Search

Obesity is a growing health problem in both children and adults, impairing physical and mental state and impacting health care system costs in both developed and developing countries. It is well-known that individuals with excessive weight gain frequently develop obesity-related complications, which are mainly known as Non-Communicable Diseases (NCDs), including cardiovascular disease, type 2 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease, hypertension, hyperlipidemia and many other risk factors proven to be associated with chronic inflammation, causing disability and reduced life expectancy. This review aims to present and discuss complications related to inflammation in pediatric obesity, the critical role of nutrition and diet in obesity-comorbidity prevention and treatment, and the impact of lifestyle. Appropriate early dietary intervention for the management of pediatric overweight and obesity is recommended for overall healthy growth and prevention of comorbidities in adulthood.

Traumatic brain injury represents physical damage to the brain tissue that induces transitory or permanent neurological disabilities. The traumatic injury activates an important inflammatory response, followed by a cascade of events that lead to neuronal loss and further brain damage. Maintaining proper ventilation, a normal level of oxygenation, and adequate blood pressure are the main therapeutic strategies performed after injury. Surgery is often necessary for patients with more serious injuries. However, to date, there are no therapies that completely resolve the brain damage suffered following the trauma. Stem cells, due to their capacity to differentiate into neuronal cells and through releasing neurotrophic factors, seem to be a valid strategy to use in the treatment of traumatic brain injury. The purpose of this review is to provide an overview of clinical trials, aimed to evaluate the use of stem cell-based therapy in traumatic brain injury. These studies aim to assess the safety and efficacy of stem cells in this disease. The results available so far are few; therefore, future studies need in order to evaluate the safety and efficacy of stem cell transplantation in traumatic brain injury.

Background and O bjectives : Neuroinflammation is associated with many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In this study, we investigate the anti-inflammatory, anti-oxidant, and anti-apoptotic properties of two non-psychoactive phytocannabinoids, cannabigerol (CBG) and cannabidiol (CBD). Materials and Methods: The motoneuron-like cell line NSC-34 differentiated by serum deprivation and with the additional treatment of all-trans retinoic acid (RA) is a valid model to investigate molecular events linked to neurodegeneration in ALS. Results: Pre-treatment with CBG (at 2.5 and 5 µM doses) alone and in combination with CBD (at 2.5 and 5 µM doses) was able to reduce neuroinflammation induced by a culture medium of LPS-stimulated macrophages. In particular, the pre-treatment with CBD at a 5 µM dose decreased TNF-α levels and increased IL10 and IL-37 expression. CBG-CBD association at a 5 µM dose also reduced NF-kB nuclear factor activation with low degradation of the inhibitor of kappaB alpha (IkBα). CBG and CBD co-administered at a 5 µM dose decreased iNOS expression and increased Nrf2 levels. Furthermore, the pre-treatment with the association of two non-psychoactive cannabinoids downregulated Bax protein expression and upregulated Bcl-2 expression. Our data show the anti-inflammatory, anti-oxidant, and anti-apoptotic effects PPARγ-mediated. Conclusions: Our results provide preliminary support on the potential therapeutic application of a CBG-CBD combination for further preclinical studies., Competing Interests: The authors declare no conflict of interest.

Uveal melanoma (UM) is the most common primary intraocular cancer in adults. In the present study, we aimed to characterize the immunological features of primary UM cancer and to provide an association with prognostic markers and outcome. Also, we assessed the influence of the microenvironment on the expression of inhibitory immune checkpoints in UM. Genes of interest included MHC Class I and Class II molecules, as well as inhibitory immune-checkpoints, i.e. PDL1, PDL2, B7-H3, B7-H4, TBFRSF6B, CD47, CD155, GAL9, HVEM and CD200. We observed significant lower levels of MHC genes in UM cells as compared to normal uveal melanocytes. Unexpectedly however, the expression levels of most of the analyzed inhibitory immune-checkpoint genes were not different in cancer cells as compared to normal melanocytes, with the exception of CD200 and HVEM, that resulted significantly reduced. On the other hand, PDL1 inversely correlated with OS, PFS and thickness of the tumor. Also, PDL1, along with PDL2, expression significantly increased under inflammatory conditions. Finally, for the first time, we propose a possible role for CD47 in the immune evasive properties of UM. We show here that CD47 is significantly upregulated by UM cells following inflammatory stimuli and that it represents a good independent predictor of disease progression. The results from this study may propel advances in the development of immune-based therapies for UM patients., Competing Interests: The authors have declared that no competing interests exist.

Aims: Spinal cord injury (SCI) occurs following damage to the spinal column. Following trauma, tissue damage is further exacerbated by a secondary damage due to a SCI-activated inflammatory process. Control of leukocytes activity is essential to therapeutic inhibition of the spinal cord damage to ameliorate the patient's conditions. The mechanisms that regulate neuroinflammation following SCI, including T-cell infiltration, have not been completely clarified. Glucocorticoids (GC) are antiinflammatory drugs widely used in therapy, including treatment of SCI. GC efficacy may be linked to many molecular mechanisms that are involved in regulation of leukocytes migration, activation, and differentiation. We have previously shown that the antiinflammatory activity of GC is in part mediated by glucocorticoid-induced leucine zipper (GILZ). Here, we investigated the role of GILZ in inflammation and spinal cord tissue damage following a spinal trauma., Methods: We address the role of GILZ in SCI-induced inflammation and tissue damage using a model of SCI in gilz knockout (gilz KO) and wild-type (WT) mice., Results: We found that GILZ deficiency is associated with a strong reduction of SCI-induced inflammation and a significantly reduced lesion area following SCI., Conclusion: These results demonstrate that GILZ is involved in induction of neuroinflammation and functional outcomes of spinal cord trauma., (© 2014 John Wiley & Sons Ltd.)

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(TG)) mice, in which GILZ is selectively over-expressed in T lymphocytes, to SCI induction. Consistent with a decreased inflammatory response, GILZ(TG) 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(TG) as compared to wild-type mice. Moreover, GILZ(TG) 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.

