Showing papers in "Antioxidants & Redox Signaling in 2015"
TL;DR: It is important to realize that oxidative stress is a nuanced phenomenon that is difficult to characterize, and one biomarker is not necessarily better than others, and the vast diversity in oxidative stress between diseases and conditions has to be taken into account when selecting the most appropriate biomarker.
Abstract: Significance: Oxidative stress is considered to be an important component of various diseases. A vast number of methods have been developed and used in virtually all diseases to measure the extent and nature of oxidative stress, ranging from oxidation of DNA to proteins, lipids, and free amino acids. Recent Advances: An increased understanding of the biology behind diseases and redox biology has led to more specific and sensitive tools to measure oxidative stress markers, which are very diverse and sometimes very low in abundance. Critical Issues: The literature is very heterogeneous. It is often difficult to draw general conclusions on the significance of oxidative stress biomarkers, as only in a limited proportion of diseases have a range of different biomarkers been used, and different biomarkers have been used to study different diseases. In addition, biomarkers are often measured using nonspecific methods, while specific methodologies are often too sophisticated or laborious for routine clin...
571 citations
TL;DR: It is imperative to know how this dual action of ROS works during NLRP3 inflammation activation on different stimuli and what relevance such spatiotemporal redox regulation ofNLRP3 inflammasomes has in cell or organ functions and possible human diseases.
Abstract: Significance: Inflammasomes are multiprotein complexes localized within the cytoplasm of the cell that are responsible for the maturation of proinflammatory cytokines such as interleukin-1β (IL-1β) and IL-18, and the activation of a highly inflammatory form of cell death, pyroptosis. In response to infection or cellular stress, inflammasomes are assembled, activated, and involved in host defense and pathophysiology of diseases. Clarification of the molecular mechanisms leading to the activation of this intracellular inflammatory machinery may provide new insights into the concept of inflammation as the root of and route to human diseases. Recent Advances: The activation of inflammasomes, specifically the most fully characterized inflammasome—the nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome, is now emerging as a critical molecular mechanism for many degenerative diseases. Several models have been developed to describe how NLRP3 inflam...
568 citations
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TL;DR: The redox code is a set of principles that defines the positioning of the nicotinamide adenine dinucleotide and thiol/disulfide and other redox systems as well as the thiol redox proteome in space and time in biological systems.
Abstract: Significance: The redox code is a set of principles that defines the positioning of the nicotinamide adenine dinucleotide (NAD, NADP) and thiol/disulfide and other redox systems as well as the thiol redox proteome in space and time in biological systems. The code is richly elaborated in an oxygen-dependent life, where activation/deactivation cycles involving O2 and H2O2 contribute to spatiotemporal organization for differentiation, development, and adaptation to the environment. Disruption of this organizational structure during oxidative stress represents a fundamental mechanism in system failure and disease. Recent Advances: Methodology in assessing components of the redox code under physiological conditions has progressed, permitting insight into spatiotemporal organization and allowing for identification of redox partners in redox proteomics and redox metabolomics. Critical Issues: Complexity of redox networks and redox regulation is being revealed step by step, yet much still needs to be lea...
435 citations
TL;DR: Whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications is discussed.
Abstract: Significance: Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Recent Advances: Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological ...
426 citations
TL;DR: Hydrogen sulfide has been recognized as a signaling molecule as well as a cytoprotectant that modulates neurotransmission, regulates vascular tone, and protects various tissues and organs from oxidative stress and ischemia-reperfusion injury.
Abstract: Significance: Hydrogen sulfide (H2S) has been recognized as a signaling molecule as well as a cytoprotectant. It modulates neurotransmission, regulates vascular tone, and protects various tissues and organs, including neurons, the heart, and kidneys, from oxidative stress and ischemia-reperfusion injury. H2S is produced from l-cysteine by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase. Recent Advances: In addition to these enzymes, we recently identified a novel pathway to produce H2S from d-cysteine, which involves d-amino acid oxidase (DAO) along with 3MST. These enzymes are localized in the cytoplasm, mitochondria, and peroxisomes. However, some enzymes translocate to organelles under specific conditions. Moreover, H2S-derived potential signaling molecules such as polysulfides and HSNO have been identified. Critical Issues: The physiological stimulations, which trigger the production of H2S and i...
