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Molsidomine HELP
Based on 289 articles since 2006

These are the 289 published articles about Molsidomine that originated from Worldwide during 2006-2015.
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · 11 · 12
1 Editorial Inhibition of nitric oxide synthase during sepsis: revival because of isoform selectivity? 2010

Stahl, Wolfgang / Matejovic, Martin / Radermacher, Peter. · ·Shock · Pubmed #20601934.

ABSTRACT: -- No abstract --

2 Review [The pharmacology of nitric oxide and nitrates]. 2010

Li, Huige / Förstermann, Ulrich. ·Institut für Pharmakologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany. · ·Pharm Unserer Zeit · Pubmed #20818683.

ABSTRACT: -- No abstract --

3 Review [Coronary spastic angina refractory to optimal medical therapy treated by angioplasty and stenting. A case report and review of literature]. 2010

Hajlaoui, N / Tarragano, F / Raisky, P / Beaufils, P / Henry, P. ·Service de cardiologie, hôpital Lariboisière, 2, rue Ambroise-Paré, 75475 Paris cedex 10, France. nadhem_2001@yahoo.fr · ·Ann Cardiol Angeiol (Paris) · Pubmed #19007921.

ABSTRACT: Medical treatment of coronary spastic angina is based classically on the association of calcium channel blockers with nitrate derivatives. Some clinical forms of spastic angina remain refractory to these medications and can thus lead to serious complications (sudden cardiac death secondary to ventricular rhythm disturbance, myocardial infarction...). When the coronary spasm is focal, percutaneous coronary angioplasty with deployment of a stent can offer an interesting therapeutic alternative. We report in this article the case of a patient who had a focal spasm of the right coronary artery, which became refractory to optimal medical treatment. This patient was well improved by percutaneous angioplasty with deployment of a stent in the spastic segment of the right coronary artery. We propose also a review of the literature of the treatment of this pathology, which still remains not well codified.

4 Review [Recent findings on nitrates: their action, bioactivation and development of tolerance]. 2008

Münzel, T. ·Medizinische Klinik für Kardiologie, Angiologie und internistische Intensivmedizin, Johannes Gutenberg Universität Mainz. tmuenzel@uni-mainz.de ·Dtsch Med Wochenschr · Pubmed #18946854.

ABSTRACT: Organic nitrates still are one of the most important drug classes used in the treatment of an acute coronary syndrome and stable coronary artery disease as well as acute and chronic congestive heart failure. The mechanism of vasodilatation comprises the release of nitric oxide, which in turn activates soluble guanylate cyclase and lowers the intracellular calcium content leading to relaxation of vascular smooth muscle. Recent research has demonstrated that highly reactive nitrates, such as nitroglycerin (or glyceryl trinitrate) and pentaerthrityl tetranitrate (PETN) are bioactivated by aldehyde dehydrogenase 2 (ALDH-2), an enzyme located in mitochondria. The enzyme, which bioactivates mono- and dinitrates is not yet identified. Despite being effective in the acute treatment of patients, its long-term efficacy is limited by the development of tolerance to nitrates and of endothelial dysfunction. Both of these side effects of nitrate therapy are due to increased production of reactive oxygen species. This review focuses on new aspects of the process of bioactivation of organic nitrates, the conception of oxidative stress of endothelial dysfunction and of the development of tolerance and their therapeutic consequences. Also discussed are more recent findings on nitric oxide donors such as molsidomine, PETN and the combination treatment of isosorbide dinitrate and hydralazine of patients with coronary artery disease and chronic heart failure.

5 Review Use of recombinant iron-superoxide dismutase as a marker of nitrative stress. 2008

Larrainzar, Estíbaliz / Urarte, Estíbaliz / Auzmendi, Iñigo / Ariz, Idoia / Arrese-Igor, Cesar / González, Esther M / Moran, Jose F. ·Departamento de Ciencias del Medio Natural, Universidad Pública de Navarra, Campus de Arrosadía, E-31006 Pamplona, Navarre, Spain. · ·Methods Enzymol · Pubmed #18433650.

ABSTRACT: Superoxide dismutases (SODs; EC are a group of metalloenzymes which are essential to protect cells under aerobic conditions. In biological systems, it has been reported that SODs and other proteins are susceptible to be attacked by peroxynitrite (ONOO(-)) which can be originated from the reaction of nitric oxide with superoxide radical. ONOO(-) is a strong oxidant molecule capable of nitrating peptides and proteins at the phenyl side chain of the tyrosine residues. In the present work, bovine serum albumin (BSA) and recombinant iron-superoxide dismutase from the plant cowpea (Vu_FeSOD) are used as target molecules to estimate ONOO(-) production. The method employs the compound SIN-1, which simultaneously generates *NO and O(2)(-) in aerobic aqueous solutions. First, assay conditions were optimized incubating BSA with different concentrations of SIN-1, and at a later stage, the effect on the tyrosine nitration and catalytic activity of Vu_FeSOD was examined by in-gel activity and spectrophotometric assays. Both BSA and Vu_FeSOD are nitrated in a dose-dependent manner, and, at least in BSA nitration, the reaction seems to be metal catalyzed.

6 Review Sex differences in oxidative stress and the impact on blood pressure control and cardiovascular disease. 2007

Sartori-Valinotti, Julio C / Iliescu, Radu / Fortepiani, Lourdes A / Yanes, Licy L / Reckelhoff, Jane F. ·Department of Physiology and Biophysics and The Center of Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi 39216-4504, USA. · ·Clin Exp Pharmacol Physiol · Pubmed #17645644.