Endothelial nitric oxide synthase (eNOS) is a dynamic enzyme tightly controlled by co- and post-translational lipid modifications, phosphorylation and regulated by protein-protein interactions. In this study we have pharmacologically modulated the activation of eNOS, at different post-translational levels, to assess the role of eNOS-derived NO and regulatory mechanisms in tissue damage associated with spinal cord injury (SCI). SC trauma was induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by oedema, neutrophil infiltration, and production of inflammatory mediators, tissue damage and apoptosis. LY294002, an inhibitor of phosphatidylinositol 3-kinase that initiates Akt-catalysed phosphorylation of eNOS on Ser1179, was administered 1 h before the induction of SCI; 24 h after SCI sections were taken for histological examination and for biochemical studies. In this study we clearly demonstrated that pre-treatment with LY294002 reversed the increased activation of eNOS and Akt observed following SCI, and developed a severe trauma characterized by oedema, tissue damage and apoptosis (measured by TUNEL staining, Bax, Bcl-2 and Fas-L expression). Histological damage also correlated with neutrophil infiltration, assessed as myeloperoxidase activity. Overall these results suggest that activation of the Akt pathway in SC tissue subject to SCI is a protective event, triggered in order to protect the injured tissue through a fine tuning of the endothelial NO pathway., (© 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

The perception of pain is altered by inflammatory processes. Anti-inflammatory drugs block this by raising the pain threshold and by reducing the inflammatory process. Melatonin is claimed to have anti-inflammatory activity in animal models of acute and chronic inflammation. However, little is known whether melatonin can reverse the hyperalgesia that is secondary to the inflammation. This study assessed the effect of melatonin on in a well-established model of hyperalgesia associated with inflammation in rats. Peroxynitrite, as generated by the interaction between superoxide anion radical exogenously supplied (O(2)(˙-) ) and endogenous nitric oxide (NO), led to the development of hyperalgesia. This subplantar injection of O(2)(˙-) into the right hindpaw evoked potent thermal hyperalgesia measured by changes in withdrawal latency. Melatonin (25-100 mg/kg, given ip 30 min prior to O(2)(˙-) ) dose dependently attenuated the hyperalgesic responses to O(2)(˙-) . Moreover, melatonin (100 mg/kg) significantly improved tissue damage and inflammation, blocked protein nitration affecting cyclooxygenase-2 and inducible nitric oxide synthase expression in paw tissue. To investigate the antinociceptive activity of melatonin and characterize the underlying mechanisms involved in this action, mitogen-activated protein kinase and NF-κB pathways were explored. Moreover, antihyperalgesic effect of melatonin derived partly from the inhibition of superoxide-driven PARP activation. These results suggest that melatonin has ameliorative potential in attenuating the hyperalgesia associated with inflammation., (© 2010 The Authors. Journal of Pineal Research © 2010 John Wiley & Sons A/S.)

PPARs belong to a subfamily of transcription nuclear factors. Three isoforms of PPARs have been identified: alpha, beta/delta, and gamma, encoded by different genes and distributed in various tissues. They play important roles in metabolic processes, such as regulation of glucose and lipid redistribution. They also have antiatherogenic, anti-inflammatory, as well as antihypertensive functions. There is good evidence that ligands of PPARs reduce tissue injury associated with I/R. This study investigated the effects of GW0742, a potent and selective PPAR-beta/delta agonist, on tissue injury, caused in a mouse model of SAO shock. IRI of the intestine was caused by clamping the superior mesenteric artery and the celiac trunk for 45 min, followed by release of the clamp, allowing reperfusion for 1 or 6 h. Only 10% of the SAO animals survived the entire 6-h reperfusion period. In a separate set of experiments after 60 min of reperfusion, animals were killed for histological examination and biochemical studies. Administration of GW0742 (0.1 mg/kg, i.p.), 5 min prior to reperfusion, significantly reduced the (1) mortality rate, (2) histological evidence of gut injury, (3) MPO activity, (4) proinflammatory cytokines (TNF-alpha, IL-1beta), (5) adhesion molecules (ICAM-1, P-selectin), (6) nitrotyrosine formation, (7) NF-kappaB expression, (8) PAR formation, and (9) apoptosis (Bax, Bcl-2, Fas-L, and TUNEL). Based on these findings, we propose that GW0742 would be useful in the treatment of various I/R diseases.

The standard iron-chelator deferoxamine is known to reduce neurological deficits. The aim of the present study was to evaluate the contribution of deferoxamine in the secondary damage in experimental spinal cord injury (SCI) in mice, induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. SCI resulted in production of inflammatory mediators, tissue damage and apoptosis. Deferoxamine treatment 30 min before and 1 and 6 h after the SCI significantly reduced: (1) GFAP immunoreactivity, (2) neutrophil infiltration, (3) NF-kappaB activation, (4) iNOS expression, (5) nitrotyrosine and MDA formation, (6) DNA damage (methyl green pyronin staining and PAR formation and (7) apoptosis (TUNEL staining, FasL, Bax and Bcl-2 expression, S-100 expression). Moreover, deferoxamine significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, the results clearly demonstrate that deferoxamine treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma.

In this study, we evaluated the effect of green tea extract (that was administered 25 mg/kg intraperitoneal at 1 and 6 h after injury) in experimental animal model of spinal cord injury. The spinal cord trauma was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterised by oedema, neutrophilic infiltration and apoptosis. Also, immunohistochemical examination demonstrated a marked increase in immune reactivity for nitrotyrosine. All parameters of inflammation were attenuated by green tea extract. The degree of spinal cord inflammation, nitrotyrosine, poli (ADP-ribosio) synthetase (PARS) and neutrophilic infiltration was markedly reduced. Green tea extract significantly ameliorated the recovery of limb function. Values shown are mean +/- SE mean of ten mice for each group. *p < 0.01 versus sham, degrees p < 0.01 versus spinal cord injury. Taken together, our results clearly demonstrate that green tea extract treatment ameliorates spinal cord injury oxidative stress.

Melatonin (N-acetyl-5-methoxytryptamine) is an efficient free radical scavenger and antioxidant, both in vitro and in vivo. The role of melatonin as an immunomodulator is, in some cases, contradictory. In this study we have investigated the therapeutic efficacy of melatonin in rats subjected to Pelagia noctiluca crude venom (of the familia Pelaguiidae; and genus Pelagia) induced acute paw inflammation. In particular, injection of the venom into the paw of rats elicited an acute inflammatory response characterized by accumulation of fluid containing a large number of polymorphonuclear neutrophils in the paw and subsequent lipid peroxidation. Furthermore, the venom promoted an expression of iNOS, nitrotyrosine and the activation of the nuclear enzyme poly (ADP-ribose) polymerase as determined by immunohistochemical analysis of paw tissues. Administration of melatonin 30 min, 1 and 6 hr after the challenge with the venom, caused a significant reduction in all the parameters of inflammation measured. Thus, based on these findings we propose that melatonin may be useful a treatment of local acute inflammation induced by P. noctiluca crude venom.