255 citations
TL;DR: The signaling at the MAMs represents a promising pharmacological target for several important human diseases and is reviewed for its key role in selected neurological disorders.
Abstract: Significance: In all cells, the endoplasmic reticulum (ER) and mitochondria are physically connected to form junctions termed mitochondria-associated membranes (MAMs). This subcellular compartment is under intense investigation because it represents a “hot spot” for the intracellular signaling of important pathways, including the synthesis of cholesterol and phospholipids, calcium homeostasis, and reactive oxygen species (ROS) generation and activity. Recent Advances: The advanced methods currently used to study this fascinating intracellular microdomain in detail have enabled the identification of the molecular composition of MAMs and their involvement within different physiopathological contexts. Critical Issues: Here, we review the knowledge regarding (i) MAMs composition in terms of protein composition, (ii) the relationship between MAMs and ROS, (iii) the involvement of MAMs in cell death programs with particular emphasis within the tumor context, (iv) the emerging role of MAMs during inflam...
242 citations
TL;DR: Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation, including molecules conjugated with lipophilic cations or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes.
Abstract: Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid- and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, cu...
198 citations
TL;DR: The levels of mitochondrial DAMPs in patients are often associated with severity and prognosis of human diseases, such as infection, asthma, ischemic heart disease, and cancer, and regulation of mitochondrial DAMP-mediated immune responses may be important to alter the progression ofhuman diseases.
Abstract: Significance: Mitochondria, vital cellular power plants to generate energy, are involved in immune responses. Mitochondrial damage-associated molecular patterns (DAMPs) are molecules that are released from mitochondria to extracellular space during cell death and include not only proteins but also DNA or lipids. Mitochondrial DAMPs induce inflammatory responses and are critically involved in the pathogenesis of various diseases. Recent Advances: Recent studies elucidate the molecular mechanisms by which mitochondrial DAMPs are released and initiate immune responses by use of genetically modulated cells or animals. Importantly, the levels of mitochondrial DAMPs in patients are often associated with severity and prognosis of human diseases, such as infection, asthma, ischemic heart disease, and cancer. Critical Issues: Although mitochondrial DAMPs can represent proinflammatory molecules in various experimental models, their roles in human diseases may be multifunctional and complex. It remains uncl...
194 citations
TL;DR: Evidence-based use of antioxidants may include site-directed application, time-limited high dosing, (functional) pharmacological repair of oxidized biomolecules, and triggers of endogenous antioxidant response systems, and ideally, patient stratification through predictive biomarkers and possibly imaging modalities.
Abstract: Significance: It is generally accepted that reactive oxygen species (ROS) scavenging molecules or antioxidants exert health-promoting effects and thus their consumption as food additives and nutraceuticals has been greatly encouraged. Antioxidants may be beneficial in situations of subclinical deficiency and increased demand or acutely upon high-dose infusion. However, to date, there is little clinical evidence for the long-term benefit of most antioxidants. Alarmingly, recent evidence points even to health risks, in particular for supplements of lipophilic antioxidants. Recent Advances: The biological impact of ROS depends not only on their quantities but also on their chemical nature, (sub)cellular and tissue location, and the rates of their formation and degradation. Moreover, ROS serve important physiological functions; thus, inappropriate removal of ROS may cause paradoxical reductive stress and thereby induce or promote disease. Critical Issues: Any recommendation on antioxidants must be ba...
192 citations
TL;DR: Investigation of the role of TrxR1 as a regulator of Nrf2 activation will facilitate further studies of redox control in diverse cells and tissues of mammals, and possibly also in animals of other classes.
