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One of the most used chemotherapy agents in clinical practice is 5-Fluorouracil (5-FU), a fluorinated pyrimidine in the category of antimetabolite agents. 5-FU is used to treat a variety of cancers, including colon, breast, pancreatic, and stomach cancers, and its efficacy lies in its direct impact on the patient's DNA and RNA. Specifically, its mechanism blocks the enzymes thymidylate synthetase and uracil phosphatase, inhibiting the synthesis of uracil, which cannot be incorporated into nuclear and cytoplasmic RNA. Despite being one of the most used drugs in oncology, it is associated with several significant side effects, including inflammation of the mouth, loss of appetite, and reduction in blood cells. In our study, we examined the reduction of side effects in a 5-FU regimen administered at doses of 15 mg/kg and 6 mg/kg for 14 days in 6-week-old male Sprague-Dawley rats. On the 14th day, the rats were treated orally for 2 weeks with 100 mg/kg of Ulva pertusa , a well-known seaweed from the Ulvaceae family, which has demonstrated powerful biological properties. The administration of this green alga alleviated the side effects of 5-FU, improving several parameters including body weight, food intake, and diarrhea index. It also helped reduce side effects in the blood, kidneys, and liver. Histological and molecular analyses were conducted on serum and colon tissues from the rats, examining changes in colon structure and the release of oxidative stress markers such as iNOS, COX-2, and nitrotyrosine. Several biochemical indicators, including SOD, CAT, GSH, MDA, and ascorbic acid, were also evaluated. Overall, our data indicated Ulva pertusa to be a promising therapeutic against 5-FU's adverse effects, therefore, it could be worthwhile to investigate the possibility of using this alga in safer cancer treatment formulations. Certainly, future preclinical and clinical studies could assess the alga's efficacy in diverse cancer treatment regimens, exploring its role as an adjuvant therapy that may reduce chemotherapy-related toxicity without compromising therapeutic outcomes.

The term "inflammatory bowel disease" (IBD) describes a class of relapse-remitting conditions that affect the gastrointestinal (GI) tract. Among these, Crohn's disease (CD) and ulcerative colitis (UC) are two of the most globally prevalent and debilitating conditions. Several articles have brought attention to the significant role that inflammation and oxidative stress cooperatively play in the development of IBD, offering a different viewpoint both on its etiopathogenesis and on strategies for the effective treatment of these conditions. Marine ecosystems may be a significant source of physiologically active substances, supporting the search for new potential clinical therapeutics. Based on this evidence, this review aims to comprehensively evaluate the activity of marine algae and deriving biomolecules in decreasing pathological features of CD and UC. To match this purpose, a deep search of the literature on PubMed (MEDLINE) and Google Scholar was performed to highlight primary biological mechanisms, the modulation of inflammatory and oxidative stress biochemical parameters, and potential clinical benefits deriving from marine species. From our findings, both macroalgae and microalgae have shown potential as therapeutic solutions for IBD due to their bioactive compounds and their anti-inflammatory and antioxidant activities which are capable of modulating markers such as cytokines, the NF-κB pathway, reactive oxidative and nitrosative species (ROS and RNS), trefoil factor 3 (TFF3), lactoferrin, SIRT1, etc. However, while we found promising preclinical evidence, more extensive and long-term clinical studies are necessary to establish the efficacy and safety of marine algae for IBD treatment.

Several reports have demonstrated the effectiveness of pistachio against oxidative stress and inflammation. In this study, we investigate if polyphenols extracts from natural raw shelled pistachios (NP) or roasted salted pistachio (RP) kernels have anti-inflammatory and antioxidant properties at lower doses than reported previously, in both in vitro and in vivo models. The monocyte/macrophage cell line J774 was used to assess the extent of protection by NP and RP pistachios against lipopolysaccharide (LPS)-induced inflammation. Moreover, antioxidant activity of NP and RP was assessed in an in vivo model of paw edema in rats induced by carrageenan (CAR) injection in the paw. Results from the in vitro study demonstrated that pre-treatment with NP (0.01, 0.1 and 0.5 mg/mL) and RP (0.01 and 0.1 mg/mL) exerted a significant protection against LPS induced inflammation. Western blot analysis showed NP reduced the degradation of IκB-α, although not significantly, whereas both NP and RP decreased the TNF-α and IL-1β production in a dose-dependent way. A significant reduction of CAR-induced histological paw damage, neutrophil infiltration and nitrotyrosine formation was observed in the rats treated with NP. These data demonstrated that, at lower doses, polyphenols present in pistachios possess antioxidant and anti-inflammatory properties. This may contribute toward a better understanding of the beneficial health effects associated with consumption of pistachios., Competing Interests: The authors declare no conflict of interest. Author disclosures: AC is scientific advisor for American Pistachio Growers.

Cnidarian toxins represent a rich source of biologically active compounds. Since they may act via oxidative stress events, the aim of the present study was to verify whether crude venom, extracted from the jellyfish Pelagia noctiluca, elicits inflammation and oxidative stress processes, known to be mediated by Reactive Oxygen Species (ROS) production, in rats. In a first set of experiments, the animals were injected with crude venom (at three different doses 6, 30 and 60 µg/kg, suspended in saline solution, i.v.) to test the mortality and possible blood pressure changes. In a second set of experiments, to confirm that Pelagia noctiluca crude venom enhances ROS formation and may contribute to the pathophysiology of inflammation, crude venom-injected animals (30 µg/kg) were also treated with tempol, a powerful antioxidant (100 mg/kg i.p., 30 and 60 min after crude venom). Administration of tempol after crude venom challenge, caused a significant reduction of each parameter related to inflammation. The potential effect of Pelagia noctiluca crude venom in the systemic inflammation process has been here demonstrated, adding novel information about its biological activity.