Glycyrrhizin, a major active constituent of liquorice root (Glycyrrhiza glabra), has a free radical scavenging property, and its effects were evaluated on an animal model of spinal cord injury (SCI) induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5-T8 laminectomy. Spinal cord injury in mice resulted in severe trauma characterized by edema, tissue damage, and apoptosis (measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin end labeling staining, Bax, and Bcl-2 expression). Immunohistochemical examination demonstrated a marked increase in immunoreactivity for nitrotyrosine, iNOS, and poly(adenosine diphosphate-ribose) in the spinal cord tissue. Additionally, we demonstrate that these inflammatory events were associated with the activation of nuclear factor-kappaB. In contrast, the degree of (1) spinal cord inflammation and tissue injury (histological score), (2) nitrotyrosine and poly(adenosine diphosphate [ADP] ribose) formation, (3) iNOS expression, (4) nuclear factor-kappaB activation, and (5) apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP-biotin end labeling, Bax, and Bcl-2) was markedly reduced in spinal cord tissue obtained from mice treated with glycyrrhizin extract (10 mg/kg, i.p., 30 min before and 1 and 6 h after SCI). In a separate set of experiments, we have clearly demonstrated that glycyrrhizin extract treatment significantly ameliorated the recovery of limb function (evaluated by motor recovery score). Taken together, our results clearly demonstrate that treatment with glycyrrhizin extract reduces the development of inflammation and tissue injury events associated with spinal cord trauma.

This study was designed to elucidate the role of peroxisome proliferator-activated receptor (PPAR)-alpha in the development of inflammation after ischemia/reperfusion injury of the kidney. We have evaluated the effects of ischemia/reperfusion on renal dysfunction, injury, and inflammation in wild-type mice or mice in which the gene for PPAR-alpha has been deleted [PPAR-alpha(-/-)] and then treated with the PPAR-alpha agonist fenofibrate. Mice were subjected to bilateral renal ischemia (30 min) and reperfusion (24 h) and received fenofibrate (3 mg/kg i.p.) before reperfusion. Plasma creatinine, urea, and aspartate aminotransferase were all used as indicators of renal dysfunction and injury. Kidneys were used for histological and immunohistochemical analysis and markers of inflammation. Fenofibrate significantly attenuated the degree of renal dysfunction, injury, and inflammation caused by ischemia/reperfusion injury. The degree of renal dysfunction, injury, and inflammation caused by ischemia/reperfusion was also significantly augmented in PPAR-alpha(-/-) mice compared with their wild-type littermates. It is interesting that fenofibrate did not protect PPAR-alpha(-/-) mice against ischemia/reperfusion injury. Therefore, we propose that ligands of PPAR-alpha may be useful in the treatment of renal ischemia/reperfusion injury and that endogenous PPAR-alpha limits the degree of renal dysfunction, injury, and inflammation associated with ischemia/reperfusion injury.

Objective: Ethyl pyruvate (EP) is a simple aliphatic ester, which has been shown to have anti-inflammatory effects in previous numerous cell culture and animal studies. In the present study, we investigated the effects of EP (75 mg/kg i.p.) on the development of shock caused by zymosan., Design: Prospective, randomized study., Setting: University-based research laboratory., Subjects: Male CD mice., Interventions: Mice received either intraperitoneally zymosan (500 mg/kg, administered i.p. as a suspension in saline) or vehicle (0.25 mL/mouse saline). EP (75 mg/kg i.p. was administered 1 and 6 hrs after zymosan administration. Organ failure and systemic inflammation in mice was assessed 18 hrs after administration of zymosan and/or EP., Measurements and Main Results: Treatment of mice with EP attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. EP also attenuated the lung, liver, and pancreatic injury and renal dysfunction caused by zymosan as well as the increase in myeloperoxidase activity in the lung and intestine caused by zymosan. Immunohistochemical analysis for inducible nitric oxide synthase, nitrotyrosine, poly (ADP-ribose), tumor necrosis factor-alpha, and interleukin-1beta revealed positive staining in pancreatic and intestinal tissue obtained from zymosan-injected mice. The degree of staining for nitrotyrosine, inducible nitric oxide synthase, poly (ADP-ribose), tumor necrosis factor-alpha, and interleukin-1beta were markedly reduced in tissue sections obtained from zymosan-injected mice, which had received EP. In addition, administration of zymosan caused a severe illness in the mice characterized by a systemic toxicity, significant loss of body weight, and a 60% of mortality at the end of observation period (7 days). Treatment with EP significantly reduced the development of systemic toxicity, the loss in body weight, and the mortality (20%) caused by zymosan., Conclusions: This study provides evidence that EP attenuates the degree of zymosan-induced shock in mice.

The aim of the present study was to examine the role of poly-(ADP-ribose) glycohydrolase (PARG) on the modulation of the inflammatory response and tissue injury associated with neurotrauma. Spinal cord trauma was induced in wild-type (WT) mice by the application of vascular clips (force of 24 g) to the dura via a two-level T(6) to T(7) laminectomy. Spinal cord injury in WT mice resulted in severe trauma characterized by edema, neutrophil infiltration, and cytokine production followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, apoptosis, and disease. The genetic disruption of the PARG gene in mice or the pharmacological inhibition of PARG with GPI 16552 [N-bis-(3-phenyl-propyl)9-oxo-fluorene-2,7-diamide] (40 mg/kg i.p. bolus), a novel and potent PARG inhibitor, significantly reduced the degree of spinal cord inflammation and tissue injury (histological score), neutrophil infiltration, cytokine production (tumor necrosis factor-alpha and interleukin-1beta), and apoptosis. In a separate experiment, we have clearly demonstrated that PARG inhibition significantly ameliorated the recovery of limb function. Taken together, our results indicate that PARG activity modulates the inflammatory response and tissue injury events associated with spinal cord trauma and participate in target organ damage under these conditions.