ABSTRACT: 1. In the present review, we addressed studies in humans and rats to determine the role that oxidative stress may play in mediating cardiovascular outcomes. 2. Biochemical evaluation of oxidative stress in both humans and spontaneously hypertensive rats gives equivocal results as to the relative levels in males versus females. Clinical trials with anti-oxidants in humans have not shown consistent results in protecting against detrimental cardiovascular outcomes. In spontaneously hypertensive rats (SHR), blockade studies using tempol or apocynin reduce renal oxidative stress and blood pressure in male SHR, but not in female rats. In addition, increasing oxidative stress with molsidomine increases blood pressure in male, but not female, SHR. Treatment with vitamins E and C reduces blood pressure in young male, but not aged, animals. Furthermore tempol is unable to reduce blood pressure in young male SHR in the absence of a functional nitric oxide system. 3. Neither human nor animal studies are consistent in terms of whether oxidative stress levels are higher in males or females. Furthermore, anti-oxidant therapy in humans often does not ameliorate, or even attenuate, the negative cardiovascular consequences of increased oxidative stress. Our studies in SHR shed light on why these outcomes occur.

7 Clinical Trial Tolerability to 1-year treatment with once-daily molsidomine in patients with stable angina. 2006

Messin, Roger / Bruhwyler, Jacques / Dubois, Claude / Famaey, Jean-Pierre / Géczy, Joseph. ·Therabel Pharma SA/NV, Brussels, Belgium. · ·Adv Ther · Pubmed #17050502.

ABSTRACT: Prolonged-release molsidomine 16 mg once daily) QD (has proved effective in the short-term treatment of patients with stable angina. The purpose of this multicenter study was to assess its long-term tolerability and clinical effectiveness. A total of 320 patients with stable angina were treated for 1 year with molsidomine 16 mg QD administered open label as monotherapy or add-on therapy, when beta blockers and/or calcium antagonists were prescribed concomitantly) in 128 patients, ie, 40% of cases), depending on the severity of disease and/or local therapeutic policies. In all, 293 patients (91.6%) completed the study. The proportion of patients who reported drug-related adverse events (AEs) was 9.1%, which is not significantly different (P=.13) from the 5.9% observed during previous short-term (2-4 wk) treatment. Headache accounted for 80.6% of all drug-related AEs and required discontinuation of the drug in one quarter of patients who reported the symptom (ie, 1.9% of the 320 patients involved in the study). No serious drug-related AEs occurred during the study. Tolerability to molsidomine, evaluated with use of a visual analog scale (VAS), improved by 20% from beginning to end of 1-year follow-up. Two-by-two Bonferroni's comparisons were significant at the .05 level between the 2-month assessment and assessments performed at 8, 10, and 12 months. No age-time interaction was noted (P=.82). Heart rate, blood pressure, electrocardiogram, and blood parameters showed no statistically significant or clinically relevant changes during the study. Compliance with treatment was satisfactory throughout the follow-up period. There was no significant change in the weekly frequency of anginal attacks and consumption of short-acting nitroderivatives during the 1-year study (P=.07 and P=.12,respectively), but their frequency was significantly (ie, approximately 50%) lower than during a preceding short-term treatment period (P<.0001 and P=.014, respectively). Subjective clinical status, evaluated through an appropriate VAS, improved by 38% from start to end of 1-year follow-up. Bonferroni's comparisons between baseline and subsequent 2-month evaluations were all significant at the .05 level. No age-time interaction could be seen for frequency of anginal attacks and consumption of short-acting nitroderivatives, nor for clinical status )P=.10, P=.11, and P=.51, respectively). Neither tolerability to molsidomine nor effectiveness of the drug was biased by concomitant antianginal therapies, insofar as none of these parameters showed a significant treatment type (ie, molsidomine administered as monotherapy or add-on therapy)-time interaction (VAS for tolerability: P=.44; angina: P=.39; nitroderivatives: P=.72; VAS for clinical status: P=.62). Molsidomine 16 mg QD administered for 1 y to patients with stable angina was well tolerated and remained effective during the entire treatment period, independent of age and concomitant antianginal therapy.

8 Article Protective Effects of Molsidomine Against Cisplatin-Induced Nephrotoxicity. 2015

Karakoc, Habib T E / Altintas, Ramazan / Parlakpinar, Hakan / Polat, Alaaddin / Samdanci, Emine / Sagir, Mustafa / Duran, Zeynep R. ·Student, Medical Faculty, Inonu University, Malatya, Turkey. · Department of Urology, Medical Faculty, Inonu University, Malatya, Turkey. · Department of Physiology, Medical Faculty, Inonu University, Malatya, Turkey. · Department of Pharmacology, Medical Faculty, Inonu University, Malatya, Turkey. · Department of Pathology, Medical Faculty, Inonu University, Malatya, Turkey. ·Adv Clin Exp Med · Pubmed #26469102.

ABSTRACT: BACKGROUND: Cisplatin, an effective chemotherapeutic agent, is used for the treatment of several types of cancers. However, cisplatin has some severe side effects such as nephrotoxicity. On the other hand, molsidomine, a NO donor, has anti-oxidative and vasodilator effects. OBJECTIVES: The aim of this study was to estimate the protective effects of molsidomine on cisplatin-induced nephrotoxicity. MATERIAL AND METHODS: Thirty-two rats were randomly divided into 4 groups as follows: (1) control; (2) received a single-dose intraperitoneal (i.p.) injection of 5 mg/kg cisplatin; (3) received single i.p. dose of molsidomine (4 mg/kg/day) for 3 consecutive days before cisplatin treatment; (4) received single i.p. dose of molsidomine (4 mg/kg/day) for 3 consecutive days. The specific biochemical markers, including antioxidants, and the histopathological alterations were evaluated. RESULTS: Cisplatin significantly increased malondialdehyde (MDA) and myeloperoxidase (MPO) levels and decreased glutathione peroxidase (GPX) level. Molsidomine significantly decreased MPO level nearly to control level; however, its ameliorating effects on MDA, SOD, CAT and GPX did not reach to significant levels. Cisplatin-induced elevation of blood-urea-nitrogen and serum-creatinine were diminished after molsidomine administration. Cisplatin also induced severe tubular degeneration, nuclear condensation, apoptosis and scattered patchy inflammation in the histological examination. Molsidomine improved all of these histological damages. CONCLUSIONS: In this study, the beneficial effect of molsidomine against cisplatin nephrotoxicity has been evaluated for the first time.