Aim: The aim of the present study was to examine the effects of 3,5-dicaffeoyl-4-malonylquinic acid (CA1), extract from Centella Asiatica, in rats subjected to experimental colitis., Results: Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulphonic acid (DNBS). CA1 was administered daily orally (0.2 or 2 mg/kg). Four days after DNBS administration, treatment with CA1 significantly reduced the appearance of diarrhoea and the loss of body weight. This was associated with a significant reduction in colonic MPO activity. CA1 also reduced NF-kappaB activation, the pro-inflammatory cytokines release, the appearance of I-NOS, nitrotyrosine, PARP and proMMP-9 and -2 activity in the colon and reduced the up-regulation of ICAM-1 and the expression of P-Selectin., Conclusions: The results of this study suggested that administration of CA1 may be beneficial for treatment of inflammatory bowel disease.

The effective treatment of pain is typically limited by a decrease in the pain-relieving action of morphine that follows its chronic administration (tolerance). Therefore, restoring opioid efficacy is of great clinical importance. In a murine model of opioid antinociceptive tolerance, repeated administration of morphine significantly stimulated the enzymatic activities of spinal cord serine palmitoyltransferase, ceramide synthase, and acid sphingomyelinase (enzymes involved in the de novo and sphingomyelinase pathways of ceramide biosynthesis, respectively) and led to peroxynitrite-derive nitroxidative stress and neuroimmune activation [activation of spinal glial cells and increase formation of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6]. Inhibition of ceramide biosynthesis with various pharmacological inhibitors significantly attenuated the increase in spinal ceramide production, nitroxidative stress, and neuroimmune activation. These events culminated in a significant inhibition of the development of morphine antinociceptive tolerance at doses devoid of behavioral side effects. Our findings implicate ceramide as a key upstream signaling molecule in the development of morphine antinociceptive tolerance and provide the rationale for development of inhibitors of ceramide biosynthesis as adjuncts to opiates for the management of chronic pain.

Melatonin (N-acetyl-5-methoxytryptamine), an indole hormone, is the chief secretory product of the pineal gland and 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. Although melatonin is reported to influence a variety of inflammatory and immune responses, evidence supporting its effects on important glioma cells-derived mediators is incomplete. We studied, in rat glioma cell line (C6), the role of melatonin (100 microm-1 mm) in the regulation of the expression of nitric oxide synthase (NOS) caused by incubation with lipopolysaccharide (LPS)/interferon (IFN)-gamma (1 microg/mL and 100 U/mL, respectively) and defined the mode of melatonin's action. Treatment with LPS/IFN-gamma for 24 hr elicited the induction of inducible (iNOS) activity as determined by nitrite and nitrate (NO(x)) accumulation in the culture medium. Preincubation with melatonin abrogated the mixed cytokines-mediated induction of iNOS. The effect of melatonin was concentration-dependent. Moreover, Western blot analysis showed that melatonin inhibited LPS/IFN-gamma-induced expression of COX-2 protein, but not that of constitutive cyclooxygenase. Inhibition of iNOS and COX-2 expression was associated with inhibition of activation of the transcription factor nuclear factor kappa B (NF-kappaB). The ability of melatonin to inhibit NF-kappaB activation was further confirmed by studies on the degradation of the inhibitor of NF-kappaB, IkappaB-alpha. Increased production of lipid peroxidation products using thiobarbituric acid assay were found in cellular contents from activated cultures. Lipid peroxidation was decreased by melatonin treatment in a concentration-dependent manner. Moreover, several genes having roles in heat-shock response were downregulated in melatonin-treated cells, such as 70 proteins, reflecting the reduced oxidative stress in these cells. The mechanisms underlying in vitro the neuroprotective properties of melatonin involve modulation of transcription factors and consequent altered gene expression, resulting in downregulation of inflammation.

Gastroesophageal reflux disease (GERD) represents one of the most prevalent foregut illnesses, affecting a large portion of individuals worldwide. Recent research has shown that inflammatory mediators such as cytokines, chemokines, and enzymes are crucial for causing esophageal mucosa alterations in GERD patients. It seems likely that the expression of various cytokines in the esophageal mucosa also induces oxidative stress by increasing the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). As humoral agents and peptidergic neurotransmitters that may support the enterogastric axis, bombesin and its related bombesin-like peptide, GRP (gastrin releasing peptide), have not been fully investigated. Therefore, considering all these assumptions, this study aimed to evaluate the influence of bombesin in reestablishing biochemical markers linked with inflammation and oxidative/nitrosative stress in GERD pathological settings. C57BL/6 mice were alternatively overfed and fasted for 56 days to induce GERD and then treated with bombesin (0.1, 0.5, and 1 mg/kg intraperitoneally) once daily for 7 days, and omeprazole was used as the positive control. After 7 days of treatment, gastric pain and inflammatory markers were evaluated. Abdominal pain was significantly reduced following bombesin administration, which was also successful in diminishing inflammatory and oxidative/nitrosative stress markers in a manner overlapping with omeprazole. Moreover, bombesin was also able to appreciably modulate gastric pH as a result of the restoration of gastric homeostasis. Overall, these observations indicated that the upregulation of bombesin and interconnected peptides is a promising alternative approach to treat GERD patients. [ABSTRACT FROM AUTHOR]

