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Introduction Sentinel Lymph Node Biopsy (SLNB) is regarded as the standard procedure for nodal staging in patients with early breast cancer. In the last decade several randomized trials have been evaluating its role and indications. Materials and methods This article reviews recent and ongoing randomized trials on SLNB. Results Four randomized controlled trials have recently shown evidence that SLNB either alone or followed by radiation therapy is effective for the management in patients with low axillary tumor burden in early breast cancer. Nine randomized controlled trials on SLNB are ongoing: four assessing its role in case of positive sentinel node, three evaluating whether SLNB itself can be omitted when the preoperative nodal imaging is negative, two are studying SLNB in the neoadjuvant setting. Discussion and conclusion SLNB either alone or with axillary radiotherapy has been shown to be non-inferior to complete axillary dissection in terms of local recurrence, disease-free survival and overall survival in early breast cancer with minimally metastatic axilla. So far, results from ongoing trials are going to confirm the appropriate treatment in patients with limited axillary nodal involvement, the role and the timing of SLNB within the neoadjuvant setting and to define whether surgery can be avoided in the axilla in early stage breast cancer patients with negative preoperative imaging. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a highly debilitating pathology that has irreversible impacts and results in functional loss. We evaluated the anti-inflammatory and immunologic role of antibody-mediated depletion of B cells through the glycoengineered anti-muCD20 antibody (18B12) in an experimental model of spinal cord compression, in vivo and ex vivo. Intraperitoneal 18B12 was administered at a dose of 30 mg/kg, 1 h and 6 h after SCI, and mice were sacrificed 24 h after trauma. We demonstrated, in vivo, that 18B12 slowed severe hindlimb motor dysfunction (Basso Mouse Scale score) and neuronal death by histological evaluation in SCI mice, as well as decreased expression of nuclear factor-kB, inducible nitric oxide synthase, cytokines, and glial fibrillary acidic protein. Also, 18B12 reduced expression of microglia, just as it lowered the expression of B and T lymphocytes. Moreover, in spinal cord organotypic cultures, pretreatment with 18B12 significantly reduced nitric oxide expression and protected cells from cell death [3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay]. In this study, we showed that 18B12 treatment reduces the development of inflammation and tissue injury by alteration of the immune system associated with SCI. This study increases the current knowledge that B-cell depletion is able to exert immunomodulating actions in damaged spinal cords. [ABSTRACT FROM AUTHOR]

Summary Background & aims The beneficial properties of the flavonoid fraction of bergamot juice (BJe) have been raising interest and have been the subject of recent studies, considering the potentiality of its health promoting substances. Flavonoids have demonstrated radical-scavenging and anti-inflammatory activities. The aim of the present study was to examine the effects of BJe in mice subjected to experimental colitis. Methods Colitis was induced in mice by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). BJe was administered daily orally (at 5, 10 and 20 mg/kg). Results Four days after DNBS administration, colon nuclear factor NF-κB translocation and MAP kinase phospho-JNK activation were increased as well as cytokine production such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Neutrophil infiltration, by myeloperoxidase (MPO) activity, in the mucosa was associated with up-regulation of adhesion molecules (ICAM-1 and P-selectin). Immunohistochemistry for nitrotyrosine and poly ADP-ribose (PAR) also showed an intense staining in the inflamed colon. Treatment with BJe decreased the appearance of diarrhea and body weight loss. This was associated with a reduction in colonic MPO activity. BJe reduced nuclear NF-κB translocation, p-JNK activation, the pro-inflammatory cytokines release, the appearance of nitrotyrosine and PAR in the colon and reduced the up-regulation of ICAM-1 and P-selectin. In addition, colon inflammation was also associated with apoptotic damage. Treatment with BJe caused a decrease of pro-apoptotic Bax expression and an increase of anti-apoptotic Bcl-2 expression. Conclusions The results of this study suggested that administration of BJe induced, partly specified, anti-inflammatory mechanisms, which potentially may be beneficial for the treatment of IBD in humans. [ABSTRACT FROM AUTHOR]

