Publications by authors named "Rosa Carnuccio"

43 Publications

The Ecto-5'-Nucleotidase/CD73 Inhibitor, α,β-Methylene Adenosine 5'-Diphosphate, Exacerbates Carrageenan-Induced Pleurisy in Rat.

Front Pharmacol 2019 11;10:775. Epub 2019 Jul 11.

Department of Pharmacy, School of Medicine, University of Naples Federico II, Via Domenico Montesano 49, Naples, Italy.

The ecto-5'-nucleotidase (ecto-5'NT/CD73) represents a crucial enzyme for endogenous adenosine generation. Several findings have shown that CD73 plays an important role in regulating vascular permeability and immune cell function. Adenosine 5'-(α,β-methylene)diphosphate (APCP) is a CD73 inhibitor, widely used as pharmacological tool to investigate the role of CD73/adenosine pathway in several and models, although it has been also shown to inhibit other ectoenzymes involved in adenosinergic pathway. Here, we evaluated the effect of APCP in the development of inflammation in carrageenan-induced pleurisy model. We found that treatment with APCP (400 µg/rat) significantly increased cell accumulation, exudate formation, and pro-inflammatory cytokine content into the pleural cavity in the acute phase (4 h) of inflammation, with no differences in the sub-acute phase (72 h) except for the regulation of monocyte chemotactic protein-1 levels. In addition, cells collected by pleural lavage fluids of APCP-treated rats, 4 h following carrageenan injection, showed increased ability to migrate , both in presence and in absence of N-formyl-L-methionyl-L-leucyl-L-phenylalanine as chemotactic stimulus, compared to cells obtained by control rats. Our results demonstrate that APCP exacerbates the early phase of carrageenan-induced pleurisy by controlling pleural effusion and polymorphonuclear migration and . This effect is likely dependent upon CD73 inhibition, although an inhibitory effect of other ectoenzymes cannot be ruled out.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2019.00775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637294PMC
July 2019

Adenosine A Receptor Agonist, 2--(2-Carboxyethyl)phenethylamino-5'--ethylcarboxamidoadenosine Hydrochloride Hydrate, Inhibits Inflammation and Increases Fibroblast Growth Factor-2 Tissue Expression in Carrageenan-Induced Rat Paw Edema.

J Pharmacol Exp Ther 2018 02 6;364(2):221-228. Epub 2017 Dec 6.

Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy (A.I., E.C., R.C., C.C.) and Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy (S.M.)

Adenosine is the final product of ATP metabolism, mainly derived from the action of 5'-nucleotidase cleavage of AMP. Cellular production of adenosine is greatly enhanced in inflamed tissues, ischemic tissues, and under hypoxia, where ATP is released from damaged cells. Much evidence has been accumulated on adenosine anti-inflammatory effects mediated through A receptor activation; A adenosine receptor has also been shown to play a role in matrix deposition and wound healing in a damaged tissue, contributing to dermal tissue protection and repair. Fibroblast growth factor-2 (FGF-2) is a powerful mitogen for fibroblast; it is expressed by several inflammatory cell types and plays a pivotal role in angiogenesis, wound healing, gastric ulcer protection. Human recombinant FGF-2 has been shown to have anti-inflammatory effects. The purpose of the present work was to investigate on the anti-inflammatory effect of systemic administration of the adenosine A agonist 2--(2-carboxyethyl)phenethylamino-5'--ethylcarboxamidoadenosine hydrochloride hydrate (CGS21680) in the rat model of carrageenan-induced paw edema. We found that CGS21680 inhibits inflammation induced by carrageenan injection into the rat paw, and this effect is associated to the local reduction of cytokine levels and dermal increase of FGF-2 expression. Our results suggest that FGF-2 might be involved in the anti-inflammatory and tissue protective effect due to A receptor activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.117.244319DOI Listing
February 2018

Simvastatin inhibits the expression of stemness‑related genes and the metastatic invasion of human cancer cells via destruction of the cytoskeleton.

Int J Oncol 2017 Dec 13;51(6):1851-1859. Epub 2017 Oct 13.

Institute of Genetics and Biophysics Andriano Buzzati Traverso, CNR, Naples, Italy.

Statins are a class of drugs that inhibit the rate-limiting steps in the cholesterol biosynthesis pathway. They act by inhibiting 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, which catalyzes the conversion of HMG-CoA to mevalonate. Blocking of mevalonate synthesis leads to inhibition of the farnesylation and geranylgeranylation of several functional proteins, such as RhoA and other small guanosine triphosphate-binding proteins, that are important in maintaining the undifferentiated status of the cells. In the present study, we hypothesized that simvastatin, likely through the inhibition of farnesylation and geranylgeranylation of Rac1, Cd42 and RhoA, induces a destruction/restructuration of the cytoskeleton that decreases mechanical strain transfer to the nuclei, inducing the loss of transmission of regulatory signals from the cytoskeleton to the nucleoskeleton. Although this remains at present a hypothesis and is not easy to define if the de-structuration of the cytoskeleton is a secondary effect of simvastatin treatment or the inhibition of post-translational protein modification have a precise role in the structuration of actin cytoskeleton, we speculate that these signal variations could inhibit the expression of certain stemness genes, which could therefore be considered nucleoskeleton-associated and mechanically regulated genes. On the other hand, the restructuration of the cytoskeleton inhibits the formation of lamellipodia and filopodia, which likely decreases the capability of cancer cells to invade the extracellular matrix, thereby modulating the equilibrium between proliferation, differentiation and metastatic invasion in human cancer cells. On the basis of our results we think that simvastatin, alone or in combination with conventional drugs, may have a possible role in cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ijo.2017.4158DOI Listing
December 2017

Palmitoylethanolamide reduces inflammation and itch in a mouse model of contact allergic dermatitis.

Eur J Pharmacol 2016 Nov 5;791:669-674. Epub 2016 Oct 5.

Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Napoli, Italy; Endocannabinoid Research Group, Italy.

In mice, 2,4-dinitrofluorobenzene (DNFB) induces contact allergic dermatitis (CAD), which, in a late phase, is characterized by mast cell (MC) infiltration and angiogenesis. Palmitoylethanolamide (PEA), an endogenous anti-inflammatory molecule, acts by down-modulating MCs following activation of the cannabinoid CB receptor and peroxisome proliferator-activated receptor-α (PPAR-α). We have previously reported the anti-inflammatory effect of PEA in the early stage of CAD. Here, we examined whether PEA reduces the features of the late stage of CAD including MC activation, angiogenesis and itching. After sensitization to DNFB, female C57BL/6J mice underwent to three DNFB challenges at days 5, 12 and 19 and treatments were given at each challenge and for two more days. CAD was expressed as Δ increase in ear thickness between challenged and un-challenged mice. PEA (5mg/kg/i.p.) reduced: i) the DNFB-induced Δ increase; ii) the number of MCs per tissue area; iii) the expression of VEGF and its receptor Flk-1. These effects were reversed by co-administration of AM630 (1mg/kg/i.p.), a CB antagonist, but not GW6471 (1mg/kg/i.p.), a PPAR-α antagonist. Finally, PEA reduced the number of ear scratchings 48h after DNFB challenge and this effect was reversed by both CB2 and PPAR-α antagonists, suggesting the involvement of both receptors. PEA, by reducing the features of late stage CAD in mice, may be beneficial in this pathological condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2016.10.005DOI Listing
November 2016

Novel non-peptide small molecules preventing IKKβ/NEMO association inhibit NF-κB activation in LPS-stimulated J774 macrophages.

Biochem Pharmacol 2016 Mar 14;104:83-94. Epub 2016 Jan 14.

Department of Pharmacy, University of Naples Federico II, Via D. Montesano 49, 80131 Naples, Italy. Electronic address:

Nuclear Factor-κB (NF-κB) is a transcription factor regulating several genes involved in important physiological and pathological processes. NF-κB has been found constitutively activated in many inflammatory/immune diseases. In addition, a positive correlation between persistent activation of NF-κB and tumor promotion has been demonstrated. Since the IKK (IκB kinase) activation is an indispensable component of all pro-inflammatory signaling pathways leading to NF-κB activation, considerable efforts have been done in order to develop novel anti-inflammatory therapeutics targeting IKK. Association of the IKK complex relies on critical interactions between the C-terminus NBD (NEMO binding domain) of the catalytic subunits IKKα and IKKβ, and the regulatory subunit NEMO (NF-κB Essential Modulator). Thus, this IKK/NEMO interacting region provides an attractive target to prevent the IKK complex formation and NF-κB activation. In this regard, we have identified non-peptide small molecule disruptors of IKKβ/NEMO complex through a structure-based virtual screening (SBVS) of the NCI chemical library. Phenothiazine 22 and its close analogues (22.2, 22.4 and 22.10) were able to reduce nitrite production and iNOS mRNA expression in J774 murine macrophages stimulated with LPS for 24h. These effects were associated with a reduced NF-κB/DNA binding activity as well as a decreased expression of phosphorylated IKKβ, IκBα and NF-κB/p65 in these cells. These observations suggest that compound 22 and its three structural analogues by inhibiting IKKβ/NEMO association mediate the blockage of NF-κB signaling pathway and may prove effective in treatment of diseases in which the IKK/NF-κB pathway is dysregulated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcp.2016.01.008DOI Listing
March 2016

Effect of hyaluronic acid on the thermogelation and biocompatibility of its blends with methyl cellulose.

Carbohydr Polym 2014 Nov 17;112:480-5. Epub 2014 Jun 17.

Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy; Interdisciplinary Research Centre on Biomaterials, CRIB, Università di Napoli Federico II, P.le Tecchio 80, Napoli, Italy. Electronic address:

Aim of this work was to investigate the influence of hyaluronic acid (HA) molecular weight on the thermogelation and biocompatibility of its blends with methyl cellulose in view of a possible application in drug delivery and/or wound healing. We found out that it was possible to obtain MC/HA blends showing a rheological behavior typical of a viscous solution at 20 °C and of a weak gel at 37 °C only when blending MC with low molecular weight HA. Moreover, the blends containing low molecular weight HA did not affect human foreskin fetal fibroblasts viability, proliferation and migration. On the contrary, the cell incubation with high molecular weight HA resulted in a marked and significant reduction of cell viability, compared to control cells. Finally, the optimized blends, in terms of rheological properties and biocompatibility, proved to be able to control and prolong bovine serum albumin release by a combined mechanism of platform dissolution and drug diffusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carbpol.2014.06.020DOI Listing
November 2014

Synthesis and pharmacological evaluation of modified adenosines joined to mono-functional platinum moieties.

Molecules 2014 Jul 3;19(7):9339-53. Epub 2014 Jul 3.

Dipartimento di Farmacia, Università degli Studi di Napoli "Federico II", via D. Montesano, 49, 80131 Napoli, Italy.

The synthesis of four novel platinum complexes, bearing N6-(6-amino-hexyl)adenosine or a 1,6-di(adenosin-N6-yl)-hexane respectively, as ligands of mono-functional cisplatin or monochloro(ethylendiamine)platinum(II), is reported. The chemistry exploits the high affinity of the charged platinum centres towards the N7 position of the adenosine base system and a primary amine of an alkyl chain installed on the C6 position of the purine. The cytotoxic behaviour of the synthesized complexes has been studied in A549 adenocarcinomic human alveolar basal epithelial and MCF7 human breast adenocarcinomic cancer cell lines, in order to investigate their effects on cell viability and proliferation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules19079339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271865PMC
July 2014

Design and characterization of a chitosan physical gel promoting wound healing in mice.