The flavonoid-rich fraction of bergamot juice (BJe) has demonstrated anti-inflammatory and antioxidant activities. The aim of work was to test the beneficial effects of BJe on the modulation of the ileum inflammation caused by intestinal ischemia/reperfusion (I/R) injury in mice. To understand the cellular mechanisms by which BJe may decrease the development of intestinal I/R injury, we have evaluated the activation of signaling transduction pathways that can be induced by reactive oxygen species production. Superior mesenteric artery and celiac trunk were occluded for 30 min and reperfused for 1 h. The animals were sacrificed after 1 h of reperfusion, for both histological and molecular examinations of the ileum tissue. The experimental results demonstrated that BJe was able to reduce histological damage, cytokines production, adhesion molecules expression, neutrophil infiltration and oxidative stress by a mechanism involved both NF-kB and MAP kinases pathways. This study indicates that BJe could represent a new treatment against inflammatory events of intestinal I/R injury. [ABSTRACT FROM AUTHOR]

The prevalence of obesity is rapidly rising around the world, and this will have a significant impact on our society as it is believed to be one of the leading causes of death. One of the main causes of these occurrences is added sugar consumption, which is associated with a higher risk of obesity, heart disease, diabetes, and brain illnesses such as Alzheimer's disease (AD). To this purpose, excess sugar might worsen oxidative damage and brain inflammation: two neuropathological signs of AD. Dimethyl fumarate (DMF) is an orally accessible methyl ester of fumaric acid with putative neuroprotective and immunomodulatory properties. In addition, DMF stimulates the nuclear factor erythroid 2-related factor 2 (Nrf-2), a key regulator of the antioxidant response mechanism in cells. The aim of the current study was to assess the potential therapeutic benefits of DMF in an in vitro model of metabolic stress induced by high and low sugar levels. We discovered that DMF reversed the negative impacts of high and low glucose exposure on the viability and oxidative stress of SH-SY5Y cells. Mechanistically, DMF's actions were mediated by Nrf-2. To this end, we discovered that DMF boosted the expression of the Nrf-2-regulated genes heme-oxygenase-1 (HO1) and manganese superoxide dismutase (MnSOD). More importantly, we found that inhibiting Nrf-2 expression prevented DMF's positive effects. Our combined findings suggest that DMF may be a valuable support for treatments for metabolic diseases. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is the most common chronically relapsing inflammatory skin disease, predominantly common in children; it is characterized by an eczematous pattern generally referable to skin dryness and itchy papules that become excoriated and lichenified in the more advanced stages of the disease. Although the pathophysiology of AD is not completely understood, numerous studies have demonstrated the complex interaction between genetic, immunological, and environmental factors, which acts to disrupt skin barrier function. Free radicals play a key role by directly damaging skin structure, inducing inflammation and weakening of the skin barrier. Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a membrane-permeable radical scavenger, known to be a stable nitroxide, which exhibits excellent antioxidant effects in several human disorders, such as osteoarthritis and inflammatory bowel diseases. Considering the few existing studies on dermatological pathologies, this study aimed to evaluate tempol, in a cream formulation, in a murine model of AD. Dermatitis was induced in mice via dorsal skin application of 0.5% Oxazolone, three times a week for two weeks. After induction, mice were treated with tempol-based cream for another two weeks at three different doses of 0.5%, 1% and 2%. Our results demonstrated the ability of tempol, at the highest percentages, to counteract AD by reducing the histological damage, decreasing mast cell infiltration, and improving the skin barrier properties, by restoring the tight junction (TJs) and filaggrin. Moreover, tempol, at 1% and 2%, was able to modulate inflammation by reducing the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway, as well as tumor necrosis factor (TNF)-α and interleukin (IL)-1β expression. Topical treatment also attenuated oxidative stress by modulating nuclear factor erythroid 2-related factor 2 (Nrf2), manganese superoxide dismutase (MnSOD), and heme oxygenase I (HO-1) expression levels. The obtained results demonstrate the numerous advantages provided by the topical administration of a tempol-based cream formulation, in reducing inflammation and oxidative stress through modulation of the NF-κB/Nrf2 signaling pathways. Therefore, tempol could represent an alternative anti-atopic approach to treating AD, thereby improving skin barrier function. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a disorder that is characterized by progressive and selective neuronal injury and cell death. Recent studies have provided accumulating evidence for a significant role of the immune system and neuroinflammation in PD pathogenesis. On this basis, many scientific articles have highlighted the anti-inflammatory and neuroprotective properties of Antrodia camphorata (AC), an edible fungus containing various bioactive compounds. This study aimed to evaluate the inhibitory effect of AC administration on neuroinflammation and oxidative stress in a murine model of MPTP-induced dopaminergic degeneration. AC (10, 30, 100 mg/kg) was administered daily by oral gavage starting 24 h after the first administration of MPTP, and mice were sacrificed 7 days after MPTP induction. In this study, treatment with AC significantly reduced the alteration of PD hallmarks, increasing tyrosine hydroxylase expression and reducing the number of alpha-synuclein-positive neurons. In addition, AC treatment restored the myelination process of neurons associated with PD and attenuated the neuroinflammatory state. Furthermore, our study demonstrated that AC was able to reduce the oxidative stress induced by MPTP injection. In conclusion, this study highlighted that AC could be a potential therapeutic agent for the treatment of neurodegenerative disorders such as PD. [ABSTRACT FROM AUTHOR]