9 Article Development of a screening method to identify regulators of MICA shedding. 2015

Kishikawa, Takahiro / Otsuka, Motoyuki / Ohno, Motoko / Yoshikawa, Takeshi / Sato, Masaya / Koike, Kazuhiko. ·Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. · Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Japan Science and Technology Agency, PRESTO, Kawaguchi, Saitama 332-0012, Japan. Electronic address: otsukamo-tky@umin.ac.jp. ·Biochem Biophys Res Commun · Pubmed #26299929.

ABSTRACT: Immune cells, such as natural killer (NK) cells, recognize virally infected and transformed cells, and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells. Shedding of NKG2D ligands is thought to be a type of counter-mechanism employed by pathogenic cells to evade from NKG2D-mediated immune surveillance. MHC class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. We previously reported that, in soluble form, MICA expression levels are significantly associated with hepatitis virus-induced hepatocellular carcinoma. Here, we report a MICA shedding assay that utilizes membrane-bound MICA tagged at its N-terminus with a nano-luciferase reporter to quantify MICA shedding into culture media. Using this method, we screened a compound library and identified putative regulators of MICA shedding that have the potential to enhance the immune reaction by simultaneously increasing cell surface MICA levels and decreasing soluble MICA levels. This shedding assay may be useful for screening regulators of cell surface molecule shedding.

10 Article Long-term effect of molsidomine, a direct nitric oxide donor, as an add-on treatment, on endothelial dysfunction in patients with stable angina pectoris undergoing percutaneous coronary intervention: results of the MEDCOR trial. 2015

Barbato, Emanuele / Herman, Arnold / Benit, Edouard / Janssens, Luc / Lalmand, Jacques / Hoffer, Etienne / Chenu, Patrick / Guédès, Antoine / Missault, Luc / Pirenne, Bruno / Cardinal, François / Vercauteren, Steven / Wijns, William. ·Cardiovascular Research Center Aalst, OLV Clinic, Aalst, Belgium; Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy. Electronic address: emanuele.barbato@olvz-aalst.be. · Berchem, Belgium. · Jessa Hospital, Campus Virga Jesse, Hasselt, Belgium. · Imelda Hospital, Bonheiden, Belgium. · CHU Charleroi, Charleroi, Belgium. · CHR Citadelle, Liège, Belgium. · CHU Dinant Godinne UCL Namur, Yvoir, Belgium. · Saint-Jan Hospital, Bruges, Belgium. · Saint-Pierre Hospital, Ottignies, Belgium. · Saint-Jean Hospital, Brussels, Belgium. · Cardiovascular Research Center Aalst, OLV Clinic, Aalst, Belgium. ·Atherosclerosis · Pubmed #25875387.

ABSTRACT: OBJECTIVE: The MEDCOR trial is a double-blind, randomized study aiming at demonstrating the superiority of molsidomine (direct NO donor) over placebo, used as add-on treatments, on improving endothelial function (EF) after 12 months, in stable angina patients undergoing percutaneous coronary intervention. METHODS: EF was assessed by peripheral vasodilator response (i.e. Endoscore) using arterial tonometry and by several biomarkers, in terms of changes versus baseline after a one-year treatment. RESULTS: The change in Endoscore was +75 ± 130% in placebo group and +39 ± 145% in molsidomine group (p = 0.143). There was a decrease in sICAM-1 with molsidomine (-6%) and an increase with placebo (+6%). The MPO activity/antigen ratio slightly increased with placebo (+9%) and strongly decreased with molsidomine (-42%) (p = 0.020). CONCLUSION: The MEDCOR trial was not able to demonstrate significant differences between molsidomine and placebo for all parameters, except the MPO activity/antigen ratio which significantly decreased with molsidomine (p = 0.020 versus placebo).

11 Article Myeloperoxidase scavenges peroxynitrite: A novel anti-inflammatory action of the heme enzyme. 2015

Koyani, Chintan N / Flemmig, Joerg / Malle, Ernst / Arnhold, Juergen. ·Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21, 8010 Graz, Austria. · Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, Philipp-Rosenthal-Straße 55, 04103 Leipzig, Germany; Institute for Medical Physics and Biophysics, Medical Faculty, University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany. · Translational Centre for Regenerative Medicine Leipzig, University of Leipzig, Philipp-Rosenthal-Straße 55, 04103 Leipzig, Germany; Institute for Medical Physics and Biophysics, Medical Faculty, University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany. Electronic address: juergen.arnhold@medizin.uni-leipzig.de. ·Arch Biochem Biophys · Pubmed #25731855.

ABSTRACT: Peroxynitrite, a potent pro-inflammatory and cytotoxic species, interacts with a variety of heme containing proteins. We addressed the question whether (i) the interaction of myeloperoxidase (MPO, an enzyme generating hypochlorous acid from hydrogen peroxide and chloride ions) with peroxynitrite affects the clearance of peroxynitrite, and (ii) if peroxynitrite could modulate the chlorinating activity of MPO. Our results show that this interaction promotes the decomposition of the highly reactive pro-inflammatory oxidant, whereby MPO Compound II (but not Compound I) is formed. The efficiency of MPO to remove peroxynitrite was enhanced by L-tyrosine, nitrite and (-)-epicatechin, substances known to reduce Compound II with high reaction rate. Next, peroxynitrite (added as reagent) diminished the chlorinating activity of MPO in the presence of hydrogen peroxide. Alternatively, SIN-1, a peroxynitrite donor, reduced hypochlorous acid formation by MPO, as measured by aminophenyl fluorescein oxidation (time kinetics) and taurine chloramine formation (end point measurement). At inflammatory loci, scavenging of peroxynitrite by MPO may overcome the uncontrolled peroxynitrite decomposition and formation of reactive species, which lead to cell/tissue damage.