J Mater Sci Mater Med 2014 Jun 2;25(6):1483-93. Epub 2014 Mar 2.

Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131, Naples, Italy.

In this study, a sterile and biocompatible chitosan (CHI) gel for wound healing applications was formulated. CHI powder was treated in autoclave (ttCHI) to prepare sterile formulations. The heat treatment modified the CHI molecular weight, as evidenced by GPC analysis, and its physical-chemical features. Differential scanning calorimetry studies indicated that the macromolecules, before and after thermal treatment, differ in the strength of water-polymer interaction leading to different viscoelastic and flow properties. Thermally treated CHI exhibited the following effects: (i) increased the proliferation and migration of human foreskin foetal fibroblasts at 24 h; (ii) accelerated wound healing (measured as area of lesion) at 3 and 10 days in an in vivo model of pressure ulcers. These effects were linked to the increase of the hydroxyproline and haemoglobin content as well as Wnt protein expression. Moreover, we found a reduction of myeloperoxidase activity and TNF-α mRNA expression. These observations suggest the potential of this novel CHI gel in wound healing and other therapeutic applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10856-014-5175-7DOI Listing
June 2014

Palmitoylethanolamide inhibits rMCP-5 expression by regulating MITF activation in rat chronic granulomatous inflammation.

Eur J Pharmacol 2014 Feb 16;725:64-9. Epub 2014 Jan 16.

Department of Pharmacy, University of Naples Federico II, Via D. Montesano, 49, 80131 Naples, Italy. Electronic address:

Chronic inflammation, a condition frequently associated with several pathologies, is characterized by angiogenic and fibrogenic responses that may account for the development of granulomatous tissue. We previously demonstrated that the chymase, rat mast cell protease-5 (rMCP-5), exhibits pro-inflammatory and pro-angiogenic properties in a model of chronic inflammation sustained by mast cells (MCs), granuloma induced by the subcutaneous carrageenan-soaked sponge implant in rat. In this study, we investigated the effects of palmitoylethanolamide (PEA), an anti-inflammatory and analgesic endogenous compound, on rMCP-5 mRNA expression and Microphtalmia-associated Transcription Factor (MITF) activation in the same model of chronic inflammation. The levels of rMCP-5 mRNA were detected using semi-quantitative RT-PCR; the protein expression of chymase and extracellular signal-regulated kinases (ERK) were analyzed by western blot; MITF/DNA binding activity and MITF phosphorylation were assessed by electrophoretic mobility shift assay (EMSA) and immunoprecipitation, respectively. The administration of PEA (200, 400 and 800 µg/ml) significantly decreased rMCP-5 mRNA and chymase protein expression induced by λ-carrageenan. These effects were associated with a significant decrease of MITF/DNA binding activity and phosphorylated MITF as well as phosphorylated ERK levels. In conclusion, our results, showing the ability of PEA to inhibit MITF activation and chymase expression in granulomatous tissue, may yield new insights into the understanding of the signaling pathways leading to MITF activation controlled by PEA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2013.12.021DOI Listing
February 2014

Enhanced antioxidant effect of trans-resveratrol: potential of binary systems with polyethylene glycol and cyclodextrin.

Drug Dev Ind Pharm 2014 Oct 17;40(10):1300-7. Epub 2013 Jul 17.

Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville , Seville , Spain .

Trans-resveratrol, a polyphenol extracted from Vitis vinifera, has different beneficial effects following its administration on the skin. Here the potential use of binary systems to enhance in vitro and in vivo activity of trans-resveratrol was investigated. Thus the aqueous solubility of trans-resveratrol was investigated in the presence of growing concentrations of polyethylene glycol (PEG) or β-cyclodextrin (βCD) as solubilizing excipients. Then, the solid dispersion of trans-resveratrol with PEG or inclusion complexes trans-resveratrol/βCD were prepared and characterised by different methods. Cytotoxicity and inhibition of reactive oxygen species (ROS) following H2O2 challenge in the presence of trans-resveratrol, alone or associated to the excipients, was evaluated on human keratinocyte HaCaT cell line. Both the trans-resveratrol-containing binary systems induced significant reduction of H2O2-induced ROS production, especially in the case of βCD that was selected for the following phase of the study. Thus, the effect of a cream containing trans-resveratrol, alone or associated to βCD, on different skin parameters such as corneometry, colorimetry and elastometry, was evaluated on human volunteers. All patients showed a visible improvement of clinical conditions with a remarkable decrease of aging signs, but this effect was higher of the hemi face treated with the βCD-containing formulation versus formulation containing trans-resveratrol alone.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/03639045.2013.817416DOI Listing
October 2014

A decoy oligonucleotide to NF-κB delivered through inhalable particles prevents LPS-induced rat airway inflammation.

Am J Respir Cell Mol Biol 2013 Aug;49(2):288-95

Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.

The inflammatory process plays a crucial role in the onset and progression of several lung pathologies, including cystic fibrosis (CF), and the involvement of NF-κB is widely recognized. The specific inhibition of NF-κB by decoy oligonucleotides delivered within the lung may be beneficial, although rationally designed systems are needed to optimize their pharmacological response. Prompted by this need, we have developed and tested in vivo an inhalable dry powder for the prolonged delivery of a decoy oligodeoxynucleotide to NF-κB (dec-ODN), consisting of large porous particles (LPPs) based on poly(lactic-co-glycolic) acid. First, LPPs containing dec-ODN (dec-ODN LPPs) were engineered to meet the aerodynamic criteria crucial for pulmonary delivery, to gain an effective loading of dec-ODN, to sustain its release, and to preserve its structural integrity in lung lining fluids. We then investigated the effects of dec-ODN LPPs in a rat model of lung inflammation induced by the intratracheal aerosolization of LPS from Pseudomonas aeruginosa. The results show that a single intratracheal insufflation of dec-ODN LPPs reduced the bronchoalveolar neutrophil infiltration induced by LPS for up to 72 hours, whereas naked dec-ODN was able to inhibit it only at 6 hours. The persistent inhibition of neutrophil infiltrate was associated with reduced NF-κB/DNA binding activity, as well as reduced IL-6, IL-8, and mucin-2 mRNA expression in lung homogenates. We consider it noteworthy that the developed LPPs, preventing the accumulation of neutrophils and NF-κB-related gene expression, may provide a new therapeutic option for the local treatment of inflammation associated with lung disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2012-0473OCDOI Listing
August 2013

Macrophage autophagy in atherosclerosis.