It is estimated that 10–50% of interventions can generate persistent post-surgical pain. Chronic post-mastectomy pain is a condition persisting for at least three months after surgery. It has been shown that physical activity in the cancer patient allows the improvement of the pain symptom. The aim of this study was to evaluate the effects of physical activity on the intensity and interference of chronic pain in the quality of life of women underwent mastectomy needed for breast cancer removal. The secondary objective was to measure the effects of physical activity on inflammatory and oxidative markers in the same population. A Numeric Rating Scale (NRS) was used to assess pain intensity, and Brief Inventory Pain (BIP) was used for assessing interference of pain in quality of life. Physical activity was measured with the International Physical Activity Questionnaire (IPAQ). Inflammatory mediators such as interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, c-reactive protein (CRP), and biomarkers of oxidative stress malondialdehyde (MDA), superoxide dismutase (SOD), and catalase (CAT) were evaluated in the blood of patients. All the evaluations were performed after three and six months after surgery. Results showed that adequate physical activity can diminish intensity and interference of pain and that these effects are associated with a reduction of blood biomarkers of inflammation. [ABSTRACT FROM AUTHOR]

Oral squamous cell carcinoma (OSCC) is a common human tumor, that originates from buccal mucosa and the tongue, associated with a high mortality rate. Currently, the treatment for OSCC involves surgery, chemotherapy and radiotherapy; however, survival outcomes for OSCC patients remain poor. For this reason, it is necessary to investigate new therapeutic strategies to counteract the progression of OSCC. In this study, we aimed to evaluate the role of dimethyl fumarate (DMF) in modulation of OSCC progression, both in vitro and in an in vivo orthotopic xenograft model. In vitro results revealed that DMF was able to reduce the expression of anti-apoptotic factors as BCL-2 and increased the expression of pro-apoptotic factors as Bax, Caspase-3 and BID. DMF appears to be involved in the modulation of oxidative stress mediators, such as MnSOD and HO-1. Furthermore, DMF showed to reduce the migratory ability of tumor cells and to modulate the expression of markers of epithelial-mesenchymal transition (EMT), as N-cadherin and E-cadherin. The in vivo study confirmed the data obtained in vitro significantly decreasing tumor mass and also reducing oxidative stress and apoptosis. Therefore, based on these results, the use of DMF could be considered a promising strategy to counteract oral cancer progression. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a devastating event followed by neurodegeneration, activation of the inflammatory cascade, and immune system. The leucine-rich-repeat kinase 2 (LRRK2) is a gene associated with Parkinson's disease (PD), moreover, its kinase activity was found to be upregulated after instigated inflammation of the central nervous system (CNS). Here, we aimed to investigate the PF06447475 (abbreviated as PF-475) role as a pharmacological LRRK2 antagonist by counteracting pathological consequences of spinal cord trauma. The in vivo model of SCI was induced by extradural compression of the spinal cord, then mice were treated with PF0-475 (2.5–5 and 10 mg/kg i.p) 1 and 6 h after SCI. We found that PF-475 treatments at the higher doses (5 and 10 mg/kg) showed a great ability to significantly reduce the degree of spinal cord tissue injury, glycogen accumulation, and demyelination of neurons associated with trauma. Furthermore, oxidative stress and cytokines expression levels, including interleukins (IL-1, IL-6, IL-10, and 12), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α), secreted and released after trauma were decreased by LRRK2 antagonist treatments. Our results suggest that the correlations between LRRK2 and inflammation of the CNS exist and that LRRK2 activity targeting could have direct effects on the intervention of neuroinflammatory disorders. [ABSTRACT FROM AUTHOR]

Abstract: Alzheimer disease (AD) is characterized by a complex heterogeneity of pathological changes, and any therapeutic approach categorically requires a multi‐targeted way. It has been demonstrated that together with the hallmarks of the disease such as neurofibrillary tangles and senile plaques, oxidative and inflammatory stress covered an important role. Dimethyl fumarate (DMF) is an orally bioavailable methyl ester of fumaric acid and activator of Nrf2 with potential neuroprotective and immunomodulating activities. Therefore, the aim of the present work was to evaluate the potential beneficial effects of DMF, compared with its active metabolite monomethyl fumarate (MMF) (both at 30 μM) in an in vitro Alzheimer's model using SH‐SY5Y human neuroblastoma cell lines stimulated with amyloid‐beta (Aβ). Moreover, the effect of DMF, compared with MMF, was evaluate by an ex vivo model using organotypic hippocampal slice cultures stimulated with Aβ1‐42 (1 μg/ml), to better understand its action in a pathological setting. In both models, DMF pre‐treatment (30 μM) preserved cellular viability from Aβ stimulation, reducing tau hyper‐phosphorylation, much more efficiently then MMF (30 μM). Moreover, DMF was able to induce an activation of manganese superoxide dismutase (MnSOD) and heme‐oxygenase‐1 (HO‐1), decreasing the severity of oxidative stress. Our results showed important multi‐protective effects of DMF pre‐treatment from Aβ stimulation both in in vitro and ex vivo models, highlighting an Nrf2/NF‐κB‐dependent mechanism, which could provide a valuable support to the therapies for neurodegenerative diseases today. [ABSTRACT FROM AUTHOR]

Vascular dementia (VaD), the second most common cause of cognitive impairment in the population, is a disease that results from reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Co-ultramicronized PEALut (co-ultra PEALut) is a new compound with beneficial effects, which include anti-inflammatory and antioxidant properties. Recently, co-ultraPEALut has been shown to exhibit neuroprotective effects in models of Parkinson's disease, cerebral ischemia and Alzheimer's disease. However, its effects on VaD remain unknown. Therefore, the purpose of the present study was to highlight the potential neuroprotective actions of co-ultraPEALut containing N-palmitoylethanolamine (PEA) and the antioxidant flavonoid luteolin (Lut) (10:1 by mass) in a mouse model of VaD induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, mice were orally treated with 1 mg/kg co-ultraPEALut daily for 15 days. On the 15th day, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Our results clearly demonstrate that co-ultraPEALut improved learning, memory ability, locomotor activity, and the reciprocal social interaction. In addition, the mice subjected to VaD and treated with the co-ultraPEALut showed a reorganization of CA1 and CA3 regions of the hippocampus and restored the number of hippocampal neurons as evidenced by NeuN expression, a specific marker of neurons. Furthermore following carotid arteries ligation, mice treated with co-ultraPEALut showed a modification of proinflammatory, proapoptotic proteins and of oxidative stress as evidenced by the expression of IκB-α, NF-κB p65, Bax, Bcl-2, inducible nitric oxide synthase, and cyclooxygenase-2. In order, co-ultraPEALut treatment restored VaD-induced loss of brain-derived neurotrophic factor and neurotrophins 3 (NT-3) expression in mice. These results confirmed that the neuroprotective effects of co-ultraPEALut were associated with its anti-inflammatory and antioxidant properties. [ABSTRACT FROM AUTHOR]