Abstract: Significance: All cells must maintain a balance between oxidants and reductants, while allowing for fluctuations in redox states triggered by signaling, altered metabolic flow, or extracellular stimuli. Furthermore, they must be able to rapidly sense and react to various challenges that would disrupt the redox homeostasis. Recent Advances: Many studies have identified Keap1 as a key sensor for oxidative or electrophilic stress, with modification of Keap1 by oxidation or electrophiles triggering Nrf2-mediated transcriptional induction of enzymes supporting reductive and detoxification pathways. However, additional mechanisms for Nrf2 regulation are likely to exist upstream of, or in parallel with, Keap1. Critical Issues: Here, we propose that the mammalian selenoprotein thioredoxin reductase 1 (TrxR1) is a potent regulator of Nrf2. A high chemical reactivity of TrxR1 and its vital role for the thioredoxin (Trx) system distinguishes TrxR1 as a prime target for electrophilic challenges. Chemical mod...
182 citations
TL;DR: This study provides a novel mechanism for fructose-induced NAFLD pathogenesis by which the ROS-TXNIP pathway mediates hepatocellular NLRP3 inflammasome activation, inflammation and lipid accumulation.
Abstract: Aims: Increased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation. Results: Rats were fed a 10% fructose diet for 8 weeks and treated with allopurinol and quercetin during the last 4 weeks. Five millimolars of fructose-exposed hepatocytes (primary rat hepatocytes, rat hepatic parenchymal cells [RHPCs], HLO2, HepG2) were co-incubated with antioxidants or caspase-1 inhibitor or subjected to TXNIP or NLRP3 siRNA interference. Fructose induced NLRP3 inflammasome activation and pro-inflammatory cytokine secretion, janus-activated kinase 2...
TL;DR: The current state of the art of pharmacological CBS inhibitors is reviewed, with special reference to the complex pharmacological actions of aminooxyacetic acid, and a controversy in the literature regarding the effects of H2S donor on cancer cell proliferation and survival is presented.
Abstract: Significance: Cancer represents a major socioeconomic problem; there is a significant need for novel therapeutic approaches targeting tumor-specific pathways. Recent Advances: In colorectal and ovarian cancers, an increase in the intratumor production of hydrogen sulfide (H2S) from cystathionine β-synthase (CBS) plays an important role in promoting the cellular bioenergetics, proliferation, and migration of cancer cells. It also stimulates peritumor angiogenesis inhibition or genetic silencing of CBS exerts antitumor effects both in vitro and in vivo, and potentiates the antitumor efficacy of anticancer therapeutics. Critical Issues: Recently published studies are reviewed, implicating CBS overexpression and H2S overproduction in tumor cells as a tumor-growth promoting “bioenergetic fuel” and “survival factor,” followed by an overview of the experimental evidence demonstrating the anticancer effect of CBS inhibition. Next, the current state of the art of pharmacological CBS inhibitors is reviewed...
TL;DR: The biochemical and biological properties of sulforaphane are discussed with a particular emphasis on the anticancer properties of the dietary compound, which possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms.
Abstract: Significance: Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. Critical Issues: In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the die...
TL;DR: Evidence is provided that low shear stress enhances PCSK9 expression in concert with ROS generation in vascular ECs and SMCs, and it is proposed thatPCSK9-ROS interaction may be important in the development of atherosclerosis in arterial channels with lowShear stress.
Abstract: Aims: To investigate a possible link between hemodynamic shear stress, reactive oxygen species (ROS) generation, and proprotein convertase subtilisin/kexin type 9 (PCSK9) expression. Results: Using a parallel-plate flow chamber, we observed that PCSK9 expression in vascular smooth muscle cells (SMCs) and endothelial cells (ECs) reached maximal value at low shear stress (3–6 dynes/cm2), and then began to decline with an increase in shear stress. PCSK9 expression increased when cells were treated with lipopolysaccharide. PCSK9 expression was always greater in SMCs than in ECs. ROS generation followed the same pattern as PCSK9 expression. Aortic branching and aorta–iliac bifurcation regions of mouse aorta that express low shear stress were also found to have greater PCSK9 expression (vs. other regions). To determine a relationship between ROS and PCSK9 expression, ECs and SMCs were treated with ROS inhibitors diphenylene-iodonium chloride and apocynin, and both markedly reduced PCSK9 expression. Rel...