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study was to evaluate the role of the PPAR-alpha receptor on the development of acute inflammation. To address this question, we used two animal models of acute inflammation (carrageenan-induced paw edema and carrageenan-induced pleurisy). We report here that when compared with PPAR-alpha wild-type mice, PPAR-alpha knockout mice (PPAR-alphaKO) mice experienced a higher rate of the extent and severity when subjected to carrageenan injection in the paw edema model or to carrageenan administration in the pleurisy model. In particular, the absence of a functional PPAR-alpha gene in PPAR-alphaKO mice resulted in a significant augmentation of various inflammatory parameters (e.g., enhancement of paw edema, pleural exudate formation, mononuclear cell infiltration, and histological injury) in vivo. Furthermore, the absence of a functional PPAR-alpha gene enhanced the staining (immunohistochemistry) for FAS ligand in the paw and in the lung and the expression of tumor necrosis factor alpha and interleukin-1beta in the lungs of carrageenan-treated mice. In conclusion, the increased inflammatory response observed in PPAR-alphaKO mice strongly suggests that a PPAR-alpha pathway modulates the degree of acute inflammation in the mice.

Abstract Background Statins such as simvastatin are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease. In addition to their cholesterol-lowering activities, statins exert pleiotropic anti-inflammatory effects, which might contribute to their beneficial effects on lipid-unrelated inflammatory diseases. Recently it has been demonstrated that the peroxisome proliferator-activated receptor (PPAR)-α mediates anti-inflammatory effects of simvastatin in vivo models of acute inflammation. Moreover, previous results suggest that PPAR-α plays a role in control of secondary inflammatory process associated with spinal cord injury (SCI). Methods With the aim to characterize the role of PPAR-α in simvastatin activity, we tested the efficacy of simvastatin (10 mg/kg dissolved in saline i.p. 1 h and 6 h after the trauma) in an experimental model of SCI induced in mice by extradural compression of the spinal cord (T6-T7 level) using an aneurysm clip with a closing force of 24 g via a four-level T5-T8 laminectomy, and comparing mice lacking PPAR-α (PPAR-α KO) with wild type (WT) mice. In order to elucidate whether the effects of simvastatin are due to activation of the PPAR-α, we also investigated the effect of a PPAR-α antagonist, GW6471 (1 mg/kg administered i.p. 30 min prior treatment with simvastatin) on the protective effects of on simvastatin. Results Results indicate that simvastatin activity is weakened in PPAR-α KO mice, as compared to WT controls. In particular, simvastatin was less effective in PPAR-α KO, compared to WT mice, as evaluated by inhibition of the degree of spinal cord inflammation, neutrophil infiltration, nitrotyrosine formation, pro-inflammmatory cytokine expression, nuclear factor (NF)-κB activation, inducible nitric-oxide synthase (iNOS) expression, and apoptosis. In addition we demonstrated that GW6471 significantly antagonized the effect of the statin and thus abolished the protective effect. Conclusions This study indicates that PPAR-α can contribute to the anti-inflammatory activity of simvastatin in SCI.

Abstract Background Emerging data implicate nicotinamide phosphoribosyl transferase (NAMPT) in the pathogenesis of cancer and inflammation. NAMPT inhibitors have proven beneficial in inflammatory animal models of arthritis and endotoxic shock as well as in autoimmune encephalitis. Given the role of inflammatory responses in spinal cord injury (SCI), the effect of NAMPT inhibitors was examined in this setting. Methods We investigated the effects of the NAMPT inhibitor FK866 in an experimental compression model of SCI. Results Twenty-four hr following induction of SCI, a significant functional deficit accompanied widespread edema, demyelination, neuron loss and a substantial increase in TNF-α, IL-1β, PAR, NAMPT, Bax, MPO activity, NF-κB activation, astrogliosis and microglial activation was observed. Meanwhile, the expression of neurotrophins BDNF, GDNF, NT3 and anti-apoptotic Bcl-2 decreased significantly. Treatment with FK866 (10 mg/kg), the best known and characterized NAMPT inhibitor, at 1 h and 6 h after SCI rescued motor function, preserved perilesional gray and white matter, restored anti-apoptotic and neurotrophic factors, prevented the activation of neutrophils, microglia and astrocytes and inhibited the elevation of NAMPT, PAR, TNF-α, IL-1β, Bax expression and NF-κB activity. We show for the first time that FK866, a specific inhibitor of NAMPT, administered after SCI, is capable of reducing the secondary inflammatory injury and partly reduce permanent damage. We also show that NAMPT protein levels are increased upon SCI in the perilesional area which can be corrected by administration of FK866. Conclusions Our findings suggest that the inflammatory component associated to SCI is the primary target of these inhibitors.

Alzheimer's disease (AD) is the most frequent cause of dementia worldwide and represents one of the leading factors for severe disability in older persons. Although its etiology is not fully known yet, AD may develop due to multiple factors, including inflammation and oxidative stress, conditions where microRNAs (miRNAs) seem to play a pivotal role as a molecular switch. All these aspects may be modulated by nutritional factors. Among them, vitamin E has been widely studied in AD, given the plausibility of its various biological functions in influencing neurodegeneration. From a cohort of old-aged people, we measured eight vitamin E forms (tocopherols and tocotrienols), thirty cytokines/chemokines, and thirteen exosome-extracted miRNAs in plasma of subjects suffering from subjects affected by AD and age-matched healthy controls (HC). The sample population included 80 subjects (40 AD and 40 HC) with a mean age of 77.6 ± 3.8 years, mostly women (45; 56.2%). Of the vitamin E forms, only α-tocopherol differed between groups, with significantly lower levels in AD. Regarding the examined inflammatory molecules, G-CSF, GM-CSF, INF-α2, IL-3, and IL-8 were significantly higher and IL-17 lower in AD than HC. Among all miRNAs examined, AD showed downregulation of miR-9, miR-21, miR29-b, miR-122, and miR-132 compared to controls. MiR-122 positively and significantly correlated with some inflammatory molecules (GM-CSF, INF-α2, IL-1α, IL-8, and MIP-1β) as well as with α-tocopherol even after correction for age and gender. A final binary logistic regression analysis showed that α-tocopherol serum levels were associated with a higher AD probability and partially mediated by miR-122. Our results suggest an interplay between α-tocopherol, inflammatory molecules, and microRNAs in AD, where miR-122 may be a good candidate as modulating factor. [ABSTRACT FROM AUTHOR]