The flavonoid-rich fraction of bergamot juice (BJe) has demonstrated anti-inflammatory and antioxidant activities. The aim of work was to test the beneficial effects of BJe on the modulation of the ileum inflammation caused by intestinal ischemia/reperfusion (I/R) injury in mice. To understand the cellular mechanisms by which BJe may decrease the development of intestinal I/R injury, we have evaluated the activation of signaling transduction pathways that can be induced by reactive oxygen species production. Superior mesenteric artery and celiac trunk were occluded for 30 min and reperfused for 1 h. The animals were sacrificed after 1 h of reperfusion, for both histological and molecular examinations of the ileum tissue. The experimental results demonstrated that BJe was able to reduce histological damage, cytokines production, adhesion molecules expression, neutrophil infiltration and oxidative stress by a mechanism involved both NF-кB and MAP kinases pathways. This study indicates that BJe could represent a new treatment against inflammatory events of intestinal I/R injury. [ABSTRACT FROM AUTHOR]

Introduction:This review briefly summarizes some of the large amount of data documenting the ability of melatonin to limit molecular and organ tissue damage in neural ischemia-reperfusion injury (stroke), where free radicals are generally considered as being responsible for much of the resulting tissue destruction. Area Covered:Melatonin actions that have been identified include its ability to directly neutralize a number of toxic reactants and stimulate antioxidative enzymes. Furthermore, several of its metabolites such as N1-acetyl-N2-formyl-5- methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMF), are themselves scavengers suggesting that there is a cascade of reactions that greatly increase the efficacy of melatonin. Expert Commentary:However, the mechanisms by which melatonin is protective in such widely diverse areas of the cell and different organs are likely not yet all identified. [ABSTRACT FROM PUBLISHER]

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]

Polyphenols have been described to have a wide range of biological activities, and many reports, published during recent years, have highlighted the beneficial effects of phenolic compounds, illustrating their promising role as therapeutic tools in several acute and chronic disorders. The purpose of study was to evaluate, in an already-assessed model of lung injury caused by bleomycin (BLM) administration, the role of resveratrol and quercetin, as well as to explore the potential beneficial properties of a mango leaf extract, rich in mangiferin, and a grape leaf extract, rich in dihydroquercetin (DHQ), on the same model. Mice were subjected to intra-tracheal administration of BLM, and polyphenols were administered by oral route immediately after BLM instillation and daily for 7 d. Treatment with resveratrol, mangiferin, quercetin and DHQ inhibited oedema formation and body weight loss, as well as ameliorated polymorphonuclear infiltration into the lung tissue and reduced the number of inflammatory cells in bronchoalveolar lavage fluid. Moreover, polyphenols suppressed inducible nitric oxide synthase expression, and prevented oxidative and nitroxidative lung injury, as shown by the reduced nitrotyrosine and poly (ADP-ribose) polymerase levels. The degree of apoptosis, as evaluated by Bid and Bcl-2 balance, was also suppressed after polyphenol treatment. Finally, these natural products down-regulated cyclo-oxygenase-2, extracellular signal-regulated kinase phosphorylated expression and reduced NF-κBp65 translocation. Our findings confirmed the anti-inflammatory effects of resveratrol and quercetin in BLM-induced lung damage, and highlight, for the first time, the protective properties of exogenous administration of mangiferin and DHQ on experimental pulmonary fibrosis. [ABSTRACT FROM PUBLISHER]

Abstract: Chronic inflammation and oxidative stress, features that are closely associated with nuclear factor (NF-?B) activation, play a key role in the development and progression of chronic kidney disease (CKD). Several animal models and clinical trials have clearly demonstrated the effectiveness of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy to improve glomerular/tubulointerstitial damage, reduce proteinuria, and decrease CKD progression, but CKD treatment still represents a clinical challenge. Bardoxolone methyl, a first-in-class oral Nrf-2 (nuclear factor erythroid 2-related factor 2) agonist that until recently showed considerable potential for the management of a range of chronic diseases, had been shown to improve kidney function in patients with advanced diabetic nephropathy (DN) with few adverse events in a phase 2 trial, but a large phase 3 study in patients with diabetes and CKD was halted due to emerging toxicity and death in a number of patients. Instead, palmitoylethanolamide (PEA) a member of the fatty acid ethanolamine family, is a novel non-steroidal, kidney friendly anti-inflammatory and anti-fibrotic agent with a well-documented safety profile, that may represent a potential candidate in treating CKD probably by a combination of pharmacological properties, including some activity at the peroxisome proliferator activated receptor alpha (PPAR-?). The aim of this review is to discuss new therapeutic approaches for the treatment of CKD, with particular reference to the outcome of two therapies, bardoxolone methyl and PEA, to improve our understanding of which pharmacological properties are responsible for the anti-inflammatory effects necessary for the effective treatment of renal disease. [Copyright &y& Elsevier]