12 Article Lack of neuronal nitric oxide synthase results in attention deficit hyperactivity disorder-like behaviors in mice. 2015

Gao, Yudong / Heldt, Scott A. ·Department of Anatomy and Neurobiology. ·Behav Neurosci · Pubmed #25621792.

ABSTRACT: Nitric oxide (NO) is an important molecule for the proper development and function of the central nervous system. In this study, we investigated the behavioral alterations in the neuronal NO synthase knockout mice (NOS1 KO) with a deficient NO production mechanism in the brain, characterizing it as a potential rodent model for attention deficit hyperactivity disorder (ADHD). NOS1 KO exhibited higher locomotor activity than their wildtype counterparts in a novel environment, as measured by open field (OF) test. In a 2-way active avoidance paradigm (TWAA), we found sex-dependent effects, where male KO displayed deficits in avoidance and escape behavior, sustained higher incidences of shuttle crossings, and higher incidences of intertrial interval crossings, suggesting learning, and/or performance impairments. On the other hand, female KO demonstrated few deficits in TWAA. Molsidomine (MSD), a NO donor, rescued TWAA deficits in male KO when acutely administered before training. In a passive avoidance paradigm, KO of both sexes displayed significantly shorter step-through latencies after training. Further, abnormal spontaneous motor activity rhythms were found in the KO during the dark phase of the day, indicating dysregulation of rhythmic activities. These data indicate that NOS1 KO mimics certain ADHD-like behaviors and could potentially serve as a novel rodent model for ADHD.

13 Article Interaction between hydrogen sulfide-induced sulfhydration and tyrosine nitration in the KATP channel complex. 2015

Kang, Minho / Hashimoto, Atsushi / Gade, Aravind / Akbarali, Hamid I. ·Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia. · Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia hiakbarali@vcu.edu. ·Am J Physiol Gastrointest Liver Physiol · Pubmed #25552582.

ABSTRACT: Hydrogen sulfide (H₂S) is an endogenous gaseous mediator affecting many physiological and pathophysiological conditions. Enhanced expression of H2S and reactive nitrogen/oxygen species (RNS/ROS) during inflammation alters cellular excitability via modulation of ion channel function. Sulfhydration of cysteine residues and tyrosine nitration are the posttranslational modifications induced by H₂S and RNS, respectively. The objective of this study was to define the interaction between tyrosine nitration and cysteine sulfhydration within the ATP-sensitive K(+) (KATP) channel complex, a significant target in experimental colitis. A modified biotin switch assay was performed to determine sulfhydration of the KATP channel subunits, Kir6.1, sulphonylurea 2B (SUR2B), and nitrotyrosine measured by immunoblot. NaHS (a donor of H₂S) significantly enhanced sulfhydration of SUR2B but not Kir6.1 subunit. 3-Morpholinosydnonimine (SIN-1) (a donor of peroxynitrite) induced nitration of Kir6.1 subunit but not SUR2B. Pretreatment with NaHS reduced the nitration of Kir6.1 by SIN-1 in Chinese hamster ovary cells cotransfected with the two subunits, as well as in enteric glia. Two specific mutations within SUR2B, C24S, and C1455S prevented sulfhydration by NaHS, and these mutations prevented NaHS-induced reduction in tyrosine nitration of Kir6.1. NaHS also reversed peroxynitrite-induced inhibition of smooth muscle contraction. These studies suggest that posttranslational modifications of the two subunits of the KATP channel interact to alter channel function. The studies described herein demonstrate a unique mechanism by which sulfhydration of one subunit modifies tyrosine nitration of another subunit within the same channel complex. This interaction provides a mechanistic insight on the protective effects of H₂S in inflammation.

14 Article Neuroprotective effect of 3-morpholinosydnonimine against Zn²⁺-induced PC12 cell death. 2015

An, Jeong Mi / Moon, Seong Ah / Hong, Soo Young / Kang, Jeong Wan / Seo, Jeong Taeg. ·Department of Oral Biology, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea. · Department of Oral & Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea. Electronic address: jeongwan@yuhs.ac. · Department of Oral Biology, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea. Electronic address: jeong@yuhs.ac. ·Eur J Pharmacol · Pubmed #25523480.

ABSTRACT: Excessive intracellular accumulation of zinc (Zn(2+)) is neurotoxic and contributes to a number of neuropathological conditions. Here, we investigated the protective effect of 3-morpholinosydnonimine (SIN-1) against Zn(2+)-induced neuronal cell death in differentiated PC12 cells. We found that Zn(2+)-induced PC12 cell death was reduced in a concentration-dependent manner by pretreatment with SIN-1. The intracellular accumulation of Zn(2+) was not affected by pretreatment with SIN-1, indicating that SIN-1-induced neuroprotection was not attributable to reduced influx of Zn(2+) into cells. SIN-1C, the stable decomposition product of SIN-1, failed to prevent Zn(2+)-induced cell death. Furthermore, the protective effect of SIN-1 against Zn(2+)-induced PC12 cell death was almost completely abolished by uric acid, a free radical scavenger, suggesting that reactive oxygen and nitrogen species generated by SIN-1 may contribute to the protective effect. SIN-1 prevented the inactivation of glutathione reductase (GR) and the increase in the ratio of oxidized glutathione/total glutathione (GSSG/total GSH) induced by Zn(2+). Addition of membrane permeable GSH ethyl ester (GSH-EE) to PC12 cells prior to Zn(2+) treatment significantly increased cell viability. We therefore conclude that SIN-1 may exert neuroprotective effect against Zn(2+)-induced cell death in differentiated PC12 cells by preventing inhibition of GR and increase in GSSG/total GSH ratio.

