Isola del Gran Sasso d'Italia, Italy
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Xie L.,National University of Singapore | Hu L.-F.,Soochow University of China | Teo X.Q.,National University of Singapore | Tiong C.X.,National University of Singapore | And 5 more authors.
PLoS ONE | Year: 2013

Parkinson's disease (PD), characterized by loss of dopaminergic neurons in the substantia nigra, is a neurodegenerative disorder of central nervous system. The present study was designed to investigate the therapeutic effect of ACS84, a hydrogen sulfide-releasing-L-Dopa derivative compound, in a 6-hydroxydopamine (6-OHDA)-induced PD model. ACS84 protected the SH-SY5Y cells against 6-OHDA-induced cell injury and oxidative stress. The protective effect resulted from stimulation of Nrf-2 nuclear translocation and promotion of anti-oxidant enzymes expression. In the 6-OHDA-induced PD rat model, intragastric administration of ACS84 relieved the movement dysfunction of the model animals. Immunofluorescence staining and High-performance liquid chromatography analysis showed that ACS84 alleviated the loss of tyrosine-hydroxylase positive neurons in the substantia nigra and the declined dopamine concentration in the injured striatums of the 6-OHDA-induced PD model. Moreover, ACS84 reversed the elevated malondialdehyde level and the decreased glutathione level in vivo. In conclusion, ACS84 may prevent neurodegeneration via the anti-oxidative mechanism and has potential therapeutic values for Parkinson's disease. © 2013 Xie et al.


Tesei A.,Irccs Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Brigliadori G.,Irccs Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Carloni S.,Irccs Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | Fabbri F.,Irccs Instituto Scientifico Romagnolo Per Lo Studio E La Cura Dei Tumori Irst | And 8 more authors.
Journal of Cellular Physiology | Year: 2012

Lung cancer is the leading cause of cancer mortality worldwide and despite efforts made to improve clinical results, continuing poor survival rates indicate that novel therapeutic approaches are needed. Valproic acid (VPA), a short-chain branched fatty acid used mainly for the treatment of epilepsy and bipolar disorder, has been shown to inhibit class I histone deacetylases (HDAC-I), a group of enzymes involved in chromatin remodeling and which are thought to play a role in tumor development. Although evidence of VPA's therapeutic efficacy has also been observed in patients with solid tumors, the very high concentration required to induce antitumor activity limits its clinical usefulness. We used a panel of NSCLC cell lines to evaluate the activity and mechanisms of action of organosulfur valproic acid derivatives, a promising new class of compounds designed to improve the safety and efficacy of the valproic acid molecule and created by coupling it with a hydrogen sulfide (H 2S)-releasing moiety. Our results highlighted the increased cytotoxic activity of the novel organosulfur derivatives, ACS33 and ACS2, with respect to VPA, starting from low concentrations. In particular, ACS2 exhibited important pro-apoptotic activity triggered by the mitochondrial pathway and also showed anti-invasion potential. Furthermore, our in vitro results identified a highly effective combination schedule of ACS2 and cisplatin capable of inducing a synergistic interaction even when the two drugs were used at low concentrations, which could prove a valid alternative to traditional chemotherapeutic regimens used for advanced lung cancer. Further studies are needed to confirm these preliminary findings. J. Cell. Physiol. 227: 3389-3396, 2012. © 2011 Wiley Periodicals, Inc. Copyright © 2011 Wiley Periodicals, Inc.