Defects in cellular functions related to altered protein homeostasis and associated progressive accumulation of pathological intracellular material is a critical process involved in the pathogenesis of many neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Autophagy is an essential mechanism that ensures neuronal health by removing long-lived proteins or defective organelles and by doing so prevents cell toxicity and death within the central nervous system. Abundant evidence has shown that neuronal autophagy pathways are altered in Alzheimer's disease, Parkinson's disease and traumas of the central nervous system including Spinal Cord Injury and Traumatic Brain Injury. In this review, we aimed to summarize the latest studies on the role that altered neuronal autophagy plays in brain health and these pathological conditions, and how this knowledge can be leveraged for the development of novel therapeutics against them. [ABSTRACT FROM AUTHOR]

Background: Peroxisome proliferator-activated receptors (PPARs) are ligand activated transcription factors belonging to the nuclear receptor superfamily. PPARs activation has a profound impact on the local immune response with consequences affecting the progression of chronic inflammatory diseases. Relatively little is known on the role of PPAR-β/δ in the regulation of inflammatory responses. The aim of the present study was to evaluate the influence of PPAR-β/δ receptor in a model of edematous pancreatitis induced in mice by administration of cerulein at supramaximal doses, as well as in necrohemorrhagic model induced by intraductal administration of sodium taurocholate (STC). Measurements: Mice were treated with cerulein (50 μg/kg) or STC (5%). GW0742 (0.3 mg/kg) was intraperitoneally administered 1 and 6 hours after cerulein injection or was injected 2 hours before STC infusion. The pancreas and exopancreatic organs were carefully removed for microscopic examination. Pancreatic weight, serum amylase, lipase, tumor necrosis factor-α and interleukin-1β levels, as well as cytokines, adhesion molecules, nitrotyrosine, poly (ADP-ribose), inducible nitric oxide, FAS ligand, Bax, Bcl-2 expression by immunohistochemistry, and myeloperoxidase activity of the pancreas were assayed. Moreover, the involvement of nuclear factor-κB pathway was investigated by Western blot analysis. Results: Intraperitoneal injection of cerulein in mice resulted in severe, acute pancreatitis characterized by edema, neutrophil infiltration and apoptosis, and elevated serum levels of amylase and lipase. Taurocholate challenge caused a clear increase in serum amylase, neutrophil infiltration, and tissue damage in the pancreas. Tissue and inflammatory changes in the pancreata were significantly less in GW0742 group than in cerulein or STC groups. In addition, the pancreatic water content was reduced in mice treated with PPAR-β/δ agonist. In the mild pancreatitis, GW0742 was also able to decrease the expression of proinflammatory cytokines and enzymes, as well as of proteins involved in apoptosis and nuclear factor-Kappa B pathway. Conclusion: GW0742 attenuated pancreatic damage in 2 different experimental models of pancreatitis in mice. [Copyright &y& Elsevier]

Abstract: Several olive oil phenolic compounds, such us oleuropein have attracted considerable attention because of their antioxidant activity, anti-atherosclerotic and anti-inflammatory properties. The aim of this experimental study was to determine the effect of oleuropein aglycone, a hydrolysis product of oleuropein, in the inflammatory response, in particular in the secondary injury associated with the mouse model of spinal cord trauma. The injury was induced by application of vascular clips to the dura via a four-level T5–T8 laminectomy in mice. Oleuropein aglycone was administered in mice (100μg/kg, 40μg/kg, 20μg/kg, 10% ethanol, i.p.) 1h and 6h after the trauma. The treatment with oleuropein aglycone significantly decreased: (1) histological damage, (2) motor recovery, (3) nuclear factor (NF)-κB expression and IKB-α degradation, (4) protein kinase A (PKA) activity and expression, (5) pro-inflammatory cytokines production such as tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β), 6) inducible nitric oxide synthase (iNOS) expression, (7) neutrophil infiltration, (8) lipid peroxidation, (9) nitrotyrosine and poly-ADP-ribose (PAR) formation, (10) glial cell-derived neurotrophic factor (GDNF) levels, (11) apoptosis (TUNEL staining, FAS ligand expression, Caspase 3, Bax and Bcl-2 expression). Thus, we propose that olive oil phenolic constituents such as oleuropein aglycone may be useful in the treatment of various inflammatory diseases. [Copyright &y& Elsevier]