15 Article Peroxynitrite-mediated nitrosative stress decreases motility and mitochondrial membrane potential in human spermatozoa. 2015

Uribe, P / Boguen, R / Treulen, F / Sánchez, R / Villegas, J V. ·Center of Reproductive Biotechnology - Scientific and Technological Bioresource Nucleus (CEBIOR - BIOREN), Universidad de La Frontera, Temuco 4811230, Chile. · Center of Reproductive Biotechnology - Scientific and Technological Bioresource Nucleus (CEBIOR - BIOREN), Universidad de La Frontera, Temuco 4811230, Chile Department of Internal Medicine, Faculty of Medicine, Universidad de La Frontera, Temuco 4781218, Chile juana.villegas@ufrontera.cl. ·Mol Hum Reprod · Pubmed #25425609.

ABSTRACT: Nitrosative stress is produced by high levels of reactive nitrogen species (RNS). The RNS include peroxynitrite, a highly reactive free radical produced from a diffusion-controlled reaction between nitric oxide and superoxide anion. Peroxynitrite causes nitration and oxidation of lipids, proteins and DNA, and is thus considered an important pathogenic mechanism in various diseases. Although high levels of peroxynitrite are associated with astenozoospermia, few reports exist regarding the in vitro effect of high levels of this RNS on human sperm. The aim of this study was to evaluate the in vitro effect of nitrosative stress caused by peroxynitrite on the viability, motility and mitochondrial membrane potential of human spermatozoa. To do this, human spermatozoa from healthy donors were exposed in vitro to 3-morpholinosydnonimine (SIN-1), a molecule that generates peroxynitrite. Incubations were done at 37°C for up to 4 h with SIN-1 concentrations between 0.2 and 1.0 mmol/l. Generation of peroxynitrite was confirmed using dihydrorhodamine 123 (DHR) by spectrophotometry and flow cytometry. Sperm viability was assessed by propidium iodide staining; sperm motility was analyzed by CASA, and the state of mitochondrial membrane potential (ΔΨm) by JC-1 staining. Viability and ΔΨm were measured by flow cytometry. The results showed an increase in DHR oxidation, demonstrating the generation of peroxynitrite through SIN-1. Peroxynitrite decreased progressive and total motility, as well as some sperm kinetic parameters. Mitochondrial membrane potential also decreased. These alterations occurred with no decrease in sperm viability. In conclusion, peroxynitrite-induced nitrosative stress impairs vital functions in the male gamete, possibly contributing to male infertility.

16 Article Impact of SIN-1-derived peroxynitrite flux on endothelial cell redox homeostasis and bioenergetics: protective role of diphenyl diselenide via induction of peroxiredoxins. 2015

Fiuza, B / Subelzú, N / Calcerrada, P / Straliotto, M R / Piacenza, L / Cassina, A / Rocha, J B T / Radi, R / de Bem, A F / Peluffo, G. ·Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina , Florianópolis, SC , Brazil. · ·Free Radic Res · Pubmed #25373783.

ABSTRACT: Increased production of reactive nitrogen (RNS) and oxygen (ROS) species and its detrimental effect to mitochondria are associated with endothelial dysfunction. This study was designed to determine the effect of a peroxynitrite flux, promoted by 1,3-morpholinosydnonimine (SIN-1), in mitochondrial function and some redox homeostasis parameters in bovine aortic endothelial cells (BAEC). Moreover, the effect of diphenyl diselenide (PhSe)2, a simple organic selenium compound, in preventing peroxynitrite-mediated cytotoxicity was also investigated. Our results showed that overnight exposure to SIN-1 (250 μM) caused a profound impairment of oxygen consumption, energy generation and reserve capacity in mitochondria of BAEC. Mitochondrial dysfunction resulted in an additional intracellular production of peroxynitrite, amplifying the phenomenon and leading to changes in redox homeostasis. Moreover, we observed an extensive decline in mitochondrial membrane potential (ΔΨm) induced by peroxynitrite and this event was associated with apoptotic-type cell death. Alternatively, the pretreatment of BAEC with (PhSe)2, hindered peroxynitrite-mediated cell damage by preserving mitochondrial and endothelial function and consequently preventing apoptosis. The protective effect of (PhSe)2 was related to its ability to improve the intracellular redox state by increasing the expression of different isoforms of peroxiredoxins (Prx-1-3), efficient enzymes in peroxynitrite detoxification.

17 Article Nitric oxide synthase inhibition decreases l-DOPA-induced dyskinesia and the expression of striatal molecular markers in Pitx3(-/-) aphakia mice. 2015

Solís, Oscar / Espadas, Isabel / Del-Bel, Elaine A / Moratalla, Rosario. ·Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002 Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain. · Department of Morphology, Physiology and Pathology, School of Odontology, University of Sao Paulo, Campus Ribeirao Preto, Brazil. · Instituto Cajal, Consejo Superior de Investigaciones Científicas, CSIC, 28002 Madrid, Spain; CIBERNED, Instituto de Salud Carlos III, Madrid, Spain. Electronic address: moratalla@cajal.csic.es. ·Neurobiol Dis · Pubmed #25281315.

ABSTRACT: Nitric oxide (NO), a gaseous messenger molecule synthesized by nitric oxide synthase (NOS), plays a pivotal role in integrating dopamine transmission in the basal ganglia and has been implicated in the pathogenesis of Parkinson disease (PD). To study the role of the nitrergic system in l-DOPA-induced dyskinesia (LID), we assessed the effect of the pharmacological manipulation of NO levels and NO/cyclic guanosine monophosphate (cGMP) signaling on LID in the Pitx3(-/-) aphakia mouse, a genetic model of PD. To evaluate the effect of decreased NO signaling on the development of LID, Pitx3(-/-) mice were chronically treated with l-DOPA and 7-nitroindazole (7-NI, a neuronal NOS inhibitor). To evaluate its effect on the expression of established LID, 7-NI was administered acutely to dyskinetic mice. The chronic 7-NI treatment attenuated the development of LID in the Pitx3(-/-) mice, and the sub-acute 7-NI treatment attenuated established dyskinesia without affecting the beneficial therapeutic effect of l-DOPA. Moreover, 7-NI significantly reduced FosB and pAcH3 expression in the acutely and chronically l-DOPA-treated mice. We also examined how increasing NO/cGMP signaling affects LID expression by acutely administering molsidomine (an NO donor) or zaprinast (a cGMP phosphodiesterase 5-PDE5 inhibitor) before l-DOPA in mice with established dyskinesia. Paradoxically, the administration of either of these drugs also significantly diminished the expression of established LID; however, the effect occurred at the expense of the antiparkinsonian l-DOPA properties. We demonstrate that targeting the NO/cGMP signaling pathway reduces dyskinetic behaviors and molecular markers, but only the 7-NI treatment preserved the antiparkinsonian effect of l-DOPA, indicating that NOS inhibitors represent a potential therapy to reduce LID.