Mediators Inflamm 2013 21;2013:584715. Epub 2013 Jan 21.

Department of Experimental Pharmacology, University of Naples Federico II, 80131 Naples, Italy.

Macrophages play crucial roles in atherosclerotic immune responses. Recent investigation into macrophage autophagy (AP) in atherosclerosis has demonstrated a novel pathway through which these cells contribute to vascular inflammation. AP is a cellular catabolic process involving the delivery of cytoplasmic contents to the lysosomal machinery for ultimate degradation and recycling. Basal levels of macrophage AP play an essential role in atheroprotection during early atherosclerosis. However, AP becomes dysfunctional in the more advanced stages of the pathology and its deficiency promotes vascular inflammation, oxidative stress, and plaque necrosis. In this paper, we will discuss the role of macrophages and AP in atherosclerosis and the emerging evidence demonstrating the contribution of macrophage AP to vascular pathology. Finally, we will discuss how AP could be targeted for therapeutic utility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2013/584715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563164PMC
August 2013

Nanomaterials toxicity and cell death modalities.

J Drug Deliv 2012 5;2012:167896. Epub 2012 Dec 5.

Dipartimento di Farmacologia Sperimentale, Facoltà di Scienze Biotecnologiche, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80139 Napoli, Italy.

In the last decade, the nanotechnology advancement has developed a plethora of novel and intriguing nanomaterial application in many sectors, including research and medicine. However, many risks have been highlighted in their use, particularly related to their unexpected toxicity in vitro and in vivo experimental models. This paper proposes an overview concerning the cell death modalities induced by the major nanomaterials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2012/167896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523142PMC
January 2013

PEI-engineered respirable particles delivering a decoy oligonucleotide to NF-κB: inhibiting MUC2 expression in LPS-stimulated airway epithelial cells.

PLoS One 2012 3;7(10):e46457. Epub 2012 Oct 3.

Department of Pharmaceutical and Toxicological Chemistry, University of Naples Federico II, Naples, Italy.

A specific and promising approach to limit inflammation and mucin iperproduction in chronic lung diseases relies on specific inhibition of nuclear Factor-κB (NF-κB) by a decoy oligonucleotide (dec-ODN). To fulfill the requirements dictated by translation of dec-ODN therapy in humans, inhalable dry powders were designed on a rational basis to provide drug protection, sustained release and to optimize pharmacological response. To this end, large porous particles (LPP) for dec-ODN delivery made of a sustained release biomaterial (poly(lactic-co-glycolic) acid, PLGA) and an "adjuvant" hydrophilic polymer (polyethylenimine, PEI) were developed and their effects on LPS-stimulated human airway epithelial cells evaluated. The composite PLGA/PEI particles containing dec-ODN (i.e., LPP(PEI)) were successfully engineered for widespread deposition in the lung and prolonged release of intact dec-ODN in vitro. LPP(PEI) caused a prolonged inhibition of IL-8 and MUC2 expression in CF human bronchial epithelial cells and human epithelial pulmonary NCI-H292 cells, respectively, as compared to naked dec-ODN. Nonetheless, as compared to previously developed LPP, the presence of PEI was essential to construct a dec-ODN delivery system able to act in mucoepidermoid lung epithelial cells. In perspective, engineering LPP with PEI may become a key factor for tuning carrier properties, controlling lung inflammation and mucin production which, in turn, can foster in vivo translation of dec-ODN therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0046457PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463602PMC
June 2013

Nanocarriers for topical administration of resveratrol: a comparative study.

Int J Pharm 2013 Jan 14;440(2):179-87. Epub 2012 Aug 14.

Department of Pharmaceutical and Toxicological Chemistry, Faculty of Pharmacy, University of Naples Federico II, via Montesano 49, Naples, Italy.

The trans-resveratrol (t-res), a non-flavonoid polyphenol extracted from different plants, has recently earned interest for application on the skin for different applications. In this work, the potential of nanocarriers, namely transfersomes and ethanol-containing vesicles, to deliver t-res into/through the skin was investigated. Thus, transfersomes with different surfactants, namely polysorbate 80 (Tw80), sodium cholate (SC) and sodium deossicholate (SDC) and ethanol-containing vesicles with different lipid composition, namely soy phosphatidylcholine (SPC) and cholesterol (chol), encapsulating t-res were prepared and characterized. The nanocarriers had a mean diameter ranging between 83 and 116 nm with a high t-res encapsulation efficiency (≥ 70%). Moreover, cytotoxicity as well as the inhibition of production of reactive oxygen species (ROS) and lipid peroxidation, following incubation of H(2)O(2)-stimulated human keratinocyte (HaCaT) with t-res, as free or encapsulated into the nanocarriers, were investigated. Only blank nanocarriers containing Tw80 or ethanol were cytotoxic and led to increase of ROS, but this effect was not observed when using nanocarriers encapsulating t-res. Finally, permeation studies on porcine skin carried out on Franz diffusion cells, showed that only ethanol-containing vesicles based SPC were able to promote t-res permeation through the skin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijpharm.2012.08.009DOI Listing
January 2013

Targeting autophagy as a novel strategy for facilitating the therapeutic action of potentiators on ΔF508 cystic fibrosis transmembrane conductance regulator.