Liu L.,Xuzhou Medical College | Cui J.,Xuzhou Medical College | Song C.-J.,Xuzhou Medical College | Bian J.-S.,National University of Singapore | And 4 more authors.
PLoS ONE | Year: 2012

The aim of this study was to examine the effect of ACS14, a hydrogen sulfide (H2S)-releasing derivative of aspirin (Asp), on Asp-induced gastric injury. Gastric hemorrhagic lesions were induced by intragastric administration of Asp (200 mg/kg, suspended in 0.5% carboxymethyl cellulose solutions) in a volume of 1 ml/100 g body weight. ACS14 (1, 5 or 10 mg/kg) was given 30 min before the Asp administration. The total area of gastric erosions, H2S concentration and oxidative stress in gastric tissues were measured three hours after administration of Asp. Treatment with Asp (200 mg/kg), but not ACS14 (430 mg/kg, at equimolar doses to 200 mg/kg Asp), for 3 h significantly increased gastric mucosal injury. The damage caused by Asp was reversed by ACS14 at 1-10 mg/kg in a concentration-dependent manner. ACS14 abrogated Asp-induced upregulation of COX-2 expression, but had no effect on the reduced PGE2 level. ACS14 reversed the decreased H2S concentrations and blood flow in the gastric tissue in Asp-treated rats. Moreover, ACS14 attenuated Asp-suppressed superoxide dismutase-1 (SOD-1) expression and GSH activity, suggesting that ACS14 may stimulate antioxidants in the gastric tissue. ACS14 also obviously inhibited Asp-induced upregulation of protein expression of oxidases including XOD, p47phox and p67phox. In conclusion, ACS14 protects Asp induced gastric mucosal injury by inhibiting oxidative stress in the gastric tissue. © 2012 Liu et al.


Liu Y.-Y.,National University of Singapore | Sparatore A.,University of Milan | Del Soldato P.,CTG Pharma | Bian J.-S.,National University of Singapore
Neurochemistry International | Year: 2011

Hydrogen sulfide (H 2S) is a novel neurotransmitter. We studied here the effect of ACS 84, a new H 2S releasing compound, on the cytotoxicity induced by amyloid beta (Aβ) in microglia. Treatment with Aβ 1-40 (25 μmol/L) for 24 h significantly inhibited MTT reduction and increased lactate dehydrogenase release in BV-2 microglia cells. Pretreatment with ACS 84 (10 μM) for 30 min attenuated the above cytotoxicity caused by Aβ 1-40, suggesting that ACS 84 may protect microglia against Aβ 1-40-induced cell injury. ACS 84 also significantly attenuated nitric oxide release and TNF-α production in BV-2 cells treated with Aβ peptides (Aβ 1-40 or Aβ 1-42), but had no significant effect on the up-regulated protein expression of cyclooxygenase 2. These data suggest that ACS 84 may produce anti-inflammatory effect via inhibition of the release of inflammatory cytokines but not via suppression of the prostanoids production. Furthermore, pretreatment with ACS 84 also attenuated mitochondrial membrane potential loss (Δψ m) caused by Aβ 1-40 in both microglia and neurons. To examine the underlying signaling mechanism, we detected the phosphorylation of p38-, JNK- and ERK-MAPKs. It was found that Aβ 1-40 stimulated phosphorylation of all above three types of MAKPs. However, ACS 84 only attenuated the activation of p38 and JNK, but had no significant effect on that of ERK. Taken together, our data suggest that ACS 84 may protect Aβ-induced cell injury via anti-inflammation and preservation of mitochondrial function in a p38 and JNK dependent mechanism. Our work suggests that ACS 84 may have potential for the treatment of neurodegenerative diseases. © 2011 Elsevier Ltd. All rights reserved.


Huang Q.,University of Saskatchewan | Huang Q.,Shanghai JiaoTong University | Sparatore A.,University of Milan | Del Soldato P.,CTG Pharma | And 3 more authors.
PLoS ONE | Year: 2014