Background Two families of polyunsaturated fatty acid (PUFA), omega-3 (ω-3) and omega-6 (ω-6), are required for physiological functions. The long chain ω-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have significant biological effects. In particular, DHA is a major component of cell membranes in the brain. It is also involved in neurotransmission. Spinal cord injury (SCI) is a highly devastating pathology that can lead to catastrophic dysfunction, with a significant reduction in the quality of life. Previous studies have shown that EPA and DHA can exert neuroprotective effects in SCI in mice and rats. The aim of this study was to analyze the mechanism of action of ω-3 PUFAs, such as DHA, in a mouse model of SCI, with a focus on the early pathophysiological processes. Methods In this study, SCI was induced in mice by the application of an aneurysm clip onto the dura mater via a four-level T5 to T8 laminectomy. Thirty minutes after compression, animals received a tail vein injection of DHA at a dose of 250 nmol/kg. All animals were killed at 24 h after SCI, to evaluate various parameters implicated in the spread of the injury. Results Our results in this in-vivo study clearly demonstrate that DHA treatment reduces key factors associated with spinal cord trauma. Treatment with DHA significantly reduced: (1) the degree of spinal cord inflammation and tissue injury, (2) pro-inflammatory cytokine expression (TNF-α), (3) nitrotyrosine formation, (4) glial fibrillary acidic protein (GFAP) expression, and (5) apoptosis (Fas-L, Bax, and Bcl-2 expression). Moreover, DHA significantly improved the recovery of limb function. Furthermore, in this study we evaluated the effect of oxidative stress on dorsal root ganglion (DRG) cells using a well-characterized in-vitro model. Treatment with DHA ameliorated the effects of oxidative stress on neurite length and branching. Conclusions Our results, in vivo and in vitro, clearly demonstrate that DHA treatment reduces the development of inflammation and tissue injury associated with spinal cord trauma. [ABSTRACT FROM AUTHOR]

Background: It has recently been demonstrated that palmitoylethanolamide (PEA), an endogenous lipid amide belonging to the N-acylethanolamine family, exerts neuroprotection in central nervous system (CNS) pathologies. In recent studies, we have demonstrated that treatment with PEA significantly reduced inflammatory secondary events associated with spinal cord injury (SCI). Since oxidative stress is considered to play an important role in neuroinflammatory disorders, in the present work we studied a new composite, a formulation including PEA and the antioxidant compound luteolin (Lut), subjected to an ultramicronization process, co-ultraPEALut. We investigated the effect of co-ultraPEALut (in the respective fixed doses of 10:1 in mass) in both an ex vivo organotypic spinal cord culture model and an in vivo model of SCI. Methods: For the organotypic cultures, spinal cords were prepared from mice at postnatal day 6 and were cut into transverse slices of 400 μm thickness to generate the lumbar organotypic slice cultures. After 7 days of culturing, the slices were mechanically injured onto the center of the slice and the co-ultraPEALut was applied at different concentrations (0.00009, 0.0009 and 0.009 g/l) 1 hour before damage. For in vivo studies, SCI was induced in mice through spinal cord compression by the application of vascular clips (force of 24 g) to the dura via a four-level T5 to T8 laminectomy, and co-ultraPEALut (1 mg/kg ip) was administered at 1 and 6 hours after SCI. At 24 hours after SCI, mice were sacrificed and the spinal cords were collected for further evaluation. Additional animals were treated similarly and sacrificed 10 days after SCI. Results: Pretreatment with co-ultraPEALut significantly reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner, restored neuronal nitric oxide synthase (nNOS) expression at all three tested concentrations, and protected cells by cell death (MTT assay) in spinal cord organotypic cultures. Moreover, we demonstrated in vivo that co-ultraPEALut 1 mg/kg reduced the severity of trauma induced by compression and improved the motor activity evaluated at 10 days post-injury. Conclusion: The present study demonstrates that the protective effect of PEA on SCI-associated neuroinflammation could be improved by co-ultramicronization with Lut possibly due to its antioxidant properties. [ABSTRACT FROM AUTHOR]

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]

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]

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]

BackgroundMechanisms of normalization of blood pressure in spontaneously hypertensive rats (SHR) during pregnancy were investigated. We hypothesized that at the end of pregnancy (20th day), the modified renal renin–angiotensin system (RAS) plays a pivotal role in this effect associated with reduced inflammation and oxidative damage.MethodsWe measured blood pressure and heart rate (HR) using a noninvasive tail-cuff method in conscious SHR and Wistar Kyoto rats (WKY). Nonpregnant (-NP) or pregnant (-P) SHR and WKY were used to compare the changes of angiotensin II (ANG II) type 1 (AT1) and type 2 (AT2) receptor expression in the kidney. Renal modification of proinflammatory enzyme expression, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) and their transcription factor nuclear factor-κB (NF-κB) were also evaluated. Renal malonyldialdehyde (MDA) content and protein nitrotyrosylation, as indicators of oxidative stress, were assessed. Moreover monocyte chemotactic protein-1 (MCP-1) mRNA was determined.ResultsOur findings indicate that the significant reduction of blood pressure induced by pregnancy in the SHR strain could be related to reduced AT1 and increased AT2 expression. We also saw a significant decline in renal NF-κB, COX-2, iNOS, and macrophage infiltration, as well as the fall in oxidative stress indicators.ConclusionsThe increased proinflammatory and oxidative variables, seen in SHR, are strongly ameliorated by pregnancy. In pregnant SHR animals, the adaptive and compensative changes of RAS and inflammation in the kidney seem to contribute to the reduction of blood pressure near term.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.68American Journal of Hypertension 2009; 22, 7, 777–783. doi:10.1038/ajh.2009.68 [ABSTRACT FROM AUTHOR]