Autophagy 2012 Nov 9;8(11):1657-72. Epub 2012 Aug 9.

European Institute for Research in Cystic Fibrosis, San Raffaele Scientific Institute, Milan, Italy.

Channel activators (potentiators) of cystic fibrosis (CF) transmembrane conductance regulator (CFTR), can be used for the treatment of the small subset of CF patients that carry plasma membrane-resident CFTR mutants. However, approximately 90% of CF patients carry the misfolded ΔF508-CFTR and are poorly responsive to potentiators, because ΔF508-CFTR is intrinsically unstable at the plasma membrane (PM) even if rescued by pharmacological correctors. We have demonstrated that human and mouse CF airways are autophagy deficient due to functional sequestration of BECN1 and that the tissue transglutaminase-2 inhibitor, cystamine, or antioxidants restore BECN1-dependent autophagy and reduce SQSTM1/p62 levels, thus favoring ΔF508-CFTR trafficking to the epithelial surface. Here, we investigated whether these treatments could facilitate the beneficial action of potentiators on ΔF508-CFTR homozygous airways. Cystamine or the superoxide dismutase (SOD)/catalase-mimetic EUK-134 stabilized ΔF508-CFTR at the plasma membrane of airway epithelial cells and sustained the expression of CFTR at the epithelial surface well beyond drug withdrawal, overexpressing BECN1 and depleting SQSTM1. This facilitates the beneficial action of potentiators in controlling inflammation in ex vivo ΔF508-CFTR homozygous human nasal biopsies and in vivo in mouse ΔF508-CFTR lungs. Direct depletion of Sqstm1 by shRNAs in vivo in ΔF508-CFTR mice synergized with potentiators in sustaining surface CFTR expression and suppressing inflammation. Cystamine pre-treatment restored ΔF508-CFTR response to the CFTR potentiators genistein, Vrx-532 or Vrx-770 in freshly isolated brushed nasal epithelial cells from ΔF508-CFTR homozygous patients. These findings delineate a novel therapeutic strategy for the treatment of CF patients with the ΔF508-CFTR mutation in which patients are first treated with cystamine and subsequently pulsed with CFTR potentiators.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/auto.21483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494594PMC
November 2012

Cacospongionolide and scalaradial, two marine sesterterpenoids as potent apoptosis-inducing factors in human carcinoma cell lines.

PLoS One 2012 3;7(4):e33031. Epub 2012 Apr 3.

Dipartimento di Farmacologia Sperimentale, Facoltà di Scienze Biotecnologiche, Università degli Studi di Napoli Federico II, Napoli, Italy.

Apoptosis, a form of programmed cell death, is a critical defence mechanism against the formation and progression of cancer and acts by eliminating potentially deleterious cells without causing such adverse effects, as inflammatory response and ensuing scar formation. Therefore, targeting apoptotic pathways becomes an intriguing strategy for the development of chemotherapeutic agents. In last decades, marine natural products, such as sesterterpenoids, have played an important role in the discovery and development of new drugs. Interestingly, many of these compounds have a strong potential as anticancer drugs by inhibiting cell proliferation and/or inducing cell death. In the present study, we investigated the effects of scalaradial and cacospongionolide, two sesterterpenoids from Cacospongia scalaris and Fasciospongia cavernosa marine sponges, on the apoptotic signalling pathway in three different human tumoral cells. Results were obtained by using DNA fragmentation, comet and viability assays, quantification of the mitochondrial transmembrane potential and Western blot. The T47D (human breast carcinoma), A431 (human epidermoid carcinoma), HeLa (human cervix carcinoma) and HCT116 (human colon carcinoma) cells were incubated for 24 h with scalaradial or cacospongionolide. Treatment of T47D cells with scalaradial or cacospongionolide for 24 h brought about a significant increase in DNA migration as well as fragmentation. Moreover, incubation of HCT116 and HeLa cells with scalaradial or cacospongionolide for 24 h caused an increased expression of pro-apoptotic proteins. Furthermore, scalaradial or cacospongionolide, added to HCT116 and HeLa cells overnight, induced a significant and concentration-dependent loss of mitochondrial transmembrane potential, an early apoptosis signalling event. These effects paralleled with those achieved with p50 and p65, NF-κB subunits, nuclear level. In conclusion, scalaradial and cacospongionolide, by determining human cancer cell apoptosis, may represent new promising compounds to inhibit cancer cell proliferation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0033031PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317917PMC
August 2012

Sustained inhibition of IL-6 and IL-8 expression by decoy ODN to NF-κB delivered through respirable large porous particles in LPS-stimulated cystic fibrosis bronchial cells.

J Gene Med 2011 Apr;13(4):200-8

Department of Experimental Pharmacology, School of Biotechnological Sciences, University of Naples Federico II, Italy.

Background: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Neutrophil-dominated inflammation and chronic bacterial infection are still considered the primary cause of bronchioectasis, respiratory failure and consequent death in CF patients. Activation of nuclear factor (NF)-κB is responsible for overproduction of cytokines, such as interleukin (IL)-6 and IL-8, in airways of CF patients. Thus, decoy oligodeoxynucleotides against NF-κB (dec-ODN) may limit lung inflammation in CF. In the present study, we studied the effects of dec-ODN delivered through biodegradable and respirable poly(D,L-lactide-co-glycolide) large porous particles (LPP) on IL-6 and IL-8 mRNA expression as well as NF-κB/DNA binding activity in cystic fibrosis cells stimulated with lipopolysaccharide (LPS) from Pseudomonas aeruginosa.

Methods: dec-ODN LPP were prepared by a modified double emulsion technique and characterized in terms of size, morphology, tapped density and dec-ODN loading. Human epithelial bronchial IB3-1 (CFTR-mutated) as well as S9 (CFTR-corrected) were stimulated with LPS from P. aeruginosa for 24 and 72 h in the absence or presence of naked dec-ODN or dec-ODN LPP.