Spinal cord injury (SCI) is a traumatic event that causes a secondary and extended inflammation characterized by infiltration of immune cells, including T lymphocytes, release of pro-inflammatory mediators in the lesion site, and tissue degeneration. Current therapeutic approaches for SCI are limited to glucocorticoids (GC) due to their potent anti-inflammatory activity. GC efficacy resides, in part, in the capability to inhibit NF-κB, T lymphocyte activation, and the consequent cytokine production. In this study, we performed experiments aimed to test the susceptibility of glucocorticoid-induced leucine zipper (GILZ) transgenic (GILZ) mice, in which GILZ is selectively over-expressed in T lymphocytes, to SCI induction. Consistent with a decreased inflammatory response, GILZ were less susceptible to SCI as compared to wild-type littermates. Notably, inhibition of NF-κB activation and nuclear translocation, diminished T lymphocytes activation and tissue infiltration, as well as decreased release of cytokines were evident in GILZ as compared to wild-type mice. Moreover, GILZ showed a reduced tumor necrosis factor-α, IL-1β, Inductible nitric oxide synthase (iNOS) and nytrotyrosine production, apoptosis, and neuronal tissue damage. Together these results indicate that GILZ mimics the anti-inflammatory effect of GC and represents a potential pharmacological target for modulation of T lymphocyte-mediated immune response in inflammatory disorders, such as SCI. [ABSTRACT FROM AUTHOR]

Summary: Background & aims: Several olive oil phenolic compounds, such us oleuropein have attracted considerable attention because of their antioxidant activity, anti-atherosclerotic and anti-inflammatory properties. The aim of this study was to investigate the effects of oleuropein aglycone, a hydrolysis product of oleuropein, in a mouse model of carrageenan-induced pleurisy. Methods: Mice were anaesthetized and subjected to a skin incision at the level of the left sixth intercostals space. The underlying muscle was dissected and saline or saline containing 2% λ-carrageenan was injected into the pleural cavity. Results: Injection of carrageenan elicited an acute inflammatory response characterized by: infiltration of neutrophils in lung tissues (P < 0.01 versus sham. P < 0.01 versus carrageenan) and subsequent lipid peroxidation (P < 0.01 versus sham. P < 0.01 versus carrageenan), increased production of tumor necrosis factor-α and interleukin-1β (P < 0.01 versus sham. P < 0.01 versus carrageenan), increased expression of adhesion molecules, increased synthesis of nitric oxide (P < 0.01 versus sham. P < 0.01 versus carrageenan), nitrotyrosine and poly-ADP-ribose (P < 0.01 versus sham. P < 0.01 versus carrageenan). Administration of oleuropein aglycone 30 min after the challenge with carrageenan, caused a significant reduction of all the parameters of inflammation measured. Conclusions: Thus, we propose that olive oil phenolic constituents may be useful in the treatment of various inflammatory diseases. [Copyright &y& Elsevier]

Abstract: NADPH-oxidase is an enzyme responsible for reactive oxygen species production (ROS) and inhibition of this enzyme represents an attractive therapeutic target for the treatment of many diseases. The aim of this study was to investigate the effects of apocynin, a NADPH-oxidase inhibitor, in a mouse model of carrageenan-induced pleurisy. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterized by: infiltration of neutrophils in lung tissues and subsequent lipid peroxidation, increased production of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and increased expression of intercellular adhesion molecule (ICAM-1) and platelet-adhesion molecule (P-selectin). Furthermore, carrageenan induced the expression of nuclear factor-κB (NF-κB) inducible nitric oxide synthase (iNOS), nitrotyrosine, poly-ADP-ribosyl polymerase (PARP) as well as induced apoptosis (TUNEL staining, FAS-ligand expression, Bax and Bcl-2 expression) and mitogen-activated protein kinase (MAPK) activation in the lung tissues. Administration of apocynin, 30min after the challenge with carrageenan, caused a significant reduction of all the parameters of inflammation measured. Thus, based on these findings we propose that NADPH oxidase inhibitor such as apocynin may be useful in the treatment of various inflammatory diseases. [Copyright &y& Elsevier]