This study investigates the effects of combination therapy with melatonin and dexamethasone on the degree of spinal cord injury caused by the application of vascular clip in mice. Spinal cord injury in mice resulted in severe trauma, characterized by edema, neutrophil infiltration, and apoptosis (measured by terminal deoxynucleotidyltransferase-mediated UTP end labeling staining, and immunoreaction of Bax, Bcl-2, and Fas Ligand). Infiltration of the spinal cord tissue with neutrophils (measured as increase in myeloperoxidase activity) was associated with enhanced immuno- histochemical and functional alterations revealed, respectively, by an increased of tumor necrosis factor (TNF)- α immunoreactivity, NOS as well as nitrotyrosine and loss of hind leg movement in spinal cord injury (SCI)-operated mice. In contrast, the degree of neutrophil infiltration at different time points, cytokine expression, histologic damage iNOS expression, apoptosis, was markedly reduced in the tissues obtained from SCI-treated mice with the combination therapy, and the motor recovery was also ameliorated. No anti-inflammatory effect was observed in animals treated with melatonin (10 mg/kg) or with dexamethasone (0.025 mg/kg) alone. This study shows that the combination therapy with melatonin and dexamethasone reduces the degree of secondary damage associated with spinal cord injury in mice, and supports the possible use of melatonin in combination with steroids to reduce the dose and the side effects related with the use of steroids for the management of inflammatory disease. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of combination therapy with melatonin and dexamethasone (DEX) on acute lung injury. In particular, we investigated the effects of combination therapy in animal models of acute lung inflammation (carrageenan-induced pleurisy). Injection of carrageenan into the pleural cavity of rats elicited an acute inflammatory response characterized by fluid accumulation in the pleural cavity which contained a large number of neutrophils [polymorphonuclear leukocyte (PMN)] as well as an infiltration of PMN in lung tissues and subsequent lipid peroxidation, and increased production of nitrite/nitrate (NOx), and prostaglandin E2 (PGE2). Furthermore, carrageenan induced an upregulation of the adhesion molecules ICAM-1 and P-selectin, inducible nitric oxide synthase, cycloxygenase-2 as well as nitrotyrosine as determined by immunohistochemical analysis of lung tissues. No anti-inflammatory effect was observed in animals treated with melatonin (10 mg/kg) or with DEX (0.01 mg/kg) alone. This study shows that the combination therapy with melatonin and DEX reduced the degree of acute lung inflammation and tissue damage associated with carrageenan-induced pleurisy in mice and supports the possible use of melatonin in combination with steroids in order to reduce the dose and the side effects related with the use of steroids for the management of inflammatory disease. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases (NDs) represents debilitating conditions characterized by degeneration of neuronal cells in specific brain areas, causing disability and death in patients. In the pathophysiology of NDs, oxidative stress, apoptosis and neuroinflammation have a key role, as demonstrated by in vivo and in vitro models. Therefore, the use of molecules with antioxidant and anti-inflammatory activities represents a possible strategy for the treatment of NDs. Many studies demonstrated the beneficial effects of fumaric acid esters (FAEs) to counteract neuroinflammation and oxidative stress. Among these molecules, dimethyl fumarate (DMF) showed a valid therapeutic approach to slow down neurodegeneration and relieve symptoms in patients with NDs. DMF is a methyl ester of fumaric acid and acts as modulator of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation. Therefore, this review aims to examine the potential beneficial effects of DMF to counteract oxidative stress and inflammation in patients with NDs. [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]

Traumatic brain injury (TBI) is a serious neuropathology that causes secondary injury mechanisms, including dynamic interplay between ischemic, inflammatory, and cytotoxic processes. Fumaric acid esters (FAEs) showed beneficial effects in pre-clinical models of neuroinflammation and toxic oxidative stress, so the aim of the present work was to evaluate the potential beneficial effects of dimethyl fumarate (DMF), the most pharmacologically effective molecules among the FAEs, in a mouse model of TBI induced by controlled cortical impact (CCI). Mice were administered DMF orally at the doses of 1, 10, and 30 mg/kg 1 h and 4 h after CCI. We performed histological, molecular, and immunohistochemistry analysis on the traumatic penumbral areas of the brain 24 h after CCI. DMF treatment notably reduced histological damage and behavioral impairments, reducing neurodegeneration as evidenced by assessments of neuronal loss, Fluoro-Jade C, and TUNEL staining; also, treatment with DMF blocked the apoptosis process increasing B-cell lymphoma 2 (Bcl-2) expression in injured cortex. Further, DMF treatment up-regulated antioxidant Kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor pathway, inducing activation of manganese superoxide dismutase and heme-oxygenase-1 and reducing 4-hydroxy-2-nonenal staining. Also, regulating the NF-κB pathway, DMF treatment decreased the severity of inflammation through a modulation of neuronal nitric oxide synthase, interleukin 1, tumor necrosis factor, cyclooxygenase 2, and myeloperoxidase activity, reducing ionized calcium-binding adapter molecule 1 and glial fibrillary acidic protein expression. Our results support the thesis that DMF may be an effective neuroprotectant after brain trauma and warrants further study. [ABSTRACT FROM AUTHOR]