Results: Stimulation of cells with LPS from P. aeruginosa caused an increase of IL-6 and IL-8 mRNA levels, which were significantly inhibited by dec-ODN LPP at 24 and 72 h, whereas naked dec-ODN inhibited those only at 24 h. Similar effects were exhibited by dec-ODN LPP or naked dec-ODN on NF-κB/DNA binding activity.

Conclusions: Our observations indicate that respirable biodegradable dec-ODN LPP may represent a promising strategy for inhibiting NF-κB transcriptional activity and related gene expression and, thus, reduce lung chronic inflammation in CF patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgm.1546DOI Listing
April 2011

Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide.

J Cell Mol Med 2011 Dec;15(12):2664-74

Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.

Emerging evidence indicates that astrogliosis is involved in the pathogenesis of neurodegenerative disorders. Our previous findings suggested cannabinoids and Autacoid Local Injury Antagonism Amides (ALIAmides) attenuate glial response in models of neurodegeneration. The present study was aimed at exploring palmitoylethanolamide (PEA) ability to mitigate β-amyloid (Aβ)-induced astrogliosis. Experiments were carried out to investigate PEA's (10(-7) M) effects upon the expression and release of pro-inflammatory molecules in rat primary astrocytes activated by soluble Aβ(1-42) (1 μg/ml) as well as to identify mechanisms responsible for such actions. The effects of Aβ and exogenous PEA on the astrocyte levels of the endocannabinoidsand of endogenous ALIAmides were also studied. The peroxisome proliferator-activated receptor (PPAR)-α (MK886, 3 μM) or PPAR-γ (GW9662, 9 nM) antagonists were co-administered with PEA. Aβ elevated endogenous PEA and d5-2-arachidonoylglycerol (2-AG) levels. Exogenous PEA blunted the Aβ-induced expression of pro-inflammatory molecules. This effect was reduced by PPAR-α antagonist. Moreover, this ALIAmide, like Aβ, increased 2-AG levels. These results indicate that PEA exhibits anti-inflammatory properties able to counteract Aβ-induced astrogliosis, and suggest novel treatment for neuroinflammatory/ neurodegenerative processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1582-4934.2011.01267.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373435PMC
December 2011

The I{kappa}B kinase inhibitor nuclear factor-{kappa}B essential modulator-binding domain peptide for inhibition of injury-induced neointimal formation.

Arterioscler Thromb Vasc Biol 2010 Dec 7;30(12):2458-66. Epub 2010 Oct 7.

Department of Experimental Pharmacology, University of Naples Federico II, Naples, Italy.

Objective: The activation of nuclear factor-κB (NF-κB) is a crucial step in the arterial wall's response to injury. The identification and characterization of the NF-κB essential modulator-binding domain (NBD) peptide, which can block the activation of the IκB kinase complex, have provided an opportunity to selectively abrogate the inflammation-induced activation of NF-κB. The aim of the present study was to evaluate the effect of the NBD peptide on neointimal formation.

Methods And Results: In the rat carotid artery balloon angioplasty model, local treatment with the NBD peptide (300 μg/site) significantly reduced the number of proliferating cells at day 7 (by 40%; P<0.01) and reduced injury-induced neointimal formation (by 50%; P<0.01) at day 14. These effects were associated with a significant reduction of NF-κB activation and monocyte chemotactic protein-1 expression in the carotid arteries of rats treated with the peptide. In addition, the NBD peptide (0.01 to 1 μmol/L) reduced rat smooth muscle cell proliferation, migration, and invasion in vitro. Similar results were observed in apolipoprotein E(-/-) mice in which the NBD peptide (150 μg/site) reduced wire-induced neointimal formation at day 28 (by 47%; P<0.01).

Conclusions: The NBD peptide reduces neointimal formation and smooth muscle cell proliferation/migration, both effects associated with the inhibition of NF-κB activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/ATVBAHA.110.215467DOI Listing
December 2010

NFkappaB decoy oligonucleotides.

Curr Opin Mol Ther 2010 Apr;12(2):203-13

University of Naples Federico II, Department of Experimental Pharmacology, via D Montesano 49, 80131 Naples, Italy.

Molecular therapy is emerging as a potential strategy for the treatment of inflammatory diseases. Decoy oligonucleotides (ONs) against NFkappaB, an inducible transcription factor that plays a critical role in several inflammatory/immune diseases, can specifically block the transcriptional activity of this transcription factor. The therapeutic potential of such decoy ONs has been investigated in several chronic inflammatory-based diseases. However, the clinical use of decoy ONs is strongly hampered by several issues, including low bioavailability, a short half-life and limited intracellular uptake. Both chemical modifications to ONs and the use of delivery systems have been investigated in order to overcome these limitations. This review summarizes the most meaningful studies on the preclinical and clinical application of decoy ONs against NFkappaB in different diseases, and highlights successful strategies that have overcome the pharmacokinetic issues associated with ONs.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2010

Oligonucleotide decoy to NF-kappaB slowly released from PLGA microspheres reduces chronic inflammation in rat.

Pharmacol Res 2009 Jul 25;60(1):33-40. Epub 2009 Mar 25.

Dipartimento di Farmacologia Sperimentale, Università degli Studi di Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy.

