Papers by Mariarosaria Bucci
The acute-phase protein haptoglobin (Hpt) binds apolipopro-tein A-I (ApoA-I) and impairs its acti... more The acute-phase protein haptoglobin (Hpt) binds apolipopro-tein A-I (ApoA-I) and impairs its action on lecithin-cholesterol acyltransferase, an enzyme that plays a key role in reverse cholesterol transport. We have previously shown that an ApoA-I mimetic peptide, P2a, displaces Hpt from ApoA-I, restoring the enzyme activity in vitro. The aim of this study was to evaluate whether P2a displaces Hpt from ApoA-I in vivo and whether this event leads to anti-inflammatory activity. Mice received subplantar injections of carrageenan. Paw volume was mea-sured before the injection and 2, 4, 6, 24, 48, 72, and 96 h thereafter. At the same time points, concentrations of HDL cholesterol (C) and cholesterol esters (CEs) were measured by high-performance liquid chromatography, and Hpt and ApoA-I plasma levels were evaluated by enzyme-linked immunosor-
is published by the American Heart Association, 7272Arteriosclerosis, Thrombosis, and Vascular Bi... more is published by the American Heart Association, 7272Arteriosclerosis, Thrombosis, and Vascular Biology
Redox Biology, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Lorenzo, Carla Cicala, Aldo Pinto, William C. Sessa, Silvana Farneti, Stefano Fiorucci and Mariar... more Lorenzo, Carla Cicala, Aldo Pinto, William C. Sessa, Silvana Farneti, Stefano Fiorucci and Mariarosaria Bucci, Fiorentina Roviezzo, Vincenzo Brancaleone, Michelle I. Lin, Annarita Di Coupled to an Enhanced Caveolin-1 Expression Diabetic Mouse Angiopathy Is Linked to Progressive Sympathetic Receptor Deletion Print ISSN: 1079-5642. Online ISSN: 1524-4636 Copyright © 2004 American Heart Association, Inc. All rights reserved. Greenville Avenue, Dallas, TX 75231 is published by the American Heart Association, 7272 Arteriosclerosis, Thrombosis, and Vascular Biology doi: 10.1161/01.ATV.0000122362.44628.09 2004; 2004;24:721-726; originally published online February 12, Arterioscler Thromb Vasc Biol. http://atvb.ahajournals.org/content/24/4/721 World Wide Web at: The online version of this article, along with updated information and services, is located on the http://atvb.ahajournals.org/content/suppl/2004/03/24/24.4.721.DC1.html Data Supplement (unedited) at:
Biomedicine & Pharmacotherapy, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Nucleic Acids Research, 2020
The thrombin binding aptamer (TBA) possesses promising antiproliferative properties. However, its... more The thrombin binding aptamer (TBA) possesses promising antiproliferative properties. However, its development as an anticancer agent is drastically impaired by its concomitant anticoagulant activity. Therefore, suitable chemical modifications in the TBA sequence would be required in order to preserve its antiproliferative over anticoagulant activity. In this paper, we report structural investigations, based on circular dichroism (CD) and nuclear magnetic resonance spectroscopy (NMR), and biological evaluation of four pairs of enantiomeric heterochiral TBA analogues. The four TBA derivatives of the d-series are composed by d-residues except for one l-thymidine in the small TT loops, while their four enantiomers are composed by l-residues except for one d-thymidine in the same TT loop region. Apart from the left-handedness for the l-series TBA derivatives, CD and NMR measurements have shown that all TBA analogues are able to adopt the antiparallel, monomolecular, ‘chair-like’ G-quadru...