Aim: Oxidative stress plays a key role in Parkinson disease (PD), and nuclear transcription factor related to NF-E2 (Nrf-2) is involved in neuroprotection against PD. The aim of the present study was to investigate a role for nuclear factor-κB (NF-κB)/Nrf-2 in the neurotherapeutic action of dimethyl fumarate (DMF) in a mouse model of PD and in vitro in SHSY-5Y cells. Results: Daily oral gavage of DMF (10, 30, and 100 mg/kg) significantly reduced neuronal cell degeneration of the dopaminergic tract and behavioral impairments induced by four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Moreover, treatment with DMF prevented dopamine depletion, increased tyrosine hydroxylase and dopamine transporter activities, and also reduced the number of α-synuclein-positive neurons. Furthermore, DMF treatment upregulated the Nrf-2 pathway, increased NeuN+/Nrf-2+ cell number in the striatum, induced activation of manganese superoxide dismutase and heme oxygenase-1, and regulated glutathione levels. Moreover, DMF reduced interleukin 1 levels, cyclooxygenase 2 activity, and nitrotyrosine neuronal nitrite oxide synthase expression. This treatment also modulated microglia activation, restored nerve growth factor levels, and preserved microtubule-associated protein 2 alterations. The protective effects of DMF treatment, via Nrf-2, were confirmed in in vitro studies, through inhibition of Nrf-2 by trigonelline. Innovation: These findings demonstrate that DMF, both in a mouse model of PD and in vitro, provides, via regulation of the NF-κB/Nrf-2 pathway, novel cytoprotective modalities that further augment the natural antioxidant response in neurodegenerative and inflammatory disease models. Conclusion: These results support the thesis that DMF may constitute a promising therapeutic target for the treatment of PD. Antioxid. Redox Signal. 27, 453-471. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the efficacy of PEA+silymarin as a combination treatment in a mouse model of renal I/R and to verify whether PEA+silymarin could exert more potent effects compared to the single substances even if administered at lower doses. Mice were subjected to bilateral renal artery occlusion (30 min) and reperfusion (6 h) and received intraperitoneally silymarin (100, 30 and 10 mg/kg) or PEA (1 mg/kg) or PEA (1 mg/kg)+silymarin (10 mg/kg) 15 min before release of clamps. Specific indicators of renal dysfunction, tubular injury, myeloperoxidase activity and malondialdehyde levels were measured. The nuclear factor κB pathway and apoptotic mechanisms were also investigated. The treatment with silymarin reduced kidney dysfunction, histological damage, neutrophil infiltration and oxidative stress in a dose dependent manner. Furthermore, PEA+silymarin showed a significant potentiated effect. Therefore, NF-κB and apoptosis pathways were also significantly inhibited. Our results clearly demonstrate that PEA+silymarin treatment attenuated the degree of renal inflammation. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the family of the N-acylethanolamines (NAEs), in rats subjected to endotoxin-induced uveitis (EIU). EIU was induced in male rats by a single footpad injection of 200 μg lipopolysaccharide (LPS). PEA was administered intraperitoneally at 1 h before and 7 h after injection of LPS. Another group of animals was treated with vehicle. Dexamethasone (DEX) was administered as a positive control. Rats were sacrificed 16 h after injection and the eyes tissues were collected for histology, immunohistochemical and western blot analyses. The histological evaluation of the iris–ciliary body showed an increase of neutrophilic infiltration and nuclear modification of vessel of endothelial cells. PEA treatment decreased the inflammatory cell infiltration and improved histological damage of eye tissues. In addition, PEA treatment reduced pro-inflammatory tumor necrosis factor (TNF-α) levels, protein extravasion and lipid peroxidation. Immunohistochemical analysis for intracellular adhesion molecule (ICAM)-1 and nitrotyrosine showed a positive staining from LPS-injected rats. The degree of staining for ICAM-1 and nitrotyrosine was significantly reduced in eye sections from LPS-injected rats treated with PEA. In addition, an increase of inducible nitric oxide synthase (iNOS) and nuclear factor (NF-κB) was also evaluated in inflammed ocular tissues by western blot. PEA strongly inhibited iNOS expression and nuclear NF-κB translocation. Thus, in this study we demonstrated that PEA reduces the degree of ocular inflammation in a rat model of EIU. [ABSTRACT FROM AUTHOR]

The article investigates the effects of glycogen synthase kinase (GSK)-3 beta inhibition on the development of experimental acute pancreatitis induced by cerulein in mice models. Results demonstrated that the injection of cerulein led to the development of acute necrotizing pancreatitis. Thiadiazolidine-8 significantly reduced the degree of pancreas injury, amylase and lipase serum levels, nuclear factor-kappaß activation and expression adhesion molecules.

Abstract: Hypericum perforatum is a medicinal plant species containing many polyphenolic compounds, namely flavonoids and phenolic acids. Since polyphenolic compounds have high antioxidant potential, we have investigated the effects of H. perforatum extract on the development of multiple organ dysfunction syndrome caused by zymosan (500mg/kg, administered i.p. as a suspension in saline) in mice. Organ failure and systemic inflammation in rats was assessed 18h after administration of zymosan and/or H. perforatum extract and monitored for 12 days (for loss of body weight and mortality). Treatment of mice with H. perforatum extract (30mg/kg i.p., 1 and 6h after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan, pulmonary, intestinal and pancreatic injury, and renal dysfunction as well as the increase in myeloperoxidase in the lung and intestine. Immunohistochemical analysis for inducible nitric oxide synthase (iNOS), nitrotyrosine, and poly(ADP-ribose) (PAR) revealed positive staining in lung and intestine tissues obtained from zymosan-injected mice. The degree of staining for nitrotyrosine, iNOS, and PAR was markedly reduced in tissue sections obtained from zymosan-treated mice, which received H. perforatum extract. In conclusion, this study provides evidence, for the first time, that H. perforatum extract attenuates the degree of zymosan-induced multiple organ dysfunction syndrome in mice. [Copyright &y& Elsevier]