Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

The mineralocorticoid receptor (MR) and mineralocorticoids regulate epithelial handling of electrolytes, and induces diverse effects on other tissues. Traditionally, the effects of MR were ascribed to ligand–receptor binding and activation of gene transcription. However, the MR also utilises a number of intracellular signalling cascades, often by transactivating unrelated receptors, to change cell function more rapidly. Although aldosterone is the physiological mineralocorticoid, it is not the sole ligand for MR. Tissue-selective and mineralocorticoid-specific effects are conferred through the enzyme 11β-hydroxysteroid dehydrogenase 2, cellular redox status and properties of the MR itself. Furthermore, not all aldosterone effects are mediated via MR, with implication of the involvement of other membrane-bound receptors such as GPER. This review will describe the ligands, receptors and intracellular mechanisms available for mineralocorticoid hormone and receptor signalling and illustrate their complex interactions in physiology and disease.

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Oxidation of ubiquinol by peroxynitrite: implications for protection of mitochondria against nitrosative damage

Biochemical Journal ◽

10.1042/bj3490035 ◽

2000 ◽

Vol 349 (1) ◽

pp. 35-42 ◽

Cited By ~ 26

Author(s):

Francisco SCHÖPFER ◽

Natalia RIOBÓ ◽

María Cecilia CARRERAS ◽

Beatriz ALVAREZ ◽

Rafael RADI ◽

...

Keyword(s):

Radical Scavenging ◽

Redox Status ◽

Experimental Models ◽

Dependent Manner ◽

Mitochondrial Membranes ◽

Concentration Dependent Manner ◽

Major Pathway ◽

Membrane Bound ◽

Spectroscopy Studies

A major pathway of nitric oxide utilization in mitochondria is its conversion to peroxynitrite, a species involved in biomolecule damage via oxidation, hydroxylation and nitration reactions. In the present study the potential role of mitochondrial ubiquinol in protecting against peroxynitrite-mediated damage is examined and the requirements of the mitochondrial redox status that support this function of ubiquinol are established. (1) Absorption and EPR spectroscopy studies revealed that the reactions involved in the ubiquinol/peroxynitrite interaction were first-order in peroxynitrite and zero-order in ubiquinol, in agreement with the rate-limiting formation of a reactive intermediate formed during the isomerization of peroxynitrite to nitrate. Ubiquinol oxidation occurred in one-electron transfer steps as indicated by the formation of ubisemiquinone. (2) Peroxynitrite promoted, in a concentration-dependent manner, the formation of superoxide anion by mitochondrial membranes. (3) Ubiquinol protected against peroxynitrite-mediated nitration of tyrosine residues in albumin and mitochondrial membranes, as suggested by experimental models, entailing either addition of ubiquinol or expansion of the mitochondrial ubiquinol pool caused by selective inhibitors of complexes III and IV. (4) Increase in membrane-bound ubiquinol partially prevented the loss of mitochondrial respiratory function induced by peroxynitrite. These findings are analysed in terms of the redox transitions of ubiquinone linked to both nitrogen-centred radical scavenging and oxygen-centred radical production. It may be concluded that the reaction of mitochondrial ubiquinol with peroxynitrite is part of a complex regulatory mechanism with implications for mitochondrial function and integrity.

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A Regulatory Role of NAD Redox Status on Flavin Cofactor Homeostasis inS. cerevisiaeMitochondria

Oxidative Medicine and Cellular Longevity ◽

10.1155/2013/612784 ◽

2013 ◽

Vol 2013 ◽

pp. 1-16 ◽

Cited By ~ 6

Author(s):

Teresa Anna Giancaspero ◽

Vittoria Locato ◽

Maria Barile

Keyword(s):

Saccharomyces Cerevisiae ◽

Nicotinamide Adenine Dinucleotide ◽

Flavin Adenine Dinucleotide ◽

Redox Balance ◽

Redox Status ◽

Cellular Redox ◽

Isolated Mitochondria ◽

Nudix Hydrolases ◽

Order Of Magnitude

Flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NAD) are two redox cofactors of pivotal importance for mitochondrial functionality and cellular redox balance. Despite their relevance, the mechanism by which intramitochondrial NAD(H) and FAD levels are maintained remains quite unclear inSaccharomyces cerevisiae. We investigated here the ability of isolated mitochondria to degrade externally added FAD and NAD (in both its reduced and oxidized forms). A set of kinetic experiments demonstrated that mitochondrial FAD and NAD(H) destroying enzymes are different from each other and from the already characterized NUDIX hydrolases. We studied here, in some detail, FAD pyrophosphatase (EC 3.6.1.18), which is inhibited by NAD+and NADH according to a noncompetitive inhibition, withKivalues that differ from each other by an order of magnitude. These findings, together with the ability of mitochondrial FAD pyrophosphatase to metabolize endogenous FAD, presumably deriving from mitochondrial holoflavoproteins destined to degradation, allow for proposing a novel possible role of mitochondrial NAD redox status in regulating FAD homeostasis and/or flavoprotein degradation inS. cerevisiae.