Nuclear factor-kappaB (NF-kappaB) plays a key role in the expression of several genes involved in the immune and inflammatory process. Previously, we demonstrated that NF-kappaB activation can be significantly inhibited by a double stranded oligodeoxynucleotide (ODN). Nevertheless, the therapeutic use of ODN requires a delivery system able to improve poor crossing of cell membranes and rapid in vivo enzymatic degradation. Poly(D,L-lactide-co-glycolide) (PLGA) microspheres can increase ODN stability in biological environment and release the encapsulated drug in long time frames. Here, we used a decoy ODN against NF-kappaB and we investigated its effect, when administered in naked form or when delivered by PLGA microspheres, in a rat model of chronic inflammation. The subcutaneous implant of lambda-carrageenin-soaked sponges caused leukocyte infiltration and formation of granulation tissue which were inhibited up to 15 days by co-injection of microspheres releasing decoy ODN whereas naked decoy ODN showed this effect only up to 5 days. Molecular analysis performed on granulation tissue demonstrated an inhibition of NF-kappaB activation correlated to a decrease of tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression. Our results suggest that microspheres could be an useful tool to improve pharmacokinetics of decoy ODN and may represent a strategy to inhibit NF-kappaB activation in chronic inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.phrs.2009.03.012DOI Listing
July 2009

Stimulation of autophagy by the p53 target gene Sestrin2.

Cell Cycle 2009 May 20;8(10):1571-6. Epub 2009 May 20.

INSERM, U848, Villejuif, France.

The oncosuppressor protein p53 regulates autophagy in a dual fashion. The pool of cytoplasmic p53 protein represses autophagy in a transcription-independent fashion, while the pool of nuclear p53 stimulates autophagy through the transactivation of specific genes. Here we report the discovery that Sestrin2, a novel p53 target gene, is involved in the induction of autophagy. Depletion of Sestrin2 by RNA interference reduced the level of autophagy in a panel of p53-sufficient human cancer cell lines responding to distinct autophagy inducers. In quantitative terms, Sestrin2 depletion was as efficient in preventing autophagy induction as was the depletion of Dram, another p53 target gene. Knockout of either Sestrin2 or Dram reduced autophagy elicited by nutrient depletion, rapamycin, lithium or thapsigargin. Moreover, autophagy induction by nutrient depletion or pharmacological stimuli led to an increase in Sestrin2 expression levels in p53-proficient cells. In strict contrast, the depletion of Sestrin2 or Dram failed to affect autophagy in p53-deficient cells and did not modulate the inhibition of baseline autophagy by a cytoplasmic p53 mutant that was reintroduced into p53-deficient cells. We conclude that Sestrin2 acts as a positive regulator of autophagy in p53-proficient cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/cc.8.10.8498DOI Listing
May 2009

Rosiglitazone reduces the inflammatory response in a model of vascular injury in rats.

Shock 2009 Dec;32(6):638-44

Department of Experimental Medicine, Excellence Centre for Cardiovascular Diseases, Second University of Naples, Naples, Italy.

Thiazolidinediones are ligands that bind to and activate the nuclear peroxisome proliferator-activated receptor gamma. They are widely used as insulin sensitizers for the treatment of type 2 diabetes. Several studies have implicated the peroxisome proliferator-activated receptor gamma agonists rosiglitazone and pioglitazone in inflammatory events. To assess the anti-inflammatory properties of rosiglitazone, we investigated its effects on the molecular and cellular inflammatory response induced by a carotid injury in the rat. Male Wistar rats were randomized into a rosiglitazone-treated group (10 mg kg(-1) day(-1)) and a control group (0.9% w/v NaCl). The drug or vehicle was administered by gavage for 7 days before carotid injury and for up to 21 days after injury. The inflammatory markers p38 mitogen-activated protein kinase, cyclooxygenase 2, nuclear factor-kappaB, and heat shock protein 47 and the influx and activity of cells in response to injury were measured. Rosiglitazone treatment significantly reduced the expression of the inflammatory markers compared with control group. p38 mitogen-activated protein kinase and nuclear factor-kappaB started to decrease a few hours after injury, whereas cyclooxygenase 2 and heat shock protein 47 expression decreased 7 and 14 days, respectively, after injury. Rosiglitazone also reduced neointima formation and inflammatory cell infiltration. In conclusion, rosiglitazone negatively regulated the inflammatory events involved in tissue repair at molecular and cellular levels. These results suggest that rosiglitazone plays a protective role in inflammatory vascular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SHK.0b013e3181a5a377DOI Listing
December 2009

NF-kappaB blockade upregulates Bax, TSP-1, and TSP-2 expression in rat granulation tissue.

J Mol Med (Berl) 2009 May 3;87(5):481-92. Epub 2009 Feb 3.

Dipartimento di Farmacologia Sperimentale, Facoltà di Scienze Biotecnologiche, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, 80131, Naples, Italy.

Several diseases are characterized by chronic inflammation, a condition frequently associated with angiogenesis and fibrogenesis that account for the development of granulation tissue. Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) is a crucial modulator of intracellular prosurvival signaling pathways and is implicated in the pathogenesis of inflammatory process. In this study, we have investigated the role of NF-kappaB in the angiogenic and fibrogenic response induced by lambda-carrageenin in a rat model of chronic inflammation at 1, 3, and 5 days. The subcutaneous implant of lambda-carrageenin-soaked sponges in rat induced a time-related increase of granulation tissue formation accompanied by intense neovascularization. These lambda-carrageenin-induced changes were significantly reduced by coinjection of wild-type oligodeoxynucleotide (WT ODN) decoy to NF-kappaB. Molecular, morphological, and ultrastructural analysis performed on whole granulation tissue demonstrated: (1) inhibition of NF-kappaB/DNA binding activity; (2) downregulation of cyclooxygenase-2, matrix metalloproteinase-9, tumor necrosis factor-alpha, and vascular endothelial growth factor; (3) upregulation of thrombospondin (TSP)-1 at 1 day and TSP-2 at 5 days; and (4) increase in Bax to Bcl-2 ratio. Our findings show that the blockade of NF-kappaB activation by WT ODN decoy prevents the development of granulation tissue induced by lambda-carrageenin-soaked sponge implant upregulating Bax as well as TSP-1 and TSP-2 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00109-009-0443-6DOI Listing
May 2009

Novel cationic liposome formulation for the delivery of an oligonucleotide decoy to NF-kappaB into activated macrophages.