Childhood obesity is constantly increasing around the world, and it has become a major public health issue. Considerable evidence indicates that overweight and obesity are important risk factors for the development of comorbidities such as cognitive decline, neuroinflammation and neurodegenerative diseases. It is known that during obesity, adipose tissue undergoes immune, metabolic and functional changes which could induce a neuroinflammatory response of the central nervous system (CNS). In this context, to inspect if obesity can start to trigger the neuroinflammation from a pediatric age, we surgically collected and analyzed adipose tissue from the periumbilical area of three obese children (AT-OB) and two normal-weight children (AT-Ctrl). We considered the transcriptomic profile of our samples to detect alterations in different biological processes that might be also involved in the inflammatory and neuroinflammatory response. Our results show alterations of lipid and fatty acids metabolism in AT-OB compared to the AT-Ctrl. We also observed an onset of inflammatory response in AT-OB. Interestingly, among the genes involved in neuroinflammation, GRN and SMO were upregulated, while IFNGR1 and SNCA were downregulated. Our study highlights that obesity may trigger inflammation and neuroinflammation from a pediatric age. [ABSTRACT FROM AUTHOR]

The mesenchymal stem cells' (MSCs) secretome includes the bioactive molecules released in the conditioned medium (CM), such as soluble proteins, free nucleic acids, lipids and extracellular vesicles. The secretome is known to mediate some of the beneficial properties related to MSCs, such as anti-inflammatory, anti-apoptotic and regenerative capacities. In this work, we aim to evaluate the anti-inflammatory potential of a new lyophilized formulation of CM derived from human periodontal ligament stem cells (hPDLSCs). With this aim, we treat hPDLSCs with lipopolysaccharide (LPS) and test the anti-inflammatory potential of lyophilized CM (LYO) through the evaluation of wound closure, transcriptomic and immunofluorescence analysis. LPS treatment increased the expression of TLR4 and of genes involved in its signaling and in p38 and NF-κB activation, also increasing the expression of cytokines and chemokines. Interestingly, LYO downregulated the expression of genes involved in Toll-like receptor 4 (TLR-4), nuclear factor kappa light chain enhancer of activated B cells (NF-κB) and p38 signaling. As a consequence, the genes encoding for cytokines and chemokines were also downregulated. Immunofluorescence acquisitions confirmed the downregulation of TLR-4 and NF-κB with the LYO treatment. Moreover, the LYO treatment also increased hPDLSCs' migration. LYO was demonstrated to contain transforming growth factor (TGF)-β3 and vascular endothelial growth factor (VEGF). These results suggest that LYO represents an efficacious formulation with anti-inflammatory potential and highlights lyophilization as a valid method to produce stable formulations of MSCs' secretome. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a complex clinical and progressive condition characterized by neuronal loss, axonal destruction and demyelination. In the last few years, adenosine receptors have been studied as a target for many diseases, including neurodegenerative conditions. The aim of this study was to investigate the effects of an adenosine receptor agonist, PDRN, in an experimental model of SCI. Moreover, since adenosine receptors stimulation may also activate the Wnt pathway, we wanted to study PDRN effects on Wnt signaling following SCI. Spinal trauma was induced by extradural compression of spinal cord at T5-T8 level in C57BL6/J mice. Animals were randomly assigned to the following groups: Sham (n = 10), SCI (n = 14), SCICPDRN (8 mg/kg/i.p.; n = 14), SCICPDRNCDMPX (8 and 10 mg/kg/i.p., respectively; n = 14). DMPX was used as an adenosine receptor antagonist to evaluate whether adenosine receptor block might prevent PDRN effects. PDRN systemically administered 1 h following SCI, protected from tissue damage, demyelination, and reduced motor deficits evaluated after 10 days. PDRN also reduced the release of the pro-inflammatory cytokines TNF-α and IL-1β, reduced BAX expression and preserved Bcl-2. Furthermore, PDRN stimulated Wnt/β-catenin pathway and decreased apoptotic process 24 h following SCI, whereas DMPX administration prevented PDRN effects on Wnt/β-catenin signaling. These results confirm PDRN anti-inflammatory activity and demonstrate that a crosstalk between Wnt/β-catenin signaling is possible by adenosine receptors activation. Moreover, these data let us hypothesize that PDRN might promote neural repair through axonal regeneration and/or neurogenesis. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a disabling progressive disease characterized by the degeneration of motor neurons, leading to muscle atrophy and paralysis. The majority of cases are sporadic, but also a familiar form of ALS exists, and some genes causative of the pathology were found. In particular, mutations in superoxide dismutase 1 (SOD1) were found in 20% of familiar cases. It is known that neuroinflammation plays a pivotal role in several neurodegenerative disorders, including ALS. Inflammasomes are protein complexes that induce inflammation in response to various stimuli, involved also in neuroinflammation. The NLRP3 inflammasome, which is the best known, after assembly, induces the activation of caspase 1, which in turn activates interleukin (IL)-1β and IL-18. The aim of this work was the evaluation of inflammasome activation in the brain of SOD1 rats, a transgenic model of ALS. We observed the increase in TLR4 and nuclear NF-κB levels in SOD1 rats. Their activation is known as priming signal for inflammasome induction. Moreover, NLRP3 protein increased, associated with the presence of active caspase 1, leading to an increase in IL-18 and IL-1β levels. In addition, IL-1β, IL-18, and IFN-γ amount increased in the spleen of SOD1 rats, together with an increased expression of CD4, CD8, CD44, and CD68 markers. In conclusion, our results showed the activation of the NLRP3 inflammasome in the brain of SOD1 rats, indicating that inflammation plays a main role in ALS. [ABSTRACT FROM AUTHOR]