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New insight on the role of liraglutide in alleviating dexamethasone-induced pancreatic cytotoxicity via improving redox status, autophagy flux and PI3K/Akt/Nrf2 signaling

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2021-0183 ◽

2021 ◽

Author(s):

Walaa Elseady ◽

Rasha Abd Ellatif ◽

Remon Estfanous ◽

Marwa Emam ◽

Walaa Arafa Keshk

Keyword(s):

Cell Function ◽

Pancreatic Injury ◽

Redox Status ◽

Protective Role ◽

Caspase 9 ◽

Β Cell ◽

Autophagy Flux ◽

Β Cell Function ◽

Underlying Mechanisms

Chronic glucocorticoids therapy is commonly complicated by steroid diabetes, while the underlying mechanisms are still elusive. Liraglutide a glucagon like peptide -1 was initially found to induce glycemic control and recently it was found to have many pleotropic effects. However, its role in pancreas remains unknown. So, the present study aims to estimate the protective role of liraglutide on dexamethasone-induced pancreatic cytotoxicity, and hyperglycemia with highlighting the possible biochemical, molecular and cellular underlying mechanisms. Twenty-eight male Wistar rats were involved in this study and were randomly divided into four groups. Group III & IV were treated with 1mg/kg dexamethasone daily for 10 days. Group II & IV were treated with liraglutide in a dose of 0.8 mg/kg/day for 2 weeks. Pancreatic caspase-9, Nrf2, pAkt and sequestrome1 (p62) levels were assessed by immunoassay. Moreover, phosphoinositide 3-kinase (PI3K) expression by real time PCR, LC3B expression by immunohistochemistry, glycemic status, β-cell function by HOMA-β index, and pancreatic redox status were assessed. Liraglutide improved blood glucose level, β-cell function, pancreatic caspase 9 level, redox status, and autophagy. Additionally, it increased pancreatic PI3K, pAkt and Nrf2 levels. Moreover, preservation of pancreatic histological and the ultrastructural morphological features of β- and α-cell were observed. In conclusion: Liraglutide protected against dexamethasone-induced pancreatic injury, hyperglycemia and decelerated the progression towards steroid diabetes via activating PI3K/Akt/Nrf2 signaling and autophagy flux pathways

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Oxidative Stress-Mediated Skeletal Muscle Degeneration: Molecules, Mechanisms, and Therapies

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/6842568 ◽

2016 ◽

Vol 2016 ◽

pp. 1-13 ◽

Cited By ~ 23

Author(s):

Min Hee Choi ◽

Jin Rong Ow ◽

Nai-Di Yang ◽

Reshma Taneja

Keyword(s):

Oxidative Stress ◽

Molecular Level ◽

Redox Homeostasis ◽

Redox Status ◽

Muscle Degeneration ◽

Dystrophic Muscle ◽

Telomere Shortening ◽

Cellular Redox ◽

Pathological Conditions

Oxidative stress is a loss of balance between the production of reactive oxygen species during cellular metabolism and the mechanisms that clear these species to maintain cellular redox homeostasis. Increased oxidative stress has been associated with muscular dystrophy, and many studies have proposed mechanisms that bridge these two pathological conditions at the molecular level. In this review, the evidence indicating a causal role of oxidative stress in the pathogenesis of various muscular dystrophies is revisited. In particular, the mediation of cellular redox status in dystrophic muscle by NF-κB pathway, autophagy, telomere shortening, and epigenetic regulation are discussed. Lastly, the current stance of targeting these pathways using antioxidant therapies in preclinical and clinical trials is examined.

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The Emerging Role of TXNIP in Ischemic and Cardiovascular Diseases; A Novel Marker and Therapeutic Target

International Journal of Molecular Sciences ◽

10.3390/ijms22041693 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1693

Author(s):

Alison Domingues ◽

Julia Jolibois ◽

Perrine Marquet de Rougé ◽

Valérie Nivet-Antoine

Keyword(s):

Oxidative Stress ◽

Cardiovascular Diseases ◽

Therapeutic Target ◽

Redox Status ◽

Interacting Protein ◽

Cellular Redox ◽

Thioredoxin Interacting Protein ◽

Potential Biomarker ◽

Ischemic Diseases

Thioredoxin interacting protein (TXNIP) is a metabolism- oxidative- and inflammation-related marker induced in cardiovascular diseases and is believed to represent a possible link between metabolism and cellular redox status. TXNIP is a potential biomarker in cardiovascular and ischemic diseases but also a novel identified target for preventive and curative medicine. The goal of this review is to focus on the novelties concerning TXNIP. After an overview in TXNIP involvement in oxidative stress, inflammation and metabolism, the remainder of this review presents the clues used to define TXNIP as a new marker at the genetic, blood, or ischemic site level in the context of cardiovascular and ischemic diseases.