Biochemical Pharmacology, 2020
Rationale: Hydrogen sulfide (H 2 S) is a physiological mediator that regulates cardiovascular hom... more Rationale: Hydrogen sulfide (H 2 S) is a physiological mediator that regulates cardiovascular homeostasis. Three major enzymes contribute to the generation of endogenously produced H 2 S, namely cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). Although the biological roles of CSE and CBS have been extensively investigated in the cardiovascular system, very little is known about that of 3-MST. In the present *
British Journal of Pharmacology, 2018
The presence of the H 2 S pathway in skeletal muscle (SKM) has recently been established. SKM exp... more The presence of the H 2 S pathway in skeletal muscle (SKM) has recently been established. SKM expresses the three constitutive H 2 S-generating enzymes in animals and humans, and it actively produces H 2 S. The main, recognized molecular targets of H 2 S, that is, potassium channels and PDEs, have been evaluated in SKM physiology in order to hypothesize a role for H 2 S signalling. SKM dysfunctions, including muscular dystrophy and malignant hyperthermia, have also been evaluated as conditions in which the H 2 S and transsulfuration pathways have been suggested to be involved. The intrinsic complexity of the molecular mechanisms involved in excitation-contraction (E-C) coupling together with the scarcity of preclinical models of SKM-related disorders have hampered any advances in the knowledge of SKM function. Here, we have addressed the role of the H 2 S pathway in E-C coupling and the relative importance of cystathionine β-synthase, cistathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase in SKM diseases.
The FASEB Journal, 2019
Nonalcoholic steatohepatitis (NASH) is associated with an increased risk of developing cardiovasc... more Nonalcoholic steatohepatitis (NASH) is associated with an increased risk of developing cardiovascular complications and mortality, suggesting that treatment of NASH might benefit from combined approaches that target the liver and the cardiovascular components of NASH. Using genetic and pharmacologic approaches, we show that G proteincoupled bile acid-activated receptor 1 (GPBAR1) agonism reverses liver and vascular damage in mouse models of NASH. NASH is associated with accelerated vascular inflammation representing an independent risk factor for development of cardiovascular diseases and cardiovascular-related mortality. GPBAR1, also known as TGR5, is a G protein-coupled receptor for secondary bile acids that reduces inflammation and promotes energy expenditure. Using genetic and pharmacologic approaches, we investigated whether GPBAR1 agonism by 6b-ethyl-3a,7b-dihydroxy-5b-cholan-24-ol (BAR501) reverses liver and vascular damage induced by exposure to a diet enriched in fat and fructose (HFD-F). Treating HFD-F mice with BAR501 reversed liver injury and promoted the browning of white adipose tissue in a Gpbar1dependent manner. Feeding HFD-F resulted in vascular damage, as shown by the increased aorta intima-media thickness and increased expression of inflammatory genes (IL-6,TNF-a, iNOS, and F4/80) and adhesion molecules (VCAM, intercellular adhesion molecule-1, and endothelial selectin) in the aorta, while reducing the expression of genes involved in NO and hydrogen sulfide generation, severely altering vasomotor activities of aortic rings in an ex vivo assay. BAR501 reversed this pattern in a Gpbar1-dependent manner, highlighting a potential role for GPBAR1 agonism in treating the liver and vascular component of NASH.
Biochimica et biophysica acta. General subjects, Jan 31, 2018
Although the thrombin binding aptamer (TBA) is endowed with both anticoagulant and antiproliferat... more Although the thrombin binding aptamer (TBA) is endowed with both anticoagulant and antiproliferative properties, it is possible to reduce the first and enhance the second one by suitable chemical modifications. Two oligonucleotides (TBA353 and TBA535) based on the TBA sequence (GGTTGGTGTGGTTGG) and containing inversion of polarity sites have been investigated by CD, UV and electrophoretic techniques for their ability to form G-quadruplex structures. Furthermore, their anticoagulant (PT assay), antiproliferative (MTT assay) and anti-motility (wound healing assay) properties against Calu-6 cells have been tested and compared with TBA. CD, UV and electrophoresis data indicate that both ODNs are able to form G-quadruplex structures. Particularly, results suggest that TBA535 adopts a G-quadruplex structure characterized by a loop arrangement different from that of TBA. Both TBA analogues drop the anticoagulant activity. However, TBA535 is endowed with a significant antiproliferative acti...