Hydrogen sulfide is a gasotransmitter with vasodilatory and anti-inflammatory properties. Aspirin is an irreversible cyclooxygenase inhibitor anti-inflammatory drug. ACS14 is a novel synthetic hydrogen sulfide releasing aspirin which inhibits cyclooxygenase and has antioxidant effects. Methylglyoxal is a chemically active metabolite of glucose and fructose, and a major precursor of advanced glycation end products formation. Methylglyoxal is harmful when produced in excess. Plasma methylglyoxal levels are significantly elevated in diabetic patients. Our aim was to investigate the effects of ACS14 on methylglyoxal levels in cultured rat aortic vascular smooth muscle cells. We used cultured rat aortic vascular smooth muscle cells for the study. Methylglyoxal was measured by HPLC after derivatization, and nitrite+nitrate with an assay kit. Western blotting was used to determine NADPH oxidase 4 (NOX4) and inducible nitric oxide synthase (iNOS) protein expression. Dicholorofluorescein assay was used to measure oxidative stress. ACS14 significantly attenuated elevation of intracellular methylglyoxal levels caused by incubating cultured vascular smooth muscle cells with methylglyoxal (30 μM) and high glucose (25 mM). ACS14, but not aspirin, caused a significant attenuation of increase in nitrite+nitrate levels caused by methylglyoxal or high glucose. ACS14, aspirin, and sodium hydrogen sulfide (NaHS, a hydrogen sulfide donor), all attenuated the increase in oxidative stress caused by methylglyoxal and high glucose in cultured cells. ACS14 prevented the increase in NOX4 expression caused by incubating the cultured VSMCs with MG (30 mM). ACS14, aspirin and NaHS attenuated the increase in iNOS expression caused by high glucose (25 mM). In conclusion, ACS14 has the novel ability to attenuate an increase in methylglyoxal levels which in turn can reduce oxidative stress, decrease the formation of advanced glycation end products and prevent many of the known deleterious effects of elevated methylglyoxal. Thus, ACS14 has the potential to be especially beneficial for diabetic patients pending further in vivo studies. © 2014 Huang et al.


Tang X.-Q.,University of South China | Chen R.-Q.,University of South China | Ren Y.-K.,University of South China | Soldato P.D.,CTG Pharma | And 4 more authors.
Medical Gas Research | Year: 2011

Background: The hydrogen sulfide-releasing sildenafil, ACS6, has been demonstrated to inhibit superoxide formation through donating hydrogen sulfide (H2S). We have found that H2S antagonizes homocysteine-induced oxidative stress and neurotoxicity. The aim of the present study is to explore the protection of ACS6 against homocysteine-triggered cytotoxicity and apoptosis and the molecular mechanisms underlying in PC12 cells. Methods. Cell viability was determined by Cell Counting Kit-8 assay. Cell apoptosis was observed using the chromatin dye Hoechst 33258 and analyzed by Flow Cytometry after propidium iodide staining. Mitochondrial membrane potential was monitored using the fluorescent dye Rh123. Intracellular reactive oxygen species were determined by oxidative conversion of cell permeable 2',7'-dichlorfluorescein-diacetate to fluorescent 2',7'-dichlorfluorescein. The expression of cleaved caspase-3 and bcl-2 and the accumulation of cytosolic cytochrome c were analyzed by Western blot. Results: We show that ACS6 protects PC12 cells against cytotoxicity and apoptosis induced by homocysteine and blocks homocysteine-triggered cytochrome c release and caspase-3 activation. ACS6 treatment results in not only prevention of homocysteine-caused mitochondrial membrane potential () loss and reactive oxygen species (ROS) overproduction but also reversal of Bcl-2 down-expression. Conclusions: These results indicate that ACS6 protects PC12 cells against homocysteine-induced cytotoxicity and apoptosis by preservation of mitochondrial function though inhibiting both loss of and accumulation of ROS as well as modulating the expression of Bcl-2. Our study provides evidence both for a neuroprotective effect of ACS6 and for further evaluation of ACS6 as novel neuroprotectants for Alzheimer's disease associated with homocysteine. © 2011 Tang et al; licensee BioMed Central Ltd.


