Current Pharmaceutical Design - Volume 24, Issue 20, 2018
Volume 24, Issue 20, 2018
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Heme Oxygenase-1: Clinical Relevance in Ischemic Stroke
Authors: Daniel Bereczki Jr., Jozsef Balla and Daniel BereczkiStroke is the second-leading cause of death and a leading cause of serious long-term disability worldwide, with an increasing global burden due to the growing and aging population. However, strict eligibility criteria for current treatment opportunities make novel therapeutic approaches desirable. Oxidative stress plays a pivotal role during cerebral ischemia, eventually leading to neuronal injury and cell death. The significant correlation between redox imbalance and ischemic stroke has led to various treatment strategies targeting the endogenous antioxidant system in order to ameliorate the adverse prognosis in patients with cerebral infarction. One of the most extensively investigated cellular defense pathway in this regard is the Nrf2-heme oxygenase-1 (HO-1) axis. In this review, our aim is to focus on the potential clinical relevance of targeting the HO-1 pathway in ischemic stroke.
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Mycoplasmas and Novel HO-1 Inducers: Recent Advances
Authors: V.M. Chernov, O.A. Chernova, A.A. Mouzykantov, L.V. Lopukhov and M.V. TrushinInflammation and the ways for its regulation: The development of an effective system for the treatment of inflammatory diseases requires comprehensive studies of the cellular signaling molecular networks comprising responses to various stressors, including pathogenic and non-pathogenic microorganisms. Significant attention on fundamental and applied research has recently focused on inducers of hemе oxygenase-1 (HO-1) and inhibitors of the expression of this enzyme, which regulates expression of this and other cytoprotective molecules and modulation of inflammation. Recent studies indicate that mycoplasmas (a major group of human pathogens of the Mollicutes) are capable of modulating inflammatory responses through the activation of the Nrf2 and the expression of HO-1. In vitro experiments demonstrate that the membrane lipoproteins (LAMPs), along with lipoprotein derivatives (lipopeptide MALP-2) in mycoplasmas cause a "cross-talk" between the pro- and antiinflammatory signaling pathways. Importantly, lipopeptide/lipoprotein - induced expression of HO-1 tends to suppress inflammation. Conclusion: The study of the molecular network that causes the corresponding outcome can facilitate the development of new approaches for the treatment of inflammatory processes. The derivatives of LAMPs and MALP-2 and of their analogues may prove promising for the treatment of diseases associated with chronic inflammation.
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M1/M2 Macrophages in Diabetic Nephropathy: Nrf2/HO-1 as Therapeutic Targets
Authors: Robert C. Landis, Kim R. Quimby and Andre R. GreenidgeThe process of inflammation is orchestrated by macrophages, according to their state of differentiation: thus, classically activated (M1) macrophages initiate the process by elaborating proinflammatory cytokines and reactive oxygen species, whereas the latter phase is controlled by alternatively activated macrophages (M2) to resolve inflammation and promote tissue remodelling with the release of growth factors. In a simple human inflammatory response, such as acute crystal arthropathy, macrophages progress linearly through M1 and M2 phases; however, in chronic inflammatory responses, such as atherosclerosis and Diabetic Nephropathy (DN), both M1 and M2 macrophages may coexist, leading to persistent inflammation and fibrosis. A key macrophage receptor that regulates conversion from M1 to M2 is CD163, the hemoglobin scavenger receptor. Scavenging of hemoglobin:haptoglobin (Hb:Hp) complexes via CD163 leads to nuclear translocation of the transcription factor Nrf2 (NF-E2-related factor 2), upregulation of heme oxygenase (HO)-1 cytoprotective protein, and release of interleukin (IL)-10 anti-inflammatory cytokine; IL-10 is then linked in a positive feedback loop to further CD163 expression. The potency of this M1/M2 switching pathway is underscored by the fact that human Hp2 polymorphisms are associated with worsened clinical outcomes for diabetic complications, including DN. Parallel observations in animals show that HO-1 activation by hemin protects against DN in rodent models of diabetes. This review discusses the concept that Nrf2/HO-1 acts as a ‘therapeutic funnel’ through which a range of natural and synthetic anti-oxidants may drive M1 to M2 switching and improved kidney function in diabetes. We also discuss our observations on the evolution of M1/M2 phenotypes in a human model of wound healing which has presented intriguing potential drug targets for DN, such as eotaxin/CCR3.