British Journal of Pharmacology, 2017
There are several reviews on NO and hydrogen sulfide (H 2 S) and their role in vascular diseases ... more There are several reviews on NO and hydrogen sulfide (H 2 S) and their role in vascular diseases in the current relevant literature. The aim of this review is to discuss, within the limits of present knowledge, the interconnection between these two gasotransmitters in vascular function. In particular, the review focuses on the role played by the balance between the NO and H 2 S pathways in either physiological or pathological conditions. The distinction between physiology and pathology has been made in order to dissect the molecular basis of this crosstalk, highlighting how and if this balance varies, depending upon the vascular status. Perspectives and possible novel therapeutic approaches are also discussed.
Nucleic Acids Research, 2015
Here we report investigations, based on circular dichroism, nuclear magnetic resonance spectrosco... more Here we report investigations, based on circular dichroism, nuclear magnetic resonance spectroscopy, molecular modelling, differential scanning calorimetry and prothrombin time assay, on analogues of the thrombin binding aptamer (TBA) in which individual thymidines were replaced by 5fluoro-2-deoxyuridine residues. The whole of the data clearly indicate that all derivatives are able to fold in a G-quadruplex structure very similar to the 'chair-like' conformation typical of the TBA. However, only ODNs TBA-F4 and TBA-F13 have shown a remarkable improvement both in the melting temperature (T m ≈ +10) and in the anticoagulant activity in comparison with the original TBA. These findings are unusual, particularly considering previously reported studies in which modifications of T4 and T13 residues in TBA sequence have clearly proven to be always detrimental for the structural stability and biological activity of the aptamer. Our results strongly suggest the possibility to enhance TBA properties through tiny straightforward modifications.
Life Sciences, 1995
Hirulog is a thrombin catalytic site inhibitor which exhibits specificity for the anionic binding... more Hirulog is a thrombin catalytic site inhibitor which exhibits specificity for the anionic binding exosite of alpha thrombin. Here, we have evaluated the effect of Hirulog (1, 5 and 10 mg/kg, 30 min pretreatment) in a rat model of endotoxemia. Intravenous injection of lipopolysaccharide from E. coli (25 mg/kg; serotype 0127:B8) caused decreases in blood pressure which were significantly reduced (about 60%) in animals pretreated with Hirulog. Rat survival to endotoxin was significantly increased in Hirulog pretreated group (5 and 10 mg/kg) up to 24 hours. Hirulog at the dose of 10 mg/kg inhibited both endotoxin-induced leukopenia at 30 and 60 minute points and thrombocytopenia at 30 minute point but not at 90 and 120 minute points. Fibrinogen levels were significantly reduced after 2 hours following endotoxin administration. Pretreatment with Hirulog (5-10 mg/kg i.v.) 30 min prior to administration of endotoxin prevented changes in fibrinogen plasma levels. These results demonstrate that Hirulog-induced inhibition of thrombin is effective in reducing toxic and lethal effects of endotoxin.
Antioxidants & Redox Signaling, 2012
Significance: Hydrogen sulfide (H 2 S) has traditionally been considered a toxic environmental po... more Significance: Hydrogen sulfide (H 2 S) has traditionally been considered a toxic environmental pollutant. In the late 1990s, the presumed solely harmful role of H 2 S has been challenged because H 2 S may also be involved in the maintenance and preservation of cardiovascular homeostasis. Recent Advances: The production of endogenous H 2 S has been attributed to three key enzymes, cystathionine c-lyase (CSE), cystathionine b-synthase, and 3mercaptopyruvate sulfurtransferase. The recognition of H 2 S as the third gaseous signaling molecule has stimulated research on a multitude of pathophysiologic events in the cardiovascular system. In particular, important roles in cardiovascular disorder processes are ascribed to the CSE/H 2 S pathway, such as atherosclerosis, myocardial infarction, hypertension, and shock. Critical Issues: Many biological activities and molecular mechanisms of H 2 S in the cardiovascular system have been demonstrated in studies using different tools, such as the genetic overexpression of CSE, the direct administration of H 2 S donors, or the use of H 2 S-releasing prodrugs. Unfortunately, the role of the CSE/H 2 S pathway in cardiovascular disease remains controversial in numerous areas, and many questions regarding the gaseous molecule still remain unanswered. Future Directions: Advances in basic research indicate that the CSE/H 2 S pathway may provide potential therapeutic targets for treating cardiovascular disorders. But the molecular targets of H 2 S still need to be identified. Antioxid. Redox Signal. 17, 106-118.