Spinal cord injury (SCI) has a significant impact on the quality and expectancy of life. It also carries a heavy economic burden, with considerable costs associated with primary care and loss of income. The normal architecture of the spinal cord is radically disrupted by injury. After the initial insult, structure and function are lost through active secondary processes that involve reactive astrocytes, glial progenitors, microglia, macrophages, fibroblasts and Schwann cells. These cells produce chemokines and cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, which mediate the recruitment of inflammatory cells to the injury site. Targeting of these cytokines represents a potential strategy to reduce the secondary damage in SCI. In this review, we focus on several emerging strategies to neutralize TNF-α, including antibodies, soluble receptors, recombinant TNF-binding proteins, TNF receptor fusion proteins, and non-specific agents (e.g. thalidomide) and discuss their potential as therapy for SCI. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to examine the effects of phenylpropanoid glycoside, teupolioside, biotechnologically produced by IRBN22 Ajuga reptans cell line, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Teupolioside was administered daily orally (0.2 or 2mgkg−1). On Day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis. Four days after DNBS administration, colon TNF-α and IL-1β productions were increased, associated with colon damage. Neutrophil infiltration, by myeloperoxidase activity, in the mucosa was associated with up-regulation of ICAM-1 and P-selectin and high levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) polymerase (PARP) showed an intense staining in the inflamed colon. Biochemical methods and zymography were used to analyze MMP-9 and -2 activities in colon tissues from DNBS-injured rats. Treatment with teupolioside significantly reduced the appearance of diarrhoea and the loss of body weight. This was associated with a remarkable amelioration in the disruption of the colonic architecture and a significant reduction in colonic myeloperoxidase activity and malondialdehyde levels. Teupolioside also reduced the pro-inflammatory cytokines release, the appearance of nitrotyrosine and PARP immunoreactivity in the colon and reduced the up-regulation of ICAM-1 and the expression of P-selectin. Therefore, teupolioside also reduced proMMP-9 and -2 activity induced in the colon by DNBS administration. The results of this study suggested that administration of teupolioside may be beneficial for treatment of inflammatory bowel disease. [Copyright &y& Elsevier]

Background & Aims: Inflammatory bowel diseases are relatively common diseases of the gastrointestinal tract. The relative therapeutic efficacy of glucocorticoids used in inflammatory bowel diseases resides in part in their capability to inhibit activity of nuclear factor κB (NF-κB), a transcription factor central to the inflammatory process, and the consequent production of T-helper 1 (Th1)-type cytokines. Previous studies indicate that increased expression in transgenic mice of glucocorticoid-induced leucine zipper (GILZ), a gene rapidly induced by glucocorticoids, inhibits NF-κB and Th1 activity. Methods: We performed experiments with the aim to test the susceptibility of GILZ transgenic (GILZ-TG) mice to dinitrobenzene sulfonic acid–induced colitis. Results: Consistent with a decreased Th1 response, GILZ-TG mice were less susceptible to colitis induction as compared with wild-type littermates, while they were more susceptible to Th2-mediated colitis. The inhibition was comparable to that obtained with dexamethasone treatment. Moreover, diminished intestinal tissue damage, associated with inhibition of NF-κB nuclear translocation, interferon-γ, tumor necrosis factor-α, and interleukin-1 production in CD4+ T lymphocytes of the lamina propria, was evident in GILZ-TG as compared with wild-type mice. In addition, inhibition of colitis development was also evident when GILZ fusion protein was delivered in vivo in dinitrobenzene sulfonic acid–treated WT animals as well as in interleukin-10 knockout mice. Conclusions: Together these results demonstrate that GILZ mimics the effects of glucocorticoids, suggesting a contribution of this protein to the anti-inflammatory activity of glucocorticoids in Th1-induced colitis. [Copyright &y& Elsevier]

Abstract: Astrocytes in the CNS produce inflammatory mediators in response to several stimuli and cytokines. Here we investigated the in vitro effect of leptin on inducible nitric oxide synthase (iNOS) expression in a glioma cell line (C6). After hormone stimulation, culture media were analysed for accumulated stable oxidation products of NO (NO2 − and NO3 −, designated as NO x ), cellular RNA was extracted to determine iNOS mRNA level by RT-PCR and cellular lysates were prepared for protein expression. Leptin induced a concentration-dependent increase of NO release, related to iNOS induction. This effect was potentiated by IFN-γ, or TNF-α, or IFN-γ plus IL-1β. Pyrrolidine dithiocarbammate (PDTC) and N-α-tosyl-l-lysine chloromethyl ketone (TLCK), two inhibitors of NF-κB activation, as well as the specific proteasome inhibitor MG132, blocked leptin-induced iNOS. The role of NF-κB was also confirmed by time course studies on degradation of IκB-α, which began to degrade 5min after treatment with leptin and returned to basal level after 30–60min. Pre-incubation of cells with MG132 inhibited leptin-induced IκB-α degradation. These results confirm the pro-inflammatory role of leptin and identify it as a potential up-regulator of cytokine-induced inflammatory response in the CNS. [Copyright &y& Elsevier]

