella Maltinti and Laura Sabatino

Molecules 2020, 25(11), 2653; https://doi.org/10.3390/molecules25112653 - 7 Jun 2020

Cited by 50 | Viewed by 5608

Abstract

Oxidative stress (OxS) is one of the main processes related to aging and a common denominator of many different chronic/degenerative diseases (e.g., cardiovascular and neurodegenerative conditions and cancer). Thus, its potential modulation by supplementation/pharmacological therapy caused a lot of interest. However, these expectations [...] Read more.

Oxidative stress (OxS) is one of the main processes related to aging and a common denominator of many different chronic/degenerative diseases (e.g., cardiovascular and neurodegenerative conditions and cancer). Thus, its potential modulation by supplementation/pharmacological therapy caused a lot of interest. However, these expectations have been mitigated by the obtainment of controversial results (beneficial, null, or adverse effects) following antioxidant interventions. Here, we discuss the current understanding of OxS assessment in health and disease, challenges and the potential of its evaluation in clinical practice, and available and future development for supplementation and pharmacologic strategies targeting OxS. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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24 pages, 1213 KiB

Open AccessReview

Nitrosative Stress and Its Association with Cardiometabolic Disorders

by Israel Pérez-Torres, Linaloe Manzano-Pech, María Esther Rubio-Ruíz, María Elena Soto and Verónica Guarner-Lans

Molecules 2020, 25(11), 2555; https://doi.org/10.3390/molecules25112555 - 31 May 2020

Cited by 71 | Viewed by 5690

Abstract

Reactive nitrogen species (RNS) are formed when there is an abnormal increase in the level of nitric oxide (NO) produced by the inducible nitric oxide synthase (iNOS) and/or by the uncoupled endothelial nitric oxide synthase (eNOS). The presence of high concentrations of superoxide [...] Read more.

Reactive nitrogen species (RNS) are formed when there is an abnormal increase in the level of nitric oxide (NO) produced by the inducible nitric oxide synthase (iNOS) and/or by the uncoupled endothelial nitric oxide synthase (eNOS). The presence of high concentrations of superoxide anions (O₂⁻) is also necessary for their formation. RNS react three times faster than O₂⁻ with other molecules and have a longer mean half life. They cause irreversible damage to cell membranes, proteins, mitochondria, the endoplasmic reticulum, nucleic acids and enzymes, altering their activity and leading to necrosis and to cell death. Although nitrogen species are important in the redox imbalance, this review focuses on the alterations caused by the RNS in the cellular redox system that are associated with cardiometabolic diseases. Currently, nitrosative stress (NSS) is implied in the pathogenesis of many diseases. The mechanisms that produce damage remain poorly understood. In this paper, we summarize the current knowledge on the participation of NSS in the pathology of cardiometabolic diseases and their possible mechanisms of action. This information might be useful for the future proposal of anti-NSS therapies for cardiometabolic diseases. Full article

(This article belongs to the Special Issue Oxidative Stress as a Pharmacological Target for Medicinal Chemistry)

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