18 Article Design of silica carrier for controlled release of molsidomine: effect of preparation methods of silica matrixes and their composites with molsidomine on the drug release kinetics in vitro. 2014

Parfenyuk, Elena V / Dolinina, Ekaterina S. ·Laboratory of Chemistry of Hybrid Nanomaterials and Supramolecular Systems, G.A. Krestov Institute of Solution Chemistry of Russian Academy of Sciences, Ivanovo, Russian Federation. Electronic address: evp@isc-ras.ru. · Laboratory of Chemistry of Hybrid Nanomaterials and Supramolecular Systems, G.A. Krestov Institute of Solution Chemistry of Russian Academy of Sciences, Ivanovo, Russian Federation. ·Eur J Pharm Biopharm · Pubmed #25269886.

ABSTRACT: Biodegradable, controlled-release carrier materials with non-toxic degradation products are very valuable for delivery of cardiovascular drugs. This study is a part of development of novel form of vasodilator molsidomine to improve pharmacokinetic and consumer properties of the drug. It focuses on the effect of preparation methods of the drug-silica composites on their release kinetics. Phenyl modified silica materials prepared by different ways were studied as potential carriers for molsidomine. The composites of molsidomine with the modified silica were synthesized via one-step sol-gel route and adsorption. The drug was adsorbed onto the phenyl modified silica prepared by co-condensation and grafting. Furthermore, the one-step sol-gel derived composites were prepared at pH 4.4 (the isoelectric point of the drug) and pH 6.3 (the zero point of charge of the silica). In vitro release kinetics of molsidomine from the synthesized composites in simulated gastric (pH 1.6) and simulated blood (pH 7.4) media was studied. Our findings demonstrate that the release of the drug can be controlled by manipulating the synthesis ways and changing the sol-gel pH. The comparative analysis of molsidomine release profiles from the composites prepared by one-step sol-gel synthesis at different pH and adsorption allows to reveal perspective composites which exhibit sustained release of molsidomine for about 36h in acidic medium close to the zero order release kinetics.

19 Article Induction of heme oxygenase‑1 expression protects articular chondrocytes against cilostazol‑induced cellular senescence. 2014

Kim, Kang Mi / Park, Si Eun / Lee, Mi Sun / Kim, Koanhoi / Park, Young Chul. ·Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Gyeongnam 626‑870, Republic of Korea. · Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan, Gyeongnam 626‑870, Republic of Korea. · Department of Pharmacology, Pusan National University School of Medicine, Yangsan, Gyeongnam 626‑870, Republic of Korea. ·Int J Mol Med · Pubmed #25175370.

ABSTRACT: Chondrocyte senescence is associated with the aging and degeneration of cartilage, and eventually leads to joint destruction. The aim of this study was to elucidate the mechanisms responsible for the cytoprotective effects of heme oxygenase‑1 (HO‑1) on chondrocytes in cartilage. Chondrocyte senescence was induced using cilostazol and measured using a specific senescence‑associated β‑galactosidase (SA‑β‑gal) staining assay. Cilostazol altered the expression of type Ⅱ collagen and β‑catenin, which are phenotypic markers of the differentiation and dedifferentiation of chondrocytes. Cilostazol also significantly induced HO‑1 expression, and the induction of HO‑1 expression was affected by a significant increase in reactive oxygen species (ROS) production caused by cilostazol treatment. Of note, pre‑treatment with 3‑morpholinosydnonimine hydrochloride (SIN‑1), an inducer of HO‑1 expression, markedly attenuated cilostazol‑induced chondrocyte senescence, and thus, we examined whether HO‑1 directly modulates chondrocyte senescence induced by cilostazol. The upregulation of HO‑1 was found to suppress cilostazol‑induced cellular senescence. In addition, the inhibition of HO‑1 activity with the iron chelator, desferrioxamine (DFO), or HO‑1 siRNA increased cilostazol‑induced chondrocyte senescence. Based on these results, it can be concluded that HO‑1 is associated with the suppression of chondrocyte senescence, and that the enforced overexpression of HO‑1 protects chondrocytes against stress‑induced senescence.

20 Article MicroRNA-302 induces proliferation and inhibits oxidant-induced cell death in human adipose tissue-derived mesenchymal stem cells. 2014

Kim, J Y / Shin, K K / Lee, A L / Kim, Y S / Park, H J / Park, Y K / Bae, Y C / Jung, J S. ·1] Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Korea [2] Medical Research Center for Ischemic Tissue Engineering, Pusan National University, Yangsan 626-870, Korea [3] BK21 Medical Science Education Center, School of Medicine, Pusan National University, Yangsan 626-870, Korea. · 1] Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Korea [2] Medical Research Center for Ischemic Tissue Engineering, Pusan National University, Yangsan 626-870, Korea. · Department of Plastic Surgery, School of Medicine, Pusan National University, Pusan 602-739, Korea. · 1] Department of Physiology, School of Medicine, Pusan National University, Yangsan 626-870, Korea [2] Medical Research Center for Ischemic Tissue Engineering, Pusan National University, Yangsan 626-870, Korea [3] BK21 Medical Science Education Center, School of Medicine, Pusan National University, Yangsan 626-870, Korea [4] Medical Research Institute, Pusan National University, Pusan 602-739, Korea. ·Cell Death Dis · Pubmed #25144720.