[Display omitted] In this work, we describe the development of targeted polymeric nanoparticles loaded with lenvatinib for the treatment of hepatocellular carcinoma (HCC). A synthetic brush copolymer (PHEA-g-BIB-pButMA-g-PEG-biotin) was synthesized from α-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA) by a three-step reaction involving atom transfer radical polymerisation (ATRP) to graft hydrophobic polybutylmethacrylate pendant groups and further conjugation with biotinylated polyethylene glycol via carbonate ester. Subsequently, lenvatinib-loaded nanoparticles were obtained and characterized demonstrating colloidal size, negative zeta potential, biotin exposure on the surface and the ability to release lenvatinib in a sustained manner. Lenvatinib-loaded nanoparticles were tested in vitro on HCC cells to evaluate their anticancer efficacy compared to free drug. Furthermore, the enhanced in vivo efficacy of lenvatinib-loaded nanoparticles on nude mice HCC xenograft models was demonstrated by evaluating tumor burdens, apoptotic markers and histological scores after administration of lenvatinib-nanoparticles via intraperitoneal or oral route. Finally, in vivo biodistribution studies were performed, demonstrating the ability of the prepared drug delivery systems to significantly accumulate in the solid tumor by active targeting, due to the presence of biotin on the nanoparticle surface. [ABSTRACT FROM AUTHOR]

Migraine is one of the most common neurological illnesses, and it is characterized by complicated neurobiology. It was confirmed the influence of inflammation and oxidative stress in migraines and also in distal organs such as the intestine. Indeed, the constant bidirectional communication between the Central Nervous System (CNS) and the gastrointestinal (GI) tract, known as the gut-brain axis, has become an attractive target involved in different human disorders. Herein, we explored the role of NADPH oxidase 2 (NOX2) in nitroglycerin (NTG)-induced migraine in mice models to discover the mechanism by which, during migraine attack, oxidative stress is sustained within trigeminal neurons and GI. Considering the inverse relationship between NOX2 and Nrf2, Nrf2 upregulation seems to be a promising approach to decrease NOX2 expression and consequently limit oxidative stress and inflammation spread in neurological and non-neurological diseases. With this aim, we exploited tempol's Nrf2-inducer ability to better understand the involvement of Nrf2/NOX2 axis in migraine and associated GI comorbidities. Behavioral tests confirmed that tempol, in a dose-dependent manner, moderated clinical signs of migraine and abdominal pain. Moreover, we demonstrated that the decrease in migraine-related symptomatology was strongly linked to the modulation of Nrf2/NOX2 signaling pathway in the brain and colon. In the brain, the rebalancing of Nrf2/NOX2 prevented neuronal loss, decreased glia reactivity while inhibiting NF-κB and NLRP3 inflammasome activation. In the colon, Nrf2 upregulation and consequent NOX2 decrease reduced the histological damage, mast cells infiltration as well as tumor necrosis factor (TNF)-α and interleukin (IL)-1β release. Furthermore, the attenuation of inflammation and oxidative stress led to the restoration of the intestinal barrier through TJs replacement. Taken as a whole, data suggested that the regulation of Nrf2/NOX2 balance is a successful way to reduce neurological and related intestinal impairments during migraine and could be of relevance for migraine-like attacks in humans. [Display omitted] • This study demonstrated the pathogenic function of NOX2, establishing that this NADPH oxidase is responsible for the increase in oxidative stress and inflammation through the gut-brain axis during the initial stages of a migraine episode. • NOX2/Nrf2 balance is a valuable target for treatment strategy aimed at improving Central Nervous System (CNS) and gastrointestinal (GI) state of health. • Nrf2 inducer compounds like tempol, resulted successfully, leading to consistent beneficial outcomes and notably decreasing migraine features. [ABSTRACT FROM AUTHOR]