Background: Neuropathic pain represents the major public health burden with a strong impact on quality life in multiple sclerosis (MS) patients. Although, some advances have been obtained in the last years, the conventional therapies remain poorly effective. Thus, the discovery of innovative approaches to improve the outcomes for MS patients is a goal of primary importance. With this aim, we investigated the efficacy of the 4-(α−L-rhamnopyranosyloxy)benzyl isothiocyanate (moringin), purified from Moringa oleifera seeds and ready-to-use as topical treatment in autoimmune encephalomyelitis (EAE), murine model of MS. Female C57BL/6 immunized with myelin oligodendrocyte glycoprotein (MOG35-55) were topically treated with 2% moringin-cream twice daily from the onset of the symptoms until the sacrifice occurred about 21 days after EAE induction. Results: Our observations showed the efficacy of 2%-moringin cream treatment in reducing clinical and histological disease score, as well as in alleviating neuropathic pain with consequent recovering of the hind limbs and response to mechanical stimuli. In particular, western blot analysis and immunohistochemical evaluations revealed that 2% moringin-cream was able to counteract the inflammatory cascade by reducing the production of pro-inflammatory cytokines (IL-17 and IFN-γ) and in parallel by increasing the expression of anti-inflammatory cytokine (IL-10). Interestingly, 2%- moringin cream treatment was found to modulate the expression of voltage-gated ion channels (results focused on P2X7, Nav 1.7, Nav 1.8 KV4.2 and α2δ-1) as well as metabotropic glutamate receptors (mGluR5 and xCT) involved in neuropathic pain initiation and maintenance. Conclusions: Finally, our evidences suggest 2%-moringin cream as a new pharmacological trend in the management of MS-induced neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: Cerebral ischemia and reperfusion (CIR) is a pathological condition characterized by a first blood supply restriction to brain followed by the consequent restoration of blood flow and simultaneous reoxygenation. The aim of this study was to evaluate the neuroprotective effects of Tuscan black kale sprout extract (TBK-SE) bioactivated with myrosinase enzyme, assessing its capability to preserve blood-brain barrier (BBB), in a rat model of CIR. Methods: CIR was induced in rats according to a classic model of carotid artery occlusion for a time period of 1 h and the reperfusion time was prolonged for seven days. Results: By immunohistochemical evaluation and western blot analysis of brain and cerebellum tissues, our data have clearly shown that administration of bioactive TBK-SE is able to restore alterations of tight junction components (claudin-5 immunolocalization). Also, bioactive TBK-SE reduces some inflammatory key-markers (p-selectin, GFAP, Iba-1, ERK1/2 and TNF-α), as well as the triggering of neuronal apoptotic death pathway (data about Bax/Bcl-2 balance, p53 and cleaved-caspase 3) and the generation of radicalic species by oxidative stress (results focused on iNOS, nitrotyrosine and Nrf2). Conclusion: Taken together, our findings lead to believe that bioactive TBK-SE exerts pharmacological properties in protecting BBB integrity through a mechanism of action that involves a modulation of inflammatory and oxidative pathway as well into control of neuronal death. [ABSTRACT FROM AUTHOR]

Background: The present study was designed to investigate the efficacy of a new formulation of alone, purified cannabidiol (CBD) (>98 %), the main non-psychotropic cannabinoid of Cannabis sativa, as a topical treatment in an experimental model of autoimmune encephalomyelitis (EAE), the most commonly used model for multiple sclerosis (MS). Particularly, we evaluated whether administration of a topical 1 % CBD-cream, given at the time of symptomatic disease onset, could affect the EAE progression and if this treatment could also recover paralysis of hind limbs, qualifying topical-CBD for the symptomatic treatment of MS. Methods: In order to have a preparation of 1 % of CBD-cream, pure CBD have been solubilized in propylene glycoland basic dense cream O/A. EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG35-55) in C57BL/6 mice. After EAE onset, mice were allocated into several experimental groups (Naïve, EAE, EAE-1 % CBD-cream, EAE-vehicle cream, CTRL-1 % CBD-cream, CTRL-vehicle cream). Mice were observed daily for signs of EAE and weight loss. At the sacrifice of the animals, which occurred at the 28 day from EAE-induction, spinal cord and spleen tissues were collected in order to perform histological evaluation, immunohistochemistry and western blotting analysis. Results: Achieved results surprisingly show that daily treatment with topical 1 % CBD-cream may exert neuroprotective effects against EAE, diminishing clinical disease score (mean of 5.0 in EAE mice vs 1.5 in EAE + CBD-cream), by recovering of paralysis of hind limbs and by ameliorating histological score typical of disease (lymphocytic infiltration and demyelination) in spinal cord tissues. Also, 1 % CBD-cream is able to counteract the EAE-induced damage reducing release of CD4 and CD8α T cells (spleen tissue localization was quantified about 10,69 % and 35,96 % of positive staining respectively in EAE mice) and expression of the main pro-inflammatory cytokines as well as several other direct or indirect markers of inflammation (p-selectin, IL-10, GFAP, Foxp3, TGF-β, IFN-γ), oxidative injury (Nitrotyrosine, iNOS, PARP) and apoptosis (Cleaved caspase 3). Conclusion: All these data suggest an interesting new profile of CBD that could lead to its introduction in the clinical management of MS and its associated symptoms at least in association with current conventional therapy. [ABSTRACT FROM AUTHOR]

Aim The discovery of new natural compounds with pharmacological properties is a field of interest widely growing. Recent literature shows that Brassica vegetables ( Cruciferae) possess therapeutic effects particularly ascribed due to their content in glucosinolates, which upon myrosinase hydrolysis release the corresponding isothiocyanates. This study examines the potential neuroprotective and immunomodulatory effects of ( R S)-glucoraphanin from Tuscan black kale ( Brassica oleracea L. var. acephala sabellica) bioactivated with myrosinase (bioactive R S- GRA) (10 mg/kg/day intraperitoneally), in an experimental autoimmune encephalomyelitis ( EAE), a model of multiple sclerosis. Methods EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide ( MOG35-55) in mice. After immunization, mice were observed daily for signs of EAE and weight loss. Clinical score was evaluated using a standardized scoring system. Results By Western blot analysis of spinal cord tissues, we have demonstrated that treatment with bioactive R S- GRA significantly decreased nuclear factor ( NF)-kB translocation, pro-inflammatory cytokine production such as interleukin-1β (IL-1β), and apoptosis (Bax and caspase 3 expression). Conclusion Our results clearly demonstrate that bioactive R S- GRA treatment may represent a useful therapeutic perspective in the treatment of this disease. [ABSTRACT FROM AUTHOR]

Abstract: Olprinone hydrochloride, a specific phosphodiesterase III inhibitor, has anti-inflammatory effects in addition to its inotropic and vasodilatory effects. The purpose of this study was to examine the beneficial effects of olprinone on cerebral ischemia reperfusion injury. In the present study, we examined the detailed mechanisms underlying the inhibitory effects of olprinone on inflammatory and apoptotic responses induced by middle cerebral artery occlusion (MCAo) in rats. Focal cerebral ischemia was induced by transient MCAo in the right hemisphere, via the external carotid artery into the internal carotid to block the origin of the median carotid artery. The rats were subjected to artery occlusion (2h) followed by reperfusion (22h). Olprinone was administered 5min before reperfusion. MCAo-induced cerebral ischemia was associated with an increase in inducible nitric oxide synthase expression, nitrotyrosine formation, as well as IL-1β expression and ICAM-1 expression in ischemic regions. Olprinone treatment showed marked reduction in infarct size compared with control rats. These expressions were markedly inhibited by olprinone treatment. We also demonstrated that olprinone reduces levels of apoptosis (TUNEL, Bax and Bcl-2 expression) resulting in a reduction in the infarct volume in ischemia–reperfusion brain injury. Based on these findings we propose that olprinone would be useful in lowering the risk of damage or improving function in ischemia–reperfusion brain injury-related disorders. [Copyright &y& Elsevier]