ABSTRACT: Mesenchymal stem cells (MSCs) are a heterogeneous population of cells that proliferate in vitro as plastic-adherent cells, have a fibroblast-like morphology, form colonies in vitro and can differentiate into bone, cartilage and fat cells. The abundance, ease and repeatable access to subcutaneous adipose tissue and the simple isolation procedures provide clear advantages for the use of human adipose tissue-derived mesenchymal stem cells (hASDCs) in clinical applications. We screened microRNAs (miRNAs) that affected the proliferation and survival of hADSCs. Transfection of miR-302d mimic increased cell proliferation and protected cells from oxidant-induced cell death in hADSCs, which was supported by flow-cytometric analysis. miR-302d did not affect the expression of Bcl-2 family members or anti-oxidant molecules. The Nrf2-Keap1 system, which is one of the major mechanisms for the cellular defense against oxidative stress, was not altered by transfection of miR-302d mimic. To identify the target of the miR-302d actions on proliferation and survival of hADSCs, a microarray analysis was performed using miR-302d-overexpressing hADSCs. Real-time PCR analysis showed that transfection of miR-302d mimic inhibited the CDKN1A and CCL5 expression. Downregulation of CDKN1A with a specific siRNA mimicked the effect of miR-302d on hADSCs proliferation, but did not affect miR-302d-induced cell survival. Downregulation of CCL5 protected oxidant-induced cell death as miR-302d, inhibited oxidant-induced reactive oxygen species (ROS) generation and the addition of recombinant CCL5 inhibited the protective action of miR-302d on oxidant-induced cell death. This study indicates that miR-302 controls proliferation and cell survival of hADSCs through different targets and that this miRNA can be used to enhance the therapeutic efficacy of hADSCs transplantation in vivo.

21 Article Soluble guanylyl cyclase activators increase the expression of tolerance to morphine analgesic effect. 2014

Durmus, N / Bagcivan, I / Ozdemir, E / Altun, A / Gursoy, S. · ·Bratisl Lek Listy · Pubmed #25023422.

ABSTRACT: OBJECTIVES: It is aimed to investigate the effects of guanylyl cyclase activation and inhibition on acute morphine antinociception and the development of tolerance to its effect. BACKGROUND: Nitric oxide-soluble guanylyl cyclase signal transduction cascade suggested to play an important role in the development of tolerance to antinociceptive effects of morphine. METHODS: Nociception was evaluated by tail flick and hot plate tests in male Wistar rats. The analgesic effects of intraperitoneal protoporphyrin IX (PPIX; an activator of soluble guanylyl cyclase), 3-morpholinosydnonimine hydrochloride (SIN-1; NO donor and activator of guanylyl cyclase), S-Nitroso-N-acetylpenicillamine (SNAP; an activator of guanylyl cyclase), 3,3-Bis (amino ethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18; NO donor activating guanylyl cyclase) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; an inhibitor of guanylyl cyclase) alone or in combination with subcutaneous morphine injection were evaluated. Their effects on morphine tolerance development were evaluated by giving these agents 20 minutes prior to twice daily morphine injection during tolerance development for 5 days. On day 6, the expression of morphine tolerance was determined. RESULTS: PPIX, SIN-1, SNAP and NOC-18 significantly increased expression of morphine tolerance while ODQ decreased. CONCLUSION: These data suggested that sGC activators have a significant role in tolerance to the analgesic effect of morphine (Tab. 1, Fig. 4, Ref. 29).

22 Article Comparative study of adsorption capacity of mesoporous silica materials for molsidomine: effects of functionalizing and solution pH. 2014

Alyoshina, N A / Agafonov, A V / Parfenyuk, E V. ·G.A. Krestov Institute of Solution Chemistry of Russian Academy of Sciences, 1 Akademicheskaya Str., Ivanovo, Russian Federation. · G.A. Krestov Institute of Solution Chemistry of Russian Academy of Sciences, 1 Akademicheskaya Str., Ivanovo, Russian Federation. Electronic address: evp@isc-ras.ru. ·Mater Sci Eng C Mater Biol Appl · Pubmed #24857479.

ABSTRACT: Adsorption capacities of mesoporous silica materials having various surface functional groups (hydroxyl, phenyl, mercaptopropyl, aminopropyl) at pH values of 4.8, 7.4, and 8.0 were studied. It was found that the maximum amount of adsorbed molsidomine is affected by method of preparation of the silica materials, chemistry of their surfaces and solution pH from where adsorption is carried out. The effects were explained by different states of the adsorbents and molsidomine in solution at the studied pH. The most efficient adsorption of molsidomine is observed onto phenyl modified silica prepared by grafting at pH4.8. Aminopropyl modified silica adsorbs the lowest amount of molsidomine and the adsorption was observed only at pH7.4. Interactions responsible for the adsorption were elucidated by spectroscopic studies.

23 Article Topical combinations to treat microvascular dysfunction of chronic postischemia pain. 2014

Laferrière, André / Abaji, Rachid / Tsai, Cheng-Yu Mark / Ragavendran, J Vaigunda / Coderre, Terence J. ·From the *Alan Edwards Centre for Research on Pain, Department of Anesthesia, †Department of Psychology, ‡Alan Edwards Centre for Research on Pain, Department of Anesthesia, Neurology and Neurosurgery, and Psychology, and §Anesthesia Research Unit, McGill University Health Centre Research Institute, Montreal, QC, Canada. · ·Anesth Analg · Pubmed #24651238.