[Display omitted] Neurodegenerative diseases such as Alzheimer's are very common today. Idebenone (IDE) is a potent antioxidant with good potential for restoring cerebral efficiency in cases of these and other medical conditions, but a serious drawback for the clinical use of IDE in neurological disorders lies in its scarce water solubility, which greatly inhibits its bioavailability. In this work, we prepared the inclusion complex of IDE with randomly methylated β-cyclodextrin (RAMEB), resulting in improved water solubility of the included drug; then its in vitro biological activity and ex vivo permeability was evalutated. The solid complex was characterized through FT-IR spectroscopy, Thermogravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC). A 78-fold improvement of the solubility of IDE in water resulted, together with a strong 1:1 host–guest interaction (association constant of 12630 M−1), and dissolution of the complex within 15 min, all evidenced during the in-solution studies. Biological in vitro studies were then performed on differentiated human neuroblastoma cells (SH-SY5Y) subjected to oxidative stress. Pretreatment with IDE/RAMEB positively affected cell viability, promoted the nuclear translocation of Nrf2, and increased the levels of GSH as well as those of the endogenous antioxidant enzymes Mn-SOD and HO-1. Lastly, the complexation significantly improved the permeation of IDE through isolated rat nasal mucosa. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) leads to severe and lasting impairments in motor and sensory functions. The intense inflammatory response following SCI is a significant challenge, and autophagy has emerged as a key factor in the recovery process. The C-C chemokine receptor type 1 (CCR1), a G-protein coupled receptor, plays a crucial role in managing the chemokine response under stress. BX471, a selective and potent CCR1 antagonist, has been explored in various disease contexts for its therapeutic potential. In this study, we assessed the effects of BX471 in a mouse model of SCI. The treatment was administered at doses of 3 and 10 mg/kg, 1 h and 6 h after the injury occurred. Results showed that BX471 significantly improved tissue structure by positively influencing autophagy and reducing inflammation. Inflammatory markers, including CCR1 ligands RANTES, MIP-1α, TNF-α, and IL-1β, were measured using Western blot analysis. Additionally, histological evaluations revealed that BX471 effectively decreased infiltration and reduced astrocyte and microglial activation, supporting the idea that enhancing autophagy through CCR1 inhibition could promote neuronal survival. The highest efficacy was observed at the 10 mg/kg dose, leading to optimal out-comes across the assessments. These findings suggest that CCR1 blockade with BX471 may offer a promising therapeutic strategy for SCI, addressing a critical gap in the current pharmacological treatment options. [Display omitted] • BX471, a CCR1 antagonist, enhances recovery in spinal cord injury (SCI) by promoting autophagy and reducing inflammation. • BX471 treatment at 10 mg/kg optimally reduced microglial activation, improving tissue structure and neuronal survival. • CCR1 inhibition emerges as a promising therapeutic strategy for SCI, addressing inflammation and autophagy dysregulation. [ABSTRACT FROM AUTHOR]

Abstract: Adenosine A2A receptor agonists may be important regulators of inflammation. The aim of this study was to investigate the effects of CGS 21680 (0.1mg/kgi.p.), an agonist of the adenosine (A2A) receptor, in a mouse model of carrageenan-induced pleurisy. Injection of carrageenan into the pleural cavity of mice elicited an acute inflammatory response characterised by: infiltration of neutrophils in lung tissues and subsequent lipid peroxidation, increased production of nitric oxide (NO), cytokines such as tumour necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and increased expression of intercellular adhesion molecule (ICAM-1) and platelet-adhesion molecule (P-selectin). Furthermore, carrageenan induced the expression of nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), nitrotyrosine, the activation of poly-ADP-ribosyl polymerase (PARP), as well as induced apoptosis (FAS-ligand expression, Bax and Bcl-2 expression) in the lung tissues. Administration of CGS 21680, 30min prior to challenge with carrageenan, caused a significant reduction of all the parameters of inflammation measured. In addition, to confirm the anti-inflammatory effect of CGS 21680, we have also evaluated the effects of CGS 21680 post-treatment (30min after the challenge with carrageenan) and we have demonstrated that also it caused a reduction of neutrophil infiltration and the degree of lung injury. Thus, based on these findings we propose that adenosine A2A receptor agonists such as CGS 21680 may be useful in the treatment of various inflammatory diseases. [Copyright &y& Elsevier]