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Co-administration of Phycocyanobilin and/or Phase 2-Inducer Nutraceuticals for Prevention of Opiate Tolerance
Authors: Mark F. McCarty and Simon Iloki-AssangaChronic use of opiates for control of chronic pain is complicated by the development of tolerance and hyperalgesia, and hence usually entails dose escalation and diminished efficacy. Our evolving understanding of the mechanisms mediating induction of morphine tolerance may enable discovery of adjunct measures which can prevent this tolerance; this essay proposes that certain nutraceuticals may have utility in this regard. Considerable evidence now points to an obligate role for production of peroxynitrite and other oxidants in the dorsal horn in development of morphine tolerance. Various isoforms of NADPH oxidase are the chief source of the superoxide which gives rise to these oxidants. Since heme oxygenase, via its products bilirubin and carbon monoxide, functions as a physiological inhibitor of various isoforms of NADPH oxidase, phase 2-inducing nutraceuticals with blood brain-barrier permeability such as lipoic acid, an effective inducer of heme oxygenase-1, may have potential for prevention of morphine tolerance; indeed, this has been demonstrated in a mouse study. The phycocyanobilin (PhyCB) chromophore of spirulina, a structural analog of biliverdin, shares bilirubin's ability to inhibit NAPDH oxidase complexes; hence, administration of spirulina or of PhyCB-enriched spirulina extracts merits evaluation in rodent models of morphine tolerance. Uric acid quenches peroxynitrite-derived radicals, and its plasma level can be boosting via supplementation with inosine; indeed, administration of inosine has been shown to counteract development of hyperalgesia in rodents. If practical doses of these agents can be shown to prevent morphine tolerance and hyperalgesia in rodents, their use as adjuvants to clinical opiate therapy should be assessed.
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Nutraceutical Targeting of Placental Synthesis of Soluble Fms-Like Tyrosine Kinase- 1 (sFlt-1) as Strategy for Preventing and Controlling Pre-eclampsia
Authors: Simon Iloki-Assanga and Mark F. McCartyThe primary driving force in preeclampsia (PE) appears to be excessive secretion of fms-like tyrosine kinase-1 (sFlt-1), a truncated decoy receptor for vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) that induces systemic endotheliopathy by depriving endothelial cells of the trophic support conferred by VEGF. Factors which boost placental sFlt-1 production in PE include hypoxia – reflecting improper placentation – oxidative stress, and deficient production of hydrogen sulfide (H2S). Nutraceutical measures which may address these issues include taurine and N-acetylcysteine – which may boost placental H2S production; spirulina and phase 2 inducers of heme oxygenase-1 such as lipoic acid – which may down-regulate placental NADPH oxidase activity; and citrulline, high-dose folate, and dietary nitrate – which by supporting placental nitric oxide production may aid proper placentation and hence prevent placental hypoxia. These agents may also help to alleviate the pathogenic impact of sFlt-1 excess. If the utility of such measures can be demonstrated in rodent models of PE, functional foods incorporating these nutraceuticals can be envisioned as aids to a healthful pregnancy. Moreover, rodent studies suggest that such prenatal supplementation may reduce risk for hypertension in adult offspring of the pregnancy. And, since women who develop PE are at markedly higher risk for cardiovascular disorders in their later life, continuing use of such supplementation – promoting effective NO and H2S bioactivity while aiding control of oxidative stress - may be advisable for the mothers.
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Where is the Clinical Breakthrough of Heme Oxygenase-1 / Carbon Monoxide Therapeutics?