ABSTRACT: BACKGROUND: Growing evidence indicates that patients with complex regional pain syndrome (CRPS) exhibit tissue abnormalities caused by microvascular dysfunction in the blood vessels of skin, muscle, and nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in an animal model of CRPS. We hypothesized that topical administration of either α2-adrenergic (α2A) receptor agonists or nitric oxide (NO) donors given to increase arterial blood flow, combined with either phosphatidic acid (PA) or phosphodiesterase (PDE) inhibitors to increase capillary blood flow, would effectively reduce allodynia and signs of microvascular dysfunction in the animal model of chronic pain. METHODS: Mechanical allodynia was induced in the hindpaws of rats with chronic postischemia pain (CPIP). Allodynia was assessed before and after topical application of vehicle, single drugs or combinations of an α2A receptor agonist (apraclonidine) or an NO donor (linsidomine), with PA or PDE inhibitors (lisofylline, pentoxifylline). A topical combination of apraclonidine + lisofylline was also evaluated for its effects on a measure of microvascular function (postocclusive reactive hyperemia) and tissue oxidative capacity (formazan production by tetrazolium reduction) in CPIP rats. RESULTS: Each of the single topical drugs produced significant dose-dependent antiallodynic effects compared with vehicle in CPIP rats (N = 30), and the antiallodynic dose-response curves of either PA or PDE inhibitors were shifted 5- to 10-fold to the left when combined with nonanalgesic doses of α2A receptor agonists or NO donors (N = 28). The potent antiallodynic effects of ipsilateral treatment with combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors were not reproduced by the same treatment of the contralateral hindpaw (N = 28). Topical combinations produced antiallodynic effects lasting up to 6 hours (N = 15) and were significantly enhanced by low-dose systemic pregabalin in early, but not late, CPIP rats (N = 18). An antiallodynic topical combination of apraclonidine + lisofylline was also found to effectively relieve depressed postocclusive reactive hyperemia in CPIP rats (N = 61) and to increase formazan production in postischemic tissues (skin and muscle) (N = 56). CONCLUSIONS: The present results support the hypothesis that allodynia in an animal model of CRPS is effectively relieved by topical combinations of α2A receptor agonists or NO donors with PA or PDE inhibitors. This suggests that topical treatments aimed at improving microvascular function by increasing both arterial and capillary blood flow produce effective analgesia for CRPS.

24 Article Effect of oxidative stress on the expression of thin filament-associated proteins in gastric smooth muscle cells. 2014

Al-Shboul, Othman Abdullah / Mustafa, Ayman / Mohammad, Mukhallad / Al-Shehabat, Mustafa / Yousef, Asmaa / Al-Hashimi, Farah. ·Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Irbid, 22110, Jordan, oashboul@just.edu.jo. · ·Cell Biochem Biophys · Pubmed #24639107.

ABSTRACT: Thin filament-associated proteins such as calponin, caldesmon, and smoothelin are believed to regulate acto-myosin interaction and thus, muscle contraction. Oxidative stress has been found to affect the normal contractile behavior of smooth muscle and is involved in the pathogenesis of a number of human diseases such as diabetes mellitus, hypertension, and atherosclerosis. However, very little is known about the effect of oxidative stress on the expression of smooth muscle contractile proteins. The aim of the current study is to investigate the effect of oxidative stress on the expression of thin filament-associated proteins in rat gastric smooth muscle. Single smooth muscle cells of the stomach obtained from Sprague-Dawley rats were used. Muscle cells were treated with hydrogen peroxide (H2O2) (500 μM) for 30 min or the peroxynitrite donor 3-morpholinosydnonimine (SIN-1) (1 mM) for 90 min to induce oxidative stress. Calponin, caldesmon, and smoothelin expressions were measured via specifically designed enzyme-linked immunosorbent assay. We found that exposure to exogenous H2O2 or incubation of dispersed gastric muscle cells with SIN-1 significantly increased the expression of calponin, caldesmon, and smoothelin proteins. In conclusion: oxidative stress increases the expression of thin filament-associated proteins in gastric smooth muscle, suggesting an important role in gastrointestinal motility disorders associated with oxidative stress.

25 Article Protective and therapeutic effect of molsidomine on bleomycin-induced lung fibrosis in rats. 2014

Kilic, Talat / Parlakpinar, Hakan / Polat, Alaadin / Taslidere, Elif / Vardi, Nigar / Sarihan, Ediz / Ermis, Hilal / Tanbag, Kevser. ·Department of Pulmonary Medicine, Inonu University School Medicine, Malatya, Turkey, talatkilic2013@gmail.com. · ·Inflammation · Pubmed #24526289.

ABSTRACT: We aimed to investigate the preventive and treatment effect of molsidomine (MOL) on bleomycin (BLC)-induced lung injury in rats. Rats were assigned into groups as follows: control group; MOL group, 10 mg/kg MOL was continued orally for 29 day; BLC group, a single intratracheal injection of BLC (2.5 mg/kg), MOL+BLC-preventive group, 10 mg/kg MOL was administered 1 day before the intratracheal BLC injection and continued for 14 days; BLC+MOL-treatment group 10 mg/kg MOL was given on 14th day after the intratracheal BLC injection and continued until sacrifice. All animals were sacrificed on 29th day after BLC administration. The semiquantitative histopathological assessment, tissue levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), total antioxidant status (TAS), total oxidant status (TOS), myeloperoxidase (MPO), and oxidative stress index (OSI) were measured. BLC-provoked histological changes were significantly detected compared to the control group. MOL restored these histological damages in different quantity in the treatment and preventive groups. BLC administration significantly decreased levels of GSH and TAS when compared to controls and these reductions was significantly ameliorated by MOL given prophylactic setting. However, therapeutic MOL administration significantly increased the TAS level decreased by BLC. The levels of MDA, MPO, and TOS were significantly increased with BLM, and these augmentations of MDA and TOS were significantly reduced by MOL given prophylactic setting. Furthermore, the OSI was higher in the BLC group, and this increase was reversed by the MOL administration before and after BLC treatment. In this study, both protective and therapeutic effects of MOL against BLC-induced lung fibrosis were demonstrated for the first time.