Activity of a new hydrogen sulfide-releasing aspirin (ACS14) on pathological cardiovascular alterations induced by glutathione depletion in rats

Rossoni, Giuseppe; Manfredi, Barbara; Tazzari, Valerio; Sparatore, Anna; Trivulzio, Silvio; Soldato, Piero Del; Berti, F.

doi:10.1016/j.ejphar.2010.08.039

Cited by 48 publications

(36 citation statements)

References 25 publications

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“…In full agreement with our in vitro findings in human blood, oral treatment with ACS14 in mice, which has previously been shown to reduce aspirin-dependent gastrointestinal damage 3,21 in rodents, potently inhibited COX and consequently arachidonic acid-dependent platelet aggregation. Platelet aggregation in blood drawn from ACS14-but not aspirintreated animals was also significantly decreased on ADP stimulation, indicating that the COX-independent platelet inhibitory effects of ACS14 were preserved even after oral treatment and that findings in mouse and human platelets were alike.…”

Section: Discussionsupporting

confidence: 80%

“…ACS14 also preserved endothelial function in an animal model of metabolic syndrome and ischemiareperfusion injury by modulating levels of glutathione and homocysteine. 21,22 The beneficial vascular effects of ACS14 observed in animal studies raise the question whether this compound exerts the same antiaggregatory effects on platelets as aspirin or whether it may combine them with previously described antiaggregatory effects of H 2 S 23,24 and thereby exceed the inhibitory effects reached by aspirin alone.…”

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confidence: 99%

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Hydrogen Sulfide–Releasing Aspirin Derivative ACS14 Exerts Strong Antithrombotic Effects In Vitro and In Vivo

Pircher

Fochler²,

Czermak³

et al. 2012

ATVB

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Objective-Hydrogen sulfide (H 2 S)-releasing NSAIDs exert potent anti-inflammatory effects beyond classical cyclooxygenase inhibition. Here, we compared the platelet inhibitory effects of the H 2 S-releasing aspirin derivative ACS14 with its mother compound aspirin to analyze additional effects on platelets. Methods and Results-In platelets of mice fed with ACS14 for 6 days (50 mg/kg per day), not only arachidonic acidinduced platelet aggregation but also ADP-dependent aggregation was decreased, an effect that was not observed with an equimolar dose of aspirin (23 mg/kg per day). ACS14 led to a significantly longer arterial occlusion time after light-dye-induced endothelial injury as well as decreased thrombus formation after ferric chloride-induced injury in the carotid artery. Bleeding time was not prolonged compared with animals treated with equimolar doses of aspirin. In vitro, in human whole blood, ACS14 (25-500 µmol/L) inhibited arachidonic acid-induced platelet aggregation, but compared with aspirin additionally reduced thrombin receptor-activating peptide-, ADP-, and collagen-dependent aggregation. In washed human platelets, ACS14 (500 µmol/L) attenuated αIIbβ3 integrin activation and fibrinogen binding and increased intracellular cAMP levels and cAMP-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Conclusion-The

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Hydrogen Sulfide–Releasing Aspirin Derivative ACS14 Exerts Strong Antithrombotic Effects In Vitro and In Vivo

Pircher

Fochler²,

Czermak³

et al. 2012

ATVB

Self Cite

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“…These findings suggest that the advantages of ACS14 in gastric protection are likely related to the enhanced H 2 S formation. ACS14 has also been shown to have strong protective effects against pathological cardiovascular alterations induced by buthionine sulfoximine (BSO), a GSH-synthase inhibitor (Rossoni et al 2010). In this study, 7-day BSO treatment increased rats' systolic blood pressure and lowered their heart rates.…”

Section: 3mentioning

confidence: 90%

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

Zhao

Pacheco

Xian

2015

Handbook of Experimental Pharmacology

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Hydrogen sulfide (H2S) was traditionally considered as a toxic gas. However, recent studies have demonstrated H2S is an endogenously generated gaseous signaling molecule (gasotransmitter) with importance on par with that of two other well-known endogenous gasotransmitters, nitric oxide (NO) and carbon monoxide (CO). Although H2S's exact mechanisms of action are still under investigation, the production of endogenous H2S and the exogenous administration of H2S have been demonstrated to elicit a wide range of physiological responses including modulation of blood pressure and protection of ischemia reperfusion injury, exertion of anti-inflammatory effects, and reduction of metabolic rate. These results strongly suggest that modulation of H2S levels could have potential therapeutic values. In this regard, synthetic H2S-releasing agents (i.e., H2S donors) are not only important research tools, but also potential therapeutic agents. This chapter summarizes the knowledge of currently available H2S donors. Their preparation, H2S releasing mechanisms, and biological applications are discussed.

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“…ACS14 and ACS21 are derivatives of aspirin and salicylic acid, respectively. Both compounds reduce hypertension and lower plasma levels of thromboxane B2 and insulin induced by glutathione depletion (54). S-diclofenac (ACS-15) efficiently suppresses LPS-induced inflammation with less gastric toxicity than parental diclofenac.…”

Section: H 2 S-based Therapeuticsmentioning

confidence: 99%

Hydrogen Sulfide Is a Signaling Molecule and a Cytoprotectant

Kimura

Shibuya²,

Kimura³

2012

Antioxidants & Redox Signaling

260

190

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Significance: Accumulating evidence shows that hydrogen sulfide may function as a signaling molecule in processes such as neuromodulation in the brain and smooth muscle relaxation in the vascular system. It also has a cytoprotective effect, since it can protect neurons and cardiac muscle from oxidative stress and ischemiareperfusion injury, respectively. Hydrogen sulfide can also modulate inflammation, insulin release, and angiogenesis. Recent Advances: The regulation of the activity of 3-mercaptopyruvate sulfur transferase (3MST) along with cysteine aminotransferase (CAT), one of the H 2 S producing pathways, has been demonstrated. The production of H 2 S by the pathway, which is regulated by Ca 2+ and facilitated by thioredoxin and dihydrolipoic acid, is also involved in H 2 S signaling as well as cytoprotection. Sulfur hydration of proteins by H 2 S has been proposed to modulate protein functions. H 2 S-sensitive fluorescent probes, which enable us to measure the localization of H 2 S in real time, have been developed. Critical Issues: The basal concentrations of H 2 S have recently been measured and found to be much lower than those initially reported. However, the concentration of H 2 S reached in stimulated cells, as well as the regulation of H 2 S producing enzymes is not well understood. It has been proposed that some of the effects of H 2 S on the regulation of enzymes and receptors might be explained through the properties of sulfane sulfur (S 0 ), another form of active sulfur. Future Directions: The determination of H 2 S concentrations in activated cells using new methods including H 2 S-sensitive fluorescent probes, as well as the investigation of the effects of H 2 S using specific inhibitors, may provide better understanding of the physiological function of this molecule. Clarifying mechanisms of H 2 S activity may also facilitate the development of new therapeutic compounds. Antioxid. Redox Signal. 17, 45-57.

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Activity of a new hydrogen sulfide-releasing aspirin (ACS14) on pathological cardiovascular alterations induced by glutathione depletion in rats

Cited by 48 publications

References 25 publications

Hydrogen Sulfide–Releasing Aspirin Derivative ACS14 Exerts Strong Antithrombotic Effects In Vitro and In Vivo

Hydrogen Sulfide–Releasing Aspirin Derivative ACS14 Exerts Strong Antithrombotic Effects In Vitro and In Vivo

Medicinal Chemistry: Insights into the Development of Novel H2S Donors

Hydrogen Sulfide Is a Signaling Molecule and a Cytoprotectant

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