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]

The aim of this study was to investigate the effects of NADPH-oxidase inhibitors, in a mouse model of zymosan. Zymosan-induced shock was induced in mice by administration of zymosan (500 mg/kg, i.p.). The pharmacological treatment was the administration of apocynin (5 mg/kg 10% DMSO i.p.) and diphenylene iodonium chloride (DPI) (1 mg/kg i.v.) 1 h and 6 h after zymosan administration. MOF and systemic inflammation in mice was assessed 18 h after administration of zymosan. NADPH-oxidase inhibitors caused a significant reduction of the (1) peritoneal exudate formation, (2) neutrophil infiltration, (3) multiple organ dysfunction syndrome, (4) nitrotyrosine, (5) poly (ADP-ribose) (PAR), (6) cytokine formation, (7) adhesion molecule expression, (8) nuclear factor (NF-κκB) expression and (9) apoptosis induced by zymosan. Moreover, NADPH-oxidase inhibitors treatment significantly reduced the systemic toxicity, the loss in body weight and the mortality caused by zymosan. This study has shown that NADPH-oxidase inhibitors attenuate the degree of zymosan-induced non-septic shock in mice. [ABSTRACT FROM AUTHOR]

Abstract: Olprinone is a specific phosphodiesterase (PDE)-III inhibitor, which has been found to have anti-inflammatory effects in addition to its main inotropic and peripheral vasodilatory effects. In the present study we investigated the effects of olprinone (0.2mg/kg, i.p.) on the development of zymosan-induced multiple organ failure in mice. Treatment with olprinone attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan. Olprinone also attenuated the lung, liver and pancreatic injury, renal dysfunction as well as the increased lung and intestine myeloperoxidase (MPO) activity caused by zymosan. Immunohistochemical analysis for inducible nitric oxide synthase (iNOS), nitrotyrosine, poly(ADP-ribose) (PAR), tumor necrosis factor-α (TNF-α) and interleuchin-1β (IL-1β) revealed positive staining in pancreatic and intestinal tissue obtained from zymosan-injected mice. The degree of staining for nitrotyrosine, iNOS, PAR, TNF-α and IL-1β was markedly reduced in tissue sections obtained from zymosan-injected mice, which had received olprinone. In addition, administration of zymosan caused a severe illness in the mice characterized by significant loss of body weight and a 60% of mortality at the end of observation period (7 days). Treatment with olprinone significantly reduced the development of systemic toxicity, loss in body weight and mortality, caused by zymosan. This study provides evidence that olprinone attenuates the degree of zymosan-induced shock in mice. [Copyright &y& Elsevier]

Background and Purpose: Zymosan-induced non-septic shock is a multi-factorial pathology that involves several organs including the kidneys, liver and lungs. Its complexity and diversity presents a continuing therapeutic challenge. Given their pleiotropic effect, statins could be beneficial in non-septic shock. One of the molecular mechanisms underlying the anti-inflammatory effect of statins involves the peroxisome proliferator-activated receptor (PPAR) α. We used a zymosan-induced non-septic shock experimental model to investigate the role of PPARα in the anti-inflammatory effects of simvastatin.Experimental Approach: Effects of simvastatin (5 or 10 mg·kg(-1) i.p.) were analysed in PPARα knock-out (KO) and PPARα wild type (WT) mice after zymosan or vehicle administration. Organ injury in lung, liver, kidney and intestine was evaluated by immunohistology. PPARα mRNA expression and nuclear factor-κB activation were evaluated in all experimental groups, 18 h after study onset. Cytokine levels were measured in plasma, and nitrite/nitrate in plasma and peritoneal exudate. Nitric oxide synthase, nitrotyrosine and poly ADP-ribose were localized by immunohistochemical methods.Key Results: Simvastatin significantly and dose-dependently increased the zymosan-induced expression of PPARα levels in all tissues analysed. It also dose-dependently reduced systemic inflammation and the organ injury induced by zymosan in lung, liver, intestine and kidney. These effects were observed in PPARαWT mice and in PPARαKO mice.Conclusions and Implications: Simvastatin protected against the molecular and cellular damage caused by systemic inflammation in our experimental model. Our results also provide new information regarding the role of PPARα in the anti-inflammatory effects of statins. [ABSTRACT FROM AUTHOR]

NADPH-oxidase is an enzyme responsible for reactive oxygen species production, 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, NADPH-oxidase inhibitor, in the modulation of secondary injury in the spinal cord. The injury was induced by application of vascular clips to the dura via a four-level T5-T8 laminectomy in mice. Treatment with Apocynin 1 and 6 h after the trauma significantly decreased (1) the degree of spinal cord inflammation and tissue injury, (2) neutrophil infiltration, (3) adhesion molecule expression, (4) nuclear transcription factor-κB expression, (5) nitrotyrosine and poly-ADP-ribose formation, (6) pro-inflammatory cytokines production, (7) apoptosis and (8) mitogen-activated protein kinase activation. Moreover, Apocynin significantly ameliorated the loss of limb function (evaluated by motor recovery score). Thus, it is proposed that Apocynin may be useful in the treatment of inflammation associated with spinal cord trauma. [ABSTRACT FROM AUTHOR]