TL;DR: The data suggest that NOX4, but not NOX1/2, and mitochondrial oxidative stress are mediators of CVD in aging under hyperlipidemic conditions.
Abstract: Aims: Increased oxidative stress and vascular inflammation are implicated in increased cardiovascular disease (CVD) incidence with age. We and others demonstrated that NOX1/2 NADPH oxidase inhibition, by genetic deletion of p47phox, in Apoe−/− mice decreases vascular reactive oxygen species (ROS) generation and atherosclerosis in young age. The present study examined whether NOX1/2 NADPH oxidases are also pivotal to aging-associated CVD. Results: Both aged (16 months) Apoe−/− and Apoe−/−/p47phox−/− mice had increased atherosclerotic lesion area, aortic stiffness, and systolic dysfunction compared with young (4 months) cohorts. Cellular and mitochondrial ROS (mtROS) levels were significantly higher in aortic wall and vascular smooth muscle cells (VSMCs) from aged wild-type and p47phox−/− mice. VSMCs from aged mice had increased mitochondrial protein oxidation and dysfunction and increased vascular cell adhesion molecule 1 expression, which was abrogated with (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl...
TL;DR: Augmentation and/or restoration of autophagy flux may provide a potential therapeutic target for treatment of TBI and SCI, and emerging data suggest that depending on the location and severity of traumatic injury, autophagic flux may be either increased or decreased after central nervous system trauma.
Abstract: Significance: Traumatic brain injury (TBI) and spinal cord injury (SCI) are major causes of death and long-term disability worldwide. Despite important pathophysiological differences between these disorders, in many respects, mechanisms of injury are similar. During both TBI and SCI, some cells are directly mechanically injured, but more die as a result of injury-induced biochemical changes (secondary injury). Autophagy, a lysosome-dependent cellular degradation pathway with neuroprotective properties, has been implicated both clinically and experimentally in the delayed response to TBI and SCI. However, until recently, its mechanisms and function remained unknown, reflecting in part the difficulty of isolating autophagic processes from ongoing cell death and other cellular events. Recent Advances: Emerging data suggest that depending on the location and severity of traumatic injury, autophagy flux—defined as the progress of cargo through the autophagy system and leading to its degradation—may be...
TL;DR: Endothelial homeostasis encompasses acute responses such as adaption of flow to tissue's demand and more sustained responses to injury such as re-endothelialization and sprouting of endothelial cells (ECs) and attraction of circulating angiogenic cells (CAC) which support repair of damaged endothelium.
Abstract: Significance: Disruption of endothelial function is considered a key event in the development and progression of atherosclerosis. Endothelial nitric oxide synthase (eNOS) is a central regulator of cellular function that is important to maintain endothelial homeostasis. Recent Advances: Endothelial homeostasis encompasses acute responses such as adaption of flow to tissue's demand and more sustained responses to injury such as re-endothelialization and sprouting of endothelial cells (ECs) and attraction of circulating angiogenic cells (CAC), both of which support repair of damaged endothelium. The balance and the intensity of endothelial damage and repair might be reflected by changes in circulating endothelial microparticles (EMP) and CAC. Flow-mediated vasodilation (FMD) is a generally accepted clinical read-out of NO-dependent vasodilation, whereas EMP are upcoming prognostically validated markers of endothelial injury and CAC are reflective of the regenerative capacity with both expressing a f...
TL;DR: The data demonstrate that VDR is a novel endogenous self-defensive and cardioprotective receptor against MI/R injury, via mechanisms reducing oxidative stress, and inhibiting apoptosis and autophagy dysfunction-mediated cell death.