British Journal of Pharmacology, 2009
Background and purpose: Endothelial NO synthase (eNOS) is a dynamic enzyme tightly controlled by ... more Background and purpose: Endothelial NO synthase (eNOS) is a dynamic enzyme tightly controlled by co-and posttranslational lipid modifications, phosphorylation and regulated by protein-protein interactions. Here we have pharmacologically modulated the activation of eNOS, at different post-translational levels, to assess the role of eNOSderived NO and of these regulatory mechanisms in intestinal injury associated with splanchnic artery occlusion (SAO) shock. Experimental approach: SAO shock was induced by clamping both the superior mesenteric artery and the celiac trunk for 45 min followed by 30 min of reperfusion. During ischemia, 15 min prior to reperfusion, mice were given geldanamycin, an inhibitor of hsp90 recruitment to eNOS, or LY-294002 an inhibitor of phosphatidylinositol 3-kinase (PI3K), an enzyme that initiates Akt-catalysed phosphorylation of eNOS on Ser 1179. After 30 min of reperfusion, samples of ileum were taken for histological examination or for biochemical studies. Key results: Either LY-294002 or geldanamycin reversed the increased activation of eNOS and Akt observed following SAO shock. These molecular effects were mirrored in vivo by an exacerbation of the intestinal damage. Histological damage also correlated with neutrophil infiltration, assessed as myeloperoxidase activity, and with an increased expression of the adhesion proteins: ICAM-I, VCAM, P-selectin and E-selectin. Conclusions and implications: Overall these results suggest that activation of the Akt pathway in ischemic regions of reperfused ileum is a protective event, triggered in order to protect the intestinal tissue from damage induced by ischaemia/ reperfusion through a fine tuning of the endothelial NO pathway.
Circulation
Introduction: Glucocorticoid (GC) excess is related to hypertension. The deletion of endothelial ... more Introduction: Glucocorticoid (GC) excess is related to hypertension. The deletion of endothelial GC-receptors abrogates the blood pressure increase, suggesting GC-induced hypertension is endothelium-dependent. In response to shear stress endothelium releases nitric oxide, endothelial derived hyperpolarizing factor (EDHF) and prostacyclin. Recently H2S has been proposed as a candidate for EDHF. H2S is mainly produced by the enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) from L-cysteine. The aim of this study was to investigate the EDHF/H2S signaling in GC-hypertension. Methods: Male Wistar rats were treated with DEX (1.5 mg/kg/sc) or vehicle (VEH) for 8 days. Systolic blood pressure (SBP) was monitored every 2 days. EDHF was evaluated in mesenteric plexus and carotid artery performing a concentration-effect curve of acetylcholine in presence of indomethacin (INDO) and nitro-L-arginine methyl ester (L-NAME). Apamin (APA) plus charibdotoxin (CTX), SKCa and BKCa ...
Treatments, Mechanisms, and Adverse Reactions of Anesthetics and Analgesics
British Journal of Pharmacology
l‐cysteine or hydrogen sulfide (H2S) donors induce a biphasic effect on precontracted isolated ve... more l‐cysteine or hydrogen sulfide (H2S) donors induce a biphasic effect on precontracted isolated vessels. The contractile effect occurs within a concentration range of 10 nM to 3 μM followed by vasodilatation at 30–100 μM. Here, we have investigated the signalling involved in the H2S‐induced contraction.
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Papers by Mariarosaria Bucci