Authors: Christopher P. Hopper, Lorenz Meinel, Christoph Steiger and Leo E. OtterbeinHeme oxygenase (HO), the rate-limiting step in the degradation of heme to biliverdin, ferrous ion, and carbon monoxide (CO), is an ancestral protective enzyme conserved across phylogenetic domains. While HO was first described in the late 1960s and progressively characterized in the following decades, there has been a surge of innovation over the past twenty years in efforts to leverage the cytoprotective power of HO in a clinical setting. Despite the plethora of preclinical data indicating extraordinary therapeutic potential, HO has remained elusive from the physician's toolbox. The leading candidate in development, CO, has long been misconstrued as a useless toxic gas. Scientists have crafted an array of CO delivery molecules and devices to harness HO, however, each endeavor was met with limitations preventing translation into clinical practice. In this discussion, we summarize the HO / CO field with a clinical and commercial development perspective. More specifically, given the enormous global efforts and capital investment into the field, we ask: where is the breakthrough therapy?
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Involvement of Heme Oxygenase-1 in Neuropsychiatric and Neurodegenerative Diseases
Authors: Vivian B. Neis, Priscila B. Rosa, Morgana Moretti and Ana Lucia S. RodriguesHeme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO-1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions. Considering that neurodegenerative diseases (Alzheimer's Disease (AD), Parkinson's Disease (PD) and Multiple Sclerosis (MS)) and neuropsychiatric disorders (depression, anxiety, Bipolar Disorder (BD) and schizophrenia) are associated with increased inflammatory markers, impaired redox homeostasis and oxidative stress, conditions that may be associated with alterations in HO-levels/activity, the purpose of this review is to present evidence on the possible role of HO-1 in these Central Nervous System (CNS) diseases. In addition, the possible therapeutic potential of targeting brain HO-1 is explored in this review.
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Heme Oxygenase and the Skin in Health and Disease
Authors: Imre L. Szabo, Anna Kenyeres, Andrea Szegedi and Attila Gabor SzollosiThe skin is often introduced as the largest organ of the human body which – being uniquely exposed to external stress – faces several types of challenges, from physical, chemical, biological, and immunological origin. Therefore, the skin is also a site where inflammation, oxidative stress and cellular damage occurs regularly. Heme oxygenase (HO), primarily functioning in the catabolism of heme, is a very important cytoprotective enzyme that has antioxidant, anti-inflammatory and anti-apoptotic properties. Given the need for an enzyme with such a combination of attributes in the skin, it is not surprising that HO is involved in physiological processes as well as pathological conditions of the skin. In the recent decade, a huge effort was undertaken to identify treatments that modify HO-activity for the treatment of inflammatory or malignant skin diseases. In this review, we highlight the role of HO in the skin in physiological conditions as well as in relevant dermatological diseases such as atopic dermatitis, psoriasis and melanoma.
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Heme Oxygenase-1 and Autophagy Linked for Cytoprotection
Authors: L.R. Vasconcellos, M.S. Siqueira, R. Moraes, L.A. Carneiro, M.T. Bozza and L.H. TravassosBackground: Heme-oxygenase (HO) catalyzes the main enzymatic step of heme degradation and generates anti-inflammatory end products with protective roles in physiological and pathological situations. The importance of HO in pathological conditions is evidenced by its pharmacological inhibition or genetic blockage in different models of stress such as infection, inflammation and oxidative stress. Under these situations, another well-known protective process triggered is autophagy. Autophagy is a homeostatic process that eliminates defective cytosolic components and organelles, allowing cells and tissues to recover through recycling of functional blocks for anabolic reactions. Recently, studies have demonstrated a link between HO activity and autophagy activation. Objective: In this review, we focus on the interplay between HO and autophagy, and highlight its importance in homeostasis maintenance under stress conditions.