Abstract: Aims: To determine the roles of vitamin D receptor (VDR) in ischemia/reperfusion-induced myocardial injury and to investigate the underlying mechanisms involved. Results: The endogenous VDR expression was detected in the mouse heart, and myocardial ischemia/reperfusion (MI/R) upregulated VDR expression. Activation of VDR by natural and synthetic agonists reduced myocardial infarct size and improved cardiac function. Mechanistically, VDR activation inhibited endoplasmic reticulum (ER) stress (determined by the reduction of CCAAT/enhancer-binding protein homologous protein expression and caspase-12 activation), attenuated mitochondrial impairment (determined by the decrease of mitochondrial cytochrome c release and caspase-9 activation), and reduced cardiomyocyte apoptosis. Furthermore, VDR activation significantly inhibited MI/R-induced autophagy dysfunction (determined by the inhibition of Beclin 1 over-activation, the reduction of autophagosomes, the LC3-II/LC3-I ratio, p62 protein abundance, an...
TL;DR: This work addresses pleiotropic effects of organic nitrates, for example, their capacity to stimulate antioxidant pathways like those demonstrated for PETN, all of which may prevent adverse effects in response to long-term therapy.
Abstract: Organic nitrates, such as nitroglycerin (GTN), isosorbide-5-mononitrate and isosorbide dinitrate, and pentaerithrityl tetranitrate (PETN), when given acutely, have potent vasodilator effects improving symptoms in patients with acute and chronic congestive heart failure, stable coronary artery disease, acute coronary syndromes, or arterial hypertension. The mechanisms underlying vasodilation include the release of •NO or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase [ALDH-2]) and activation of the enzyme, soluble guanylyl cyclase. Increasing cyclic guanosine-3′,-5′-monophosphate (cGMP) levels lead to an activation of the cGMP-dependent kinase I, thereby causing the relaxation of the vascular smooth muscle by decreasing intracellular calcium concentrations. The hemodynamic and anti-ischemic effects of organic nitrates are rapidly lost upon long-term (low-dose) administration due to the rapid development of tolerance and endothelial ...
TL;DR: A deeper understanding of mitochondrial quality control programs' impact on intracellular inflammatory signaling will improve the approach to the restoration of mitochondrial homeostasis in the resolution of acute inflammation.
Abstract: Significance: Mitochondria play a vital role in cellular homeostasis and are susceptible to damage from inflammatory mediators released by the host defense. Cellular recovery depends, in part, on mitochondrial quality control programs, including mitochondrial biogenesis. Recent Advances: Early-phase inflammatory mediator proteins interact with PRRs to activate NF-κB-, MAPK-, and PKB/Akt-dependent pathways, resulting in increased expression or activity of coactivators and transcription factors (e.g., PGC-1α, NRF-1, NRF-2, and Nfe2l2) that regulate mitochondrial biogenesis. Inflammatory upregulation of NOS2-induced NO causes mitochondrial dysfunction, but NO is also a signaling molecule upregulating mitochondrial biogenesis via PGC-1α, participating in Nfe2l2-mediated antioxidant gene expression and modulating inflammation. NO and reactive oxygen species generated by the host inflammatory response induce the redox-sensitive HO-1/CO system, causing simultaneous induction of mitochondrial biogenesis ...
TL;DR: The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway.
Abstract: Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1–7) [Ang(1–7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear. Aims: To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway. Results: In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and α-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 ...
TL;DR: An extensive knowledge of the effects of protein oxidation on the aging process and its contribution to the development of age-related diseases could enable further strategies to reduce age- related impairments.
Abstract: Significance: A constant accumulation of oxidized proteins takes place during aging. Oxidation of proteins leads to a partial unfolding and, therefore, to aggregation. Protein aggregates impair the activity of cellular proteolytic systems (proteasomes, lysosomes), resulting in further accumulation of oxidized proteins. In addition, the accumulation of highly crosslinked protein aggregates leads to further oxidant formation, damage to macromolecules, and, finally, to apoptotic cell death. Furthermore, protein oxidation seems to play a role in the development of various age-related diseases, for example, neurodegenerative diseases. Recent Advances: The highly oxidized lipofuscin accumulates during aging. Lipofuscin formation might cause impaired lysosomal and proteasomal degradation, metal ion accumulation, increased reactive oxygen species formation, and apoptosis. Critical Issues: It is still unclear to which extent protein oxidation is involved in the progression of aging and in the development ...