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In vivo assessment of silver nanoparticle induced reactive oxygen species reveals tissue specific effects on cellular redox status in the nematode Caenorhabditis elegans

The Science of The Total Environment ◽

10.1016/j.scitotenv.2020.137665 ◽

2020 ◽

Vol 721 ◽

pp. 137665 ◽

Cited By ~ 1

Author(s):

Lisa M. Rossbach ◽

Deborah H. Oughton ◽

Erica Maremonti ◽

Claire Coutris ◽

Dag A. Brede

Keyword(s):

Reactive Oxygen Species ◽

Caenorhabditis Elegans ◽

Silver Nanoparticle ◽

Redox Status ◽

Oxygen Species ◽

Nematode Caenorhabditis Elegans ◽

Cellular Redox ◽

Specific Effects ◽

In Vivo Assessment

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Post-Translational S-Nitrosylation of Proteins in Regulating Cardiac Oxidative Stress

Antioxidants ◽

10.3390/antiox9111051 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1051 ◽

Cited By ~ 1

Author(s):

Xiaomeng Shi ◽

Hongyu Qiu

Keyword(s):

Therapeutic Potential ◽

Heart Diseases ◽

Redox Homeostasis ◽

Redox Status ◽

Cardiac Protection ◽

Cellular Functions ◽

Post Translational Modifications ◽

Cellular Redox ◽

Novel Therapeutic Strategies

Like other post-translational modifications (PTMs) of proteins, S-nitrosylation has been considered a key regulatory mechanism of multiple cellular functions in many physiological and disease conditions. Emerging evidence has demonstrated that S-nitrosylation plays a crucial role in regulating redox homeostasis in the stressed heart, leading to discoveries in the mechanisms underlying the pathogenesis of heart diseases and cardiac protection. In this review, we summarize recent studies in understanding the molecular and biological basis of S-nitrosylation, including the formation, spatiotemporal specificity, homeostatic regulation, and association with cellular redox status. We also outline the currently available methods that have been applied to detect S-nitrosylation. Additionally, we synopsize the up-to-date studies of S-nitrosylation in various cardiac diseases in humans and animal models, and we discuss its therapeutic potential in cardiac protection. These pieces of information would bring new insights into understanding the role of S-nitrosylation in cardiac pathogenesis and provide novel avenues for developing novel therapeutic strategies for heart diseases.

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Effects of Sodium-Glucose Co-Transporter 2 Inhibitors on Vascular Cell Function and Arterial Remodeling

International Journal of Molecular Sciences ◽

10.3390/ijms22168786 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8786

Author(s):

William Durante ◽

Ghazaleh Behnammanesh ◽

Kelly J. Peyton

Keyword(s):

Cell Function ◽

Sglt2 Inhibitors ◽

Aortic Aneurysms ◽

Specific Effects ◽

Abdominal Aortic ◽

Patients With Diabetes ◽

Pulmonary Arterial ◽

And Migration ◽

Selection Of

Cardiovascular disease is the leading cause of morbidity and mortality in diabetes. Recent clinical studies indicate that sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with diabetes. The mechanism underlying the beneficial effect of SGLT2 inhibitors is not completely clear but may involve direct actions on vascular cells. SGLT2 inhibitors increase the bioavailability of endothelium-derived nitric oxide and thereby restore endothelium-dependent vasodilation in diabetes. In addition, SGLT2 inhibitors favorably regulate the proliferation, migration, differentiation, survival, and senescence of endothelial cells (ECs). Moreover, they exert potent antioxidant and anti-inflammatory effects in ECs. SGLT2 inhibitors also inhibit the contraction of vascular smooth muscle cells and block the proliferation and migration of these cells. Furthermore, studies demonstrate that SGLT2 inhibitors prevent postangioplasty restenosis, maladaptive remodeling of the vasculature in pulmonary arterial hypertension, the formation of abdominal aortic aneurysms, and the acceleration of arterial stiffness in diabetes. However, the role of SGLT2 in mediating the vascular actions of these drugs remains to be established as important off-target effects of SGLT2 inhibitors have been identified. Future studies distinguishing drug- versus class-specific effects may optimize the selection of specific SGLT2 inhibitors in patients with distinct cardiovascular pathologies.

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