Abstract: Coronary ischemia and subsequent reperfusion result in deleterious effects, one of the principal ones being vascular and myocardial inflammation. Olprinone hydrochloride, a specific phosphodiesterase III inhibitor, has anti-inflammatory effects in addition to its inotropic and vasodilator effects. The purpose of this study was to examine the beneficial effects of olprinone on myocardial ischemia–reperfusion injury. Myocardial ischemia–reperfusion injury was caused by clamping the LAD (left anterior descending) coronary artery for 25min followed by a release of the clamp allowing reperfusion for 1h. Olprinone i.p. (0.2mg/kg, i.p.) was administrated 15min after ischemia. The olprinone administration significantly reduced the: (1) histological evidence of myocardial injury, (2) pro-inflammatory cytokines: tumor necrosis factor-α (TNF-α) and Interleukin-1β (IL-1β), (3) adhesion molecules: Inter-Cellular Adhesion Molecule 1 (ICAM-1) and P-Selectin, (4) nitrotyrosine formation, (5) nuclear factor kappa-B (NF-κB) expression, (6) Poly (ADP-ribose) (PAR) formation, and (7) apoptosis (Bax, Bcl-2, Fas-L and terminal deoxynucleotidyl transferase-mediated UTP end labeling (TUNEL). Based on these findings this study provides the evidence that treatment with olprinone ameliorated the inflammatory process associated with myocardial ischemia–reperfusion in rats and suggests that this drug may have potential in the treatment of various ischemia and reperfusion diseases. [ABSTRACT FROM AUTHOR]

We have investigated the effects of WY14643, a potent peroxisome proliferator activator receptor-α (PPAR-α) agonist, in a rat model of ligature-induced periodontitis. Male Sprague-Dawley rats were lightly anaesthetized with pentobarbitone (35mg/kg). Sterile, 2-0 black braided silk thread was placed around the cervix of the lower left first molar and knotted medially. Animals received WY14643 (1mg/kg i.p, daily for eight days). Eighths days after placement of the ligature, we evaluated several markers of inflammation such us (1) myeloperoxidase activity, (2) a cytokines and adhesion molecules expression, (3) NF-κB expression, (4) iNOS expression, (5) the nitration of tyrosine residues, (6) activation of the nuclear enzyme poly(ADP-ribose) polymerase, (7) apoptosis, and (8) the degree of gingivomucosal tissues injury. Administration of WY14643 significantly decreased all of the parameters of inflammation as described above. These results demonstrate that WY14643 exerts an anti-inflammatory role during experimental periodontitis and is able to ameliorate the tissue damage. [ABSTRACT FROM AUTHOR]

The aim of the present study was to assess the effect of a metalloporphyrinic peroxynitrite decomposition catalyst, ww-85, in the pathophysiology of spinal cord injury (SCI) in mice. Spinal cord trauma was induced by the application of vascular clips to the dura via a four-level T5-T8 laminectomy. SCI in mice resulted in severe trauma characterized by oedema, neutrophil infiltration, production of inflammatory mediators, tissue damage and apoptosis. ww-85 treatment (30-300 µg/kg, i.p. 1 h after the SCI) significantly reduced in a dose-dependent manner: (1) the degree of spinal cord inflammation and tissue injury, (2) neutrophil infiltration (myeloperoxidase activity), (3) nitrotyrosine formation and PARP activation, (4) pro-inflammatory cytokines expression, (5) NF-κB activation and (6) apoptosis. Moreover, ww-85 significantly ameliorated the recovery of limb function (evaluated by motor recovery score) in a dose-dependent manner. The results demonstrate that ww-85 treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma. [ABSTRACT FROM AUTHOR]

Interleukin-10 (IL-10) exerts a wide spectrum of regulatory activities in the immune and inflammatory response. The aim of this study was to investigate the role of endogenous IL-10 on the modulation of the secondary events in mice subjected to spinal cord injury induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5–T8 laminectomy. IL-10 wild-type mice developed severe spinal cord damage characterized by oedema, tissue damage and apoptosis (measured by Annexin-V, terminal deoxynucleotidyltransferase-mediated UTP end labeling staining, Bax, Bcl-2, and Fas-L expression). Immunohistochemistry demonstrated a marked increase of localization of TNF-α, IL-1β and S100β, while western blot analysis shown an increased immunoreactivity of inducible nitric oxide synthase in the spinal cord tissues. The absence of IL-10 in IL-10 KO mice resulted in a significant augmentation of all the above described parameters. We have also demonstrated that the genetic absence of IL-10 worsened the recovery of limb function when compared with IL-10 wild-type mice group (evaluated by motor recovery score). Taken together, our results clearly demonstrate that the presence of IL-10 reduces the development of inflammation and tissue injury events associated with spinal cord trauma. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) are associated with matrix turnover in both physiological and pathological conditions. Several data indicate that MMPs play an important role in the pathogenesis of colitis. Various evidence has documented that the pineal secretory product melatonin exerts an important anti-inflammatory effect in different experimental models including colitis. However, no reports are available on the relationship between the activity and expression of MMPs and anti-inflammatory effect of melatonin. The aim of the present study was to evaluate whether melatonin prevents the experimental colitis in rats by regulating MMP-9 and MMP-2 activity and expression. Colitis was induced by intracolonic instillation of dinitrobenzene sulphonic acid (DNBS). Four days after DNBS administration, colon TNF- α production was associated with colon damage. Biochemical methods and zymography were used to analyse MMP-9 and MMP-2 activities in colon tissues from DNBS-injured rats. Our studies reveal that melatonin prevented colon injury and lipid peroxidation in rats at 4 days after DNBS-induced colitis. Melatonin also reduced proMMP-9 and MMP-2 activities that were induced in the colon tissues by DNBS administration. Reduced MMP-9 and MMP-2 activities were associated with reduced expression of TNF- α. We conclude that melatonin’s ability to reduce DNBS-induced colon injury in rats is related to a reduction in proMMP-9 and MMP-2 activities and expression. [ABSTRACT FROM AUTHOR]

Abstract: Poly(ADP-ribose) is synthesized from nicotinamide adenine dinucleotide (NAD) by poly(ADP-ribose) polymerase 1 (PARP-1) and degraded by poly(ADP-ribose) glycohydrolase (PARG). The aim of the present study was to examine the role of PARG in the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). Mice lacking the functional 110-kDa isoform of PARG (PARG110KO mice) were resistant to colon injury induced by DNBS. The mucosa of colon tissues showed reduction of myeloperoxidase activity and attenuated staining for intercellular adhesion molecule 1 and vascular cell adhesion molecule 1. Moreover, overproduction of proinflammatory factors TNF-α and IL-1β and activation of cell death signaling pathway, i.e., the FAS ligand, were inhibited in these mutant mice. Finally pharmacological treatment of WT mice with GPI 16552 and 18214, two novel PARG inhibitors, showed a significant protective effect in DNBS-induced colitis. These genetic and pharmacological studies demonstrate that PARG modulates the inflammatory response and tissue injury events associated with colitis and PARG may be considered as a novel target for pharmacological intervention for the pathogenesis. [Copyright &y& Elsevier]