Giustarini D.,University of Siena | Del Soldato P.,CTG Pharma | Sparatore A.,University of Milan | Rossi R.,University of Siena
Free Radical Biology and Medicine | Year: 2010

The H2S-releasing aspirin (ACS14) containing a dithiolethione moiety has been demonstrated to maintain the thromboxane-suppressing activity of the parent compound, but it seems to spare the gastric mucosa by affecting redox imbalance through increased H2S/glutathione (GSH) formation. Nevertheless, the mechanisms by which ACS14 is able to elevate the levels of these agents has not been fully elucidated so far.In this manuscript the effect of an acute ip administration of ACS14 and of its dithiolethione moiety (5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, ADTOH) on the overall thiol content of rat tissues and on the main enzymes involved in the maintenance of thiol homeostasis is reported. ACS14 and ADTOH treatments were shown to induce a significant increase not only of GSH but also of cysteine in plasma and in several rat tissues as well as of H2S plasma levels. Conversely, a significant decrease of homocysteine in most rat organs and in plasma was observed. Most of these phenomena are supposed to be linked to the elevated intracellular levels of cysteine induced by treatments with either ACS14 or ADTOH. © 2010 Elsevier Inc.


Lee M.,University of British Columbia | Tazzari V.,University of Milan | Giustarini D.,University of Siena | Rossi R.,University of Siena | And 4 more authors.
Journal of Biological Chemistry | Year: 2010

The main lesion in Parkinson disease (PD) is loss of substantia nigra dopaminergic neurons. Levodopa (L-DOPA) is the most widely used therapy, but it does not arrest disease progression. Some possible contributing factors to the continuing neuronal loss are oxidative stress, including oxidation of L-DOPA, and neurotoxins generated by locally activated microglia and astrocytes. A possible method of reducing these factors is to produce L-DOPA hybrid compounds that have antioxidant and antiinflammatory properties. Here we demonstrate the properties of four such L-DOPA hybrids based on coupling L-DOPA to four different hydrogen sulfide-donating compounds. The donors themselves were shown to be capable of conversion by isolated mitochondria to H2S or equivalent SH- ions. This capability was confirmed by in vivo results, showing a large increase in intracerebral dopamine and glutathione after iv administration in rats. When human microglia, astrocytes, and SH-SY5Y neuroblastoma cells were treated with these donating agents, they all accumulated H2S intracellularly as did their derivatives coupled to L-DOPA. The donating agents and the L-DOPA hybrids reduced the release of tumor necrosis factor-α, interleukin-6, and nitric oxide from stimulated microglia, astrocytes as well as the THP-1 and U373 cell lines. They also demonstrated a neuroprotective effect by reducing the toxicity of supernatants from these stimulated cells to SH-SY5Y cells. L-DOPA itself was without effect in any of these assays. The H2S-releasing L-DOPA hybrid molecules also inhibited MAO B activity. They may be useful for the treatment of PD because of their significant antiinflammatory, antioxidant, and neuroprotective properties. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Sparatore A.,University of Milan | Santus G.,CTG Pharma | Giustarini D.,University of Siena | Rossi R.,University of Siena | Del Soldato P.,CTG Pharma
Expert Review of Clinical Pharmacology | Year: 2011

A new class of hydrogen sulfide (H 2S)-donating hybrids combined with pharmacologically active compounds is presented in this article. The pharmacological profiles of some hybrid lead compounds in the areas of inflammation, H 2S-donating diclofenac (ACS 15); cardiovascular, H 2S-donating aspirin (ACS 14); urology, H 2S-donating sildenafil (ACS 6); and neurodegenerative, H 2S-donating latanoprost (ACS 67) for glaucoma treatment and H 2S-donating levodopa (ACS 84) for Parkinsons disease, are described. The new H 2S-releasing hybrids demonstrate remarkable improvement in activity and tolerability as compared with the related parent compounds, suggesting an active pharmacological role for H 2S. Finally the mechanism(s) of action of glutathione-dependent and independent, and of gas (H 2S) release (spontaneous or enzymatic) and its implications for clinical pharmacology perspectives will be also discussed. © 2011 Expert Reviews Ltd.

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