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Parkinson's Disease: Alpha Synuclein, Heme Oxygenase and Biotherapeutic Countermeasures
Authors: David D. Haines, Maxim V. Trushin, Stephen Rose, Iloki A. S. Bernard and Fadia F. MahmoudNeurodegenerative disorders have been and remain persistent sources of enormous suffering throughout human history. The tragedy of their impact on human relationships, physical vitality, and fundamental dignity cannot be understated. Parkinson's disease (PD), one of the most common of these terrible illnesses, has a global incidence of approximately two-to-four percent of the human population, along with devastating social and economic impact. The present review analyzes aspects of PD pathophysiology that offer particularly attractive strategies for the development of improved prevention and therapy. The occurrence, symptoms, pathogenesis, and etiology of PD are considered, with focus on how the Alpha synuclein protein, which normally regulates neurotransmitter release, is aggregated by oxidative stressors into toxic inclusions, prominently including Lewy bodies and insoluble fibrils that disrupt the organization of brain areas responsible for motor control. The contribution to a progressively prooxidant tissue environment resulting from interaction between advanced glycation end products (AGEs) and their cognate receptors (RAGEs) is examined here as a significant driver of PD. This review also explores strategies currently being developed by a U.S.-Russian team that may reduce the risk and severity of PD by use of recombinant atoxic derivatives (ad) of botulinum neurotoxins (BoNT/A ad), that traffic inducers of the cytoprotective enzyme heme oxygenase to selected midbrain neurons, at which Alpha synuclein aggregation occurs. Considered together, the topic material presented here provides both researchers and clinicians with a short but concise overview of the current understanding of PD pathology and approaches to biotherapeutic (precision) countermeasures to its onset and progression.
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Role of Heme Oxygenases in Cardiovascular Syndromes and Co-morbidities
Authors: David D. Haines and Arpad TosakiCardiovascular Diseases (CVD), are the leading cause of human mortality worldwide and the focus of the intensive investigation is to characterize their pathogenesis. This review examines contribution to CVD of heme oxygenases (HOs), heat shock protein enzymes, comprising 3 isoforms: HO-1 (inducible), HO-2 (constitutively expressed) and HO-3 (function presently undefined), which constitute a primary endogenous countermeasure to oxidative tissue damage. Their role as CVD countermeasures is considered in the context of atherosclerosis, consequences of which are the leading cause of CVD deaths and from which 5 major syndromes may develop, namely: coronary artery disease and stroke, peripheral artery disease, kidney disease, cardiopulmonary disease and cerebrovascular disease. Over 75% of CVD deaths result from Coronary artery disease and stroke, with the severity of these conditions correlating with a systemic increase of the endogenous antioxidant bilirubin, produced by HO degradation of heme. Peripheral artery disease, (PAD) resulting from constricted arteries of the extremities is a painful and disabling condition, the severity of which correlates with elevated serum HO. Whether this represents an adaptive response or the enzyme is a contributor to PAD, remains to be determined. CVD symptoms, particularly hypertension, damage the vasculature and filtering structures of the kidneys and may be ameliorated by HO inducers. Interestingly, constitutive renal expression of HO-2 indicates that the enzyme is vital for healthy kidney function. Right ventricular hypertrophy and increased vascular resistance in blood vessels of the lungs exhibit mutually reinforcing positive feedback to result in cardiopulmonary heart disease, with morbidity and mortality resulting from associated inflammation and may be decreased with HO-1 inducers. Cerebrovascular disease, a major CVD complication affecting brain vasculature, with resulting susceptibility to stroke, maybe potently ameliorated by HO-1 inducers. Conclusion: Each of the six major categories of CVD exhibit features of pathogenesis that hold potential as future therapeutic targets, for modulated heme oxygenase activity.
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Volumes & issues
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Volume 31 (2025)
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Volume (2025)
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Volume 30 (2024)
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Volume 29 (2023)
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Volume 28 (2022)
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Volume 27 (2021)
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Volume 26 (2020)
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Volume 25 (2019)
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Volume 24 (2018)
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Volume 23 (2017)
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Volume 22 (2016)
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Volume 21 (2015)
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Volume 20 (2014)
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Volume 19 (2013)
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Volume 18 (2012)
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Volume 17 (2011)
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Volume 16 (2010)
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Volume 15 (2009)
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Volume 14 (2008)
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Volume 13 (2007)
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Volume 12 (2006)
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Volume 11 (2005)
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Volume 10 (2004)
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Volume 9 (2003)
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Volume 8 (2002)
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Volume 7 (2001)
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Volume 6 (2000)
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