Eur J Pharm Biopharm 2008 Sep 29;70(1):7-18. Epub 2008 Mar 29.

Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Naples, Italy.

Nuclear factor-kappaB (NF-kappaB) is involved in several pathological processes, such as inflammation. Pro-inflammatory genes expression can be down-regulated by using an oligonucleotide (ODN) decoy to NF-kappaB. Cationic liposomes are largely used to improve ODN uptake into cells, although a higher transfection efficiency and a lower toxicity are required to use them in therapy. In this work, we investigated the potential of a novel liposome formulation, based on the recently synthesised cationic lipid (2,3-didodecyloxypropyl) (2-hydroxyethyl) dimethylammonium bromide (DE), as the delivery system for a double stranded ODN decoy to NF-kappaB. Liposomes composed of DE or DE mixed with 1,2-dioleyl-sn-glycero-3-phosphoethanolamine or cholesterol as helper lipids were complexed with ODN at different +/- charge ratios. In vitro uptake and the effect of ODN, naked or complexed with DE-containing liposomes, were evaluated in lipopolysaccharide-stimulated RAW 264.7 macrophages. The use of helper lipids increased liposome physical stability up to 1 year at 4 degrees C. ODN complexed with DE/cholesterol liposomes, at the +/- charge ratio of 8, showed a limited cytotoxicity and the highest inhibition of nitrite production, inducible nitric oxide synthase protein expression and NF-kappaB/DNA binding activity. Confocal microscopy confirmed a high ODN cell uptake obtained with DE/cholesterol liposomes at the highest +/- charge ratio.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpb.2008.03.012DOI Listing
September 2008

Regulation of autophagy by cytoplasmic p53.

Nat Cell Biol 2008 Jun 4;10(6):676-87. Epub 2008 May 4.

INSERM, U848, France.

Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncb1730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676564PMC
June 2008

A Polysaccharide from tomato (Lycopersicon esculentum) peels affects NF-kappaB activation in LPS-stimulated J774 macrophages.

J Nat Prod 2007 Oct 1;70(10):1636-9. Epub 2007 Sep 1.

Dipartimento di Farmacologia Sperimentale, Facoltà di Scienze Biotecnologiche, Università degli Studi di Napoli Federico II, Via D. Montesano, 49, 80131 Napoli, Italy.

We investigated the effect of PS ( 1) on nitrite and reactive oxygen species (ROS) production in J774 macrophages stimulated with bacterial lipopolysaccharide (LPS) for 24 h. PS ( 1) inhibited in a concentration-dependent manner nitrite and ROS production as well as inducible nitric oxide synthase (iNOS) protein expression induced by LPS. Incubation of cells with PS ( 1) determined a significant decrease of nuclear factor-kappaB (NF-kappaB)/DNA binding activity which was correlated with a marked reduction of iNOS mRNA levels. These results show that PS ( 1) inhibits NF-kappaB activation and iNOS gene expression by preventing the reactive species production and suggest a role for this compound in controlling oxidative stress and/or inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/np070168zDOI Listing
October 2007

Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-gamma.

Eur J Pharmacol 2007 Jul 6;566(1-3):192-9. Epub 2007 Apr 6.

Dipartimento di Farmacologia Sperimentale, Via D. Montesano, 49, Università degli Studi di Napoli Federico II, 80131 Naples, Italy.

Oxidative stress plays an important role in inflammatory process of celiac disease. We have studied the effect of the lycopene, quercetin and tyrosol natural antioxidants on the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) gene expression in RAW 264.7 macrophages stimulated by gliadin in association with IFN-gamma. The IFN-gamma plus gliadin combination treatment was capable of enhancing iNOS and COX-2 gene expression and nuclear factor-kappaB (NF-kappaB), interferon regulatory factor-1 (IRF-1) and signal transducer and activator of transcription-1alpha (STAT-1alpha) activation induced by reactive oxygen species generation at 24 h. Lycopene, quercetin and tyrosol inhibited all these effects. The results here reported suggest that these compounds may represent non toxic agents for the control of pro-inflammatory genes involved in celiac disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2007.03.051DOI Listing
July 2007

Local administration of WIN 55,212-2 reduces chronic granuloma-associated angiogenesis in rat by inhibiting NF-kappaB activation.

J Mol Med (Berl) 2007 Jun 20;85(6):635-45. Epub 2007 Apr 20.

Dipartimento di Farmacologia Sperimentale, Università degli Studi di Napoli Federico II, Via D. Montesano 49, Napoli, 80131, Italy.

Chronic inflammation is often associated with granuloma formation that is a hallmark of many human diseases. The transcription factor nuclear factor-kappa B (NF-kappaB) plays a central role in this process by regulating the expression of several pro-inflammatory genes. Cannabinoids (CBs) from Cannabis sativa L. exert a large number of biological effects including anti-inflammatory and anti-angiogenic effects. In this study, we investigated the role of CBs on granuloma formation induced by lambda-carrageenin-soaked sponge implant in rat. Our results show that local administration of WIN 55,212-2, a CB(1)/CB(2) agonist, given daily or at time of implantation significantly decreased weight and neo-angiogenesis in granuloma tissue and inhibited nuclear factor-kappa B (NF-kappaB)/DNA binding that was associated with a reduced inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), and vascular endothelial growth factor (VEGF) messenger RNA (mRNA) and protein expression. Also, arachidonyl-2-chloroethylamide (ACEA), a CB(1) selective agonist, and JWH-015, a CB(2) selective agonist, exhibited the same effects that were reversed by SR141716-A and SR144528, respectively, CB(1) and CB(2) selective antagonists. These results indicate that CBs given locally may represent a potential therapeutic tool in controlling chronic inflammation avoiding psychotropic effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00109-007-0188-zDOI Listing
June 2007