TL;DR: GSK2795039 is the first small molecule to demonstrate inhibition of the NOX2 enzyme in vivo, and was selective over other NOX isoforms, xanthine oxidase, and endothelial nitric oxide synthase enzymes.
Abstract: Aims: The NADPH oxidase (NOX) family of enzymes catalyzes the formation of reactive oxygen species (ROS). NOX enzymes not only have a key role in a variety of physiological processes but also contribute to oxidative stress in certain disease states. To date, while numerous small molecule inhibitors have been reported (in particular for NOX2), none have demonstrated inhibitory activity in vivo. As such, there is a need for the identification of improved NOX inhibitors to enable further evaluation of the biological functions of NOX enzymes in vivo as well as the therapeutic potential of NOX inhibition. In this study, both the in vitro and in vivo pharmacological profiles of GSK2795039, a novel NOX2 inhibitor, were characterized in comparison with other published NOX inhibitors. Results: GSK2795039 inhibited both the formation of ROS and the utilization of the enzyme substrates, NADPH and oxygen, in a variety of semirecombinant cell-free and cell-based NOX2 assays. It inhibited NOX2 in an NADPH comp...
TL;DR: A review of the evidence for H2S-mediated O2 sensing is critically examined in this paper, which is based on a variety of experimental evidence including; (1) the effects of exogenous hydrogen sulfide mimic hypoxia, (2) H2s production and/or metabolism is biochemically coupled to O2, (3) tissue H 2S concentration is inversely related to Po 2 at physiologically relevant Po 2s, (4) compounds that inhibit or augment H 2 S production inhibit and augment hypoxic responses, (5) H 2
Abstract: Eukaryotic cells depend upon oxygen (O2) for their survival and elaborate mechanisms have evolved in multicellular animals, especially vertebrates, to monitor the availability of environmental O2, the efficiency of O2 extraction from the environment, ensure adequate O2 delivery to tissues and even to regulate cellular metabolism when O2 availability is compromised. In vertebrates, specialized O2 “sensing” cells have developed to carry out many of these processes. Although all O2 sensing cells ultimately couple low Po 2 (hypoxia) to physiological responses, how these cells actually detect hypoxia, i.e., the “O2 sensor” remains controversial. We have recently proposed that hydrogen sulfide (H2S) through its O2-dependent metabolism is a universal and phylogenetically ancient O2 sensing mechanism. This hypothesis is based on a variety of experimental evidence including; (1) the effects of exogenous H2S mimic hypoxia, (2) H2S production and/or metabolism is biochemically coupled to O2, (3) tissue H2S concentration is inversely related to Po 2 at physiologically relevant Po 2s, (4) compounds that inhibit or augment H2S production inhibit and augment hypoxic responses, (5) H2S acts upon effector mechanisms known to mediate hypoxic responses, (6) H2S was key to the origin of life and the advent of eukaryotic cells and the reciprocal relationship between O2 and H2S has been inexorably intertwined throughout evolution. The evidence for H2S-mediated O2 sensing is critically examined in this review.
TL;DR: It is suggested that the lower levels of oxidative stress incurred by TTS-noise exposure induce autophagy, which promotes OHC survival and leads to OHC death and NIHL.
Abstract: Aims: Reactive oxygen species play a dual role in mediating both cell stress and defense pathways. Here, we used pharmacological manipulations and siRNA silencing to investigate the relationship between autophagy and oxidative stress under conditions of noise-induced temporary, permanent, and severe permanent auditory threshold shifts (temporary threshold shift [TTS], permanent threshold shift [PTS], and severe PTS [sPTS], respectively) in adult CBA/J mice. Results: Levels of oxidative stress markers (4-hydroxynonenal [4-HNE] and 3-nitrotyrosine [3-NT]) increased in outer hair cells (OHCs) in a noise-dose-dependent manner, whereas levels of the autophagy marker microtubule-associated protein light chain 3 B (LC3B) were sharply elevated after TTS but rose only slightly in response to PTS and were unaltered by sPTS noise. Furthermore, green fluorescent protein (GFP) intensity increased in GFP-LC3 mice after TTS-noise exposure. Treatment with rapamycin, an autophagy activator, significantly increase...