Abstract: Iron is essential for many biological processes and its deficiency or excess is involved in pathological conditions. At cellular level, the maintenance of iron homeostasis is largely accomplished by the transferrin receptor (TfR-1) and by ferritin, whose expression is mainly regulated post-transcriptionally by iron regulatory proteins (IRPs). This study examines the hypothesis that modification of serum estrogen levels by ovariectomy and 17β-estradiol (E2) treatment in rats modulate serum iron-status parameters and iron metabolism in adipose tissue. In particular, we evaluated the RNA binding of IRP1 by electrophoretic mobility-shift assay and IRP1, ferritin, and TfR-1 expression in adipose tissue by Western blot analysis. Ovariectomy, besides a lowered serum iron and transferrin iron binding capacity, remarkably decreased the binding activity of IRP1 in peritoneal and subcutaneous adipose tissues, and these effects were reversed by E2 treatment. Moreover, ovariectomy determined a decrease of IRP1 expression, which was significant in subcutaneous adipose tissue. Consistent with IRP1 regulation, an increase of ferritin and a decrease of TfR-1 expression were observed in peritoneal adipose tissue from ovariectomized animals, while the treatment with E2 reconstituted TfR-1 level. A similar expression profile of TfR-1 was observed in subcutaneous adipose tissue, where ferritin level did not change in ovariectomized animals, and was increased after E2 treatment. Our results indicate that estrogen level changes can regulate the binding activity of the IRP1, and consequently ferritin and TfR-1 expression in adipose tissue, suggesting a relationship among serum and tissue iron parameters, estrogen status and adiposity. [Copyright &y& Elsevier]

Abstract: The aim of the present study was to assess the contribution of peroxynitrite formation in the pathophysiology of spinal cord injury (SCI) in mice. To this purpose, we used a peroxynitrite decomposition catalyst, 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTSPP). Spinal cord trauma was induced by the application of vascular clips (force of 24g) to the dura via a four-level T5–T8 laminectomy. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, production of inflammatory mediators, tissue damage, and apoptosis. FeTSPP treatment (10–100 mg/kg, i.p.) significantly reduced in dose-dependent manner 1 and 4 h after the SCI (1) the degree of spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) nitrotyrosine formation and poly-(ADP-ribose) polymerase activation, (4) proinflammmaory cytokines expression, (5) NF-κB activation, and (6) apoptosis (TUNEL staining, Bax and Bcl-2 expression). Moreover, FeTSPP significantly ameliorated the recovery of limb function (evaluated by motor recovery score) in a dose-dependent manner. Taken together, our results clearly demonstrate that FeTSPP treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma similarly to dexamethasone, a well-known antiinflammatory agent which we have used as positive control. [Copyright &y& Elsevier]

Abstract: GSH plays multiple roles in the nervous system including free radical scavenger, redox modulator of ionotropic receptor activity, and possible neurotransmitter. A lot of evidence suggests that GSH is involved in the pathogenesis of neurodegenerative disorders, like spinal cord injury (SCI). This study was undertaken to determine if the inhibition of endogenous glutathione, by l-buthionine-(S,R)-sulfoximine (BSO), affords protection against peroxynitrite-mediated toxicity in response to the spinal cord injury in vivo. The spinal cord of damaged animals showed a significant elevation of biochemical, immunohistochemical and functional parameters, increasing, respectively, neutrophils infiltration, lipid peroxidation, nitrotyrosine formation, PAR expression, apoptosis (measured by TUNEL staining) and loss of hind legs movement in SCI-operated mice. In contrast, the administration of BSO led to worsening of this already compromised setting, increasing the degree of (1) neutrophil infiltration, (2) lipid peroxidation, (3) histological damage, (4) apoptosis, (5) nitrotyrosine formation, (6) PAR expression, (7) apoptosis (measured by TUNEL staining) and (7) loss of hind legs movement. Thus, endogenous glutathione plays an important protective role against secondary damage after SCI. [Copyright &y& Elsevier]