TL;DR: The activation of the inflammasome in the heart during ischemic and nonischemic injury represents an exaggerated response to sterile injury and promotes adverse cardiac remodeling and failure.
Abstract: Significance: An inflammatory response follows an injury of any nature, and while such a response is an attempt to promote healing, it may, itself, result in further injury. Recent Advances: The inflammasome is a macromolecular structure recently recognized as a central mediator in the acute inflammatory response. The inflammasome senses the injury and it amplifies the response by leading to the release of powerful pro-inflammatory cytokines, interleukin-1β (IL-1β) and IL-18. Critical Issues: The activation of the inflammasome in the heart during ischemic and nonischemic injury represents an exaggerated response to sterile injury and promotes adverse cardiac remodeling and failure. Future Directions: Pilot clinical trials have explored blockade of the inflammasome-derived IL-1β and have shown beneficial effects on cardiac function. Additional clinical studies testing this approach are warranted. Moreover, specific inflammasome inhibitors that are ready for clinical use are currently lacking. Anti...
TL;DR: Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy.
Abstract: Significance: Epigenetic inactivation of pivotal genes involved in cell growth is a hallmark of human pathologies, in particular cancer. Histone acetylation balance obtained through opposing actions of histone deacetylases (HDACs) and histone acetyltransferases is one epigenetic mechanism controlling gene expression and is, thus, associated with disease etiology and progression. Interfering pharmacologically with HDAC activity can correct abnormalities in cell proliferation, migration, vascularization, and death. Recent Advances: Histone deacetylase inhibitors (HDACi) represent a new class of cytostatic agents that interfere with the function of HDACs and are able to increase gene expression by indirectly inducing histone acetylation. Several HDACi, alone or in combination with DNA-demethylating agents, chemopreventive, or classical chemotherapeutic drugs, are currently being used in clinical trials for solid and hematological malignancies, and are, thus, promising candidates for cancer therapy. ...
TL;DR: This review highlights the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis and discusses emerging roles for mitochondrial sIRTuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context.
Abstract: Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyl-lysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. F...
TL;DR: This work has shown that a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired, and links these target proteins in future to specific disease states will be essential for translating the oxidative stress concept into the clinic.
Abstract: SIGNIFICANCE
Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear.
RECENT ADVANCES
We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach.
CRITICAL ISSUES
Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired.
FUTURE DIRECTIONS
Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic. Antioxid. Redox Signal. 23, 1171-1185.
TL;DR: There is a rapidly expanding body of evidence for important roles of hydrogen sulfide in protecting against tissue injury, reducing inflammation, and promoting repair, and there is strong evidence that novel, H2S-based therapeutics are safe and effective in animal models.
Abstract: Significance: There is a rapidly expanding body of evidence for important roles of hydrogen sulfide in protecting against tissue injury, reducing inflammation, and promoting repair. There is also growing evidence that H2S can be successfully exploited in drug development. Recent Advances: H2S synthesis and degradation are regulated in circumstances of inflammation and injury so as to promote repair and re-establish homeostasis. Novel H2S-releasing drugs exhibit enhanced anti-inflammatory and pro-restorative effects, while having reduced adverse effects in many tissues. Critical Issues: H2S is a pleiotropic mediator, having effects on many elements in the inflammatory cascade and promoting the resolution of inflammation and injury. It also contributes significantly to mucosal defence in the gastrointestinal tract, and in host defence against infection. There is strong evidence that novel, H2S-based therapeutics are safe and effective in animal models, and several are progressing through human tria...