Abstract: Protein tyrosine kinases help to regulate the expression of many genes, which play an important role in the pathophysiology of a number of diseases. Here we investigate the effects of the tyrosine kinase inhibitors, AG126 and AG556 on the degree of experimental spinal cord trauma induced by the application of vascular clips to the dura via a four-level T4–T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by oedema, neutrophil infiltration, production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with AG126 and AG556 significantly reduced the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) neutrophil infiltration (myeloperoxidase activity), (3) iNOS, nitrotyrosine, and PARP expression and (4) apoptosis (TUNEL staining and Bax and Bcl-2 expression). In a separate set of experiments, AG126 and AG556 significantly ameliorated the recovery of limb function (evaluated by motor recovery score). This study provides an experimental evidence that (1) prevention of the activation of protein tyrosine kinases reduces the development of inflammation and tissue injury associated with spinal cord trauma, and (2) inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of spinal cord trauma. [Copyright &y& Elsevier]

• An innovative Lab-On-Fiber probe for the real-time dose monitoring was developed. • The exposure to ∼ 2 MGy X-rays led to a reduction of the PMMA thickness (26–40 %). • PMMA compaction was observed for ultra-high doses of X-rays, electrons and protons. • The absorbed dose is the main parameter affecting the PMMA relative compaction. Next generation High Energy Physics (HEP) accelerators will require new devices and technologies capable of operating in extreme environments characterized by ultra-high radiation doses up to the MGy levels. To this aim, we report on an innovative Lab-On-Fiber (LOF) probe for the real-time dose monitoring. The proposed platform is based on a metallo-dielectric nanostructured grating made of gold and poly(methyl methacrylate) (PMMA) patterned on the termination of single mode fibers. The nanostructure has been judiciously designed to support a plasmonic resonance in the reflection spectrum occurring at near infrared wavelengths. Electron beam lithography was used for the fabrication of two LOF prototypes, which in turn, were exposed to X-rays with a total dose of 2.02 MGy and a dose rate of 88 kGy/h. Reflection spectra acquired during the irradiation revealed a clear dependence of the LOF resonance wavelength and depth on the absorbed dose, confirming the outcomes of our previous proton campaign. Morphological characterization of the irradiated samples showed that the main radiation induced effect is the reduction of the PMMA thickness (ranging between 26 % and 40 %), which in turn strongly affects the resonance behavior. Quantitative morphological measurements have been used to achieve a fair and objective correlation with our numerical modelling. Moreover, we investigated the effect of ultra-high doses of several radiation types, including X-rays, electrons and protons, on the thickness of PMMA nanolayers deposited on planar substrates. Experimental results revealed that the amount of absorbed dose (1.9–16.06 MGy) is the main parameter affecting the PMMA relative compaction (9.5–59.1 %), while the influence of the radiation type, dose rate and initial PMMA thickness can be considered negligible. Overall, these results pave the way to the development of radiation type independent PMMA assisted LOF dosimeters operating at MGy doses for the radiation monitoring in future HEP experiments. [ABSTRACT FROM AUTHOR]

The aim of study was to examine the anti-inflammatory and analgesic effects of adelmidrol, an analogue of palmitoylethanolamide (PEA), in animal models of acute and chronic inflammation [carrageenan-induced paw edema (CAR) and collagen-induced arthritis (CIA)]. In order to elucidate whether the action of adelmidrol is related to activation of peroxisome proliferator-activated receptors (PPAR-α or PPAR-γ), we investigated the effects of PPAR-γ antagonist, GW9662 on adelmidrol mechanism. CAR induced paw edema, hyperalgesia and the activation of pro-inflammatory NF-κB pathway were markedly reduced by treatment with adelmidrol. GW9662, (administered prior to adelmidrol treatment), antagonized the effect of adelmidrol abolishing its positive action. On the contrary, the genetic absence of PPAR-α receptor did not modify the beneficial results of adelmidrol treatment in the acute model of inflammation. In addition, for the first time, we demonstrated that adelmidrol was able to ameliorate both the clinical signs and the histopathology of the joint and the hind paw during chronic inflammation. In particular, the degree of oxidative damage and proinflammatory cytokines and chemokines production were significantly reduced in adelmidrol-treated mice. Moreover, in CIA model, the effect of GW9662 pre-treatment on adelmidrol mechanism was also confirmed. Thus, in this study, we report that adelmidrol reduces the development of acute and chronic inflammation and could represent a novel therapeutic approach for inflammation and pain. [ABSTRACT FROM AUTHOR]