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Co-micronized Palmitoylethanolamide/Polydatin Treatment Causes Endometriotic Lesion Regression in a Rodent Model of Surgically Induced Endometriosis

Endometriosis is a chronic, painful disease characterized by the presence of endometrial glands and stroma outside the uterine cavity. Palmitoylethanolamide (PEA), an endogenous fatty acid amide, has anti-inflammatory and neuroprotective effects. PEA lacks free radical scavenging activity, unlike polydatin (PLD), a natural precursor of resveratrol. The aim of this study was to investigate the effect of orally administered co-micronized PEA/polydatin [m(PEA/PLD)] in an autologous rat model of surgically induced endometriosis. Endometriosis was induced in female Wistar albino rats by auto-transplantation of uterine squares (implants) into the intestinal mesentery and peritoneal cavity. Rats were distributed into one control group and one treatment group (10 animals each): m(PEA/PLD) 10 mg/kg/day. At 28 days after surgery the relative volume of the endometrioma was determined. Endometrial-like tissue was confirmed by histology: Masson trichrome and toluidine blue were used to detect fibrosis and mast cells, respectively. The treated group displayed a smaller cyst diameter, with improved fibrosis score and mast cell number decrease. m(PEA/PLD) administration decreased angiogenesis (vascular endothelial growth factor), nerve growth factor, intercellular adhesion molecule, matrix metalloproteinase 9 expression, and lymphocyte accumulation. m(PEA/PLD) treatment also reduced peroxynitrite formation, (poly-ADP)ribose polymerase activation, IkB\u3b1 phosphorylation and nuclear facor-kB traslocation in the nucleus. Our results suggested that m(PEA/PLD) may be of use to inhibit development of endometriotic lesions in rats

Brisk walking can be a maximal effort in heart failure patients: a comparison of cardiopulmonary exercise and 6 min walking test cardiorespiratory data

Aims Cardiopulmonary exercise test (CPET) and 6 min walking test (6MWT) are frequently used in heart failure (HF). CPET is a maximal exercise, whereas 6MWT is a self-selected constant load test usually considered a submaximal, and therefore safer, exercise, but this has not been tested previously. The aim of this study was to compare the cardiorespiratory parameters collected during CPET and 6MWT in a large group of healthy subjects and patients with HF of different severity.Methods and results Subjects performed a standard maximal CPET and a 6MWT wearing a portable device allowing breath-by-breath measurement of cardiorespiratory parameters. HF patients were grouped according to their CPET peak oxygen uptake (peak(V) over-dotO(2)). One hundred and fifty-five subjects were enrolled, of whom 40 were healthy (59 +/- 8 years; male 67%) and 115 were HF patients (69 +/- 10 years; male 80%; left ventricular ejection fraction 34.6 +/- 12.0%). CPET peak(V) over-dotO(2) was 13.5 +/- 3.5 ml/kg/min in HF patients and 28.1 +/- 7.4 mL/kg/min in healthy subjects (P < 0.001). 6MWT-(V) over-dotO(2) was 98 +/- 20% of the CPET peak(V) over-dotO(2) values in HF patients, while 72 +/- 20% in healthy subjects (P < 0.001). 6MWT-(V) over-dot was >110% of CPET peak(V) over-dotO(2) in 42% of more severe HF patients (peak(V) over-dotO(2) < 12 mL/kg/min). Similar results have been found for ventilation and heart rate. Of note, the slope of the relationship between (V) over-dotO(2) at 6MWT, reported as a percentage of CPET peak(V) over-dotO(2) vs. 6MWT (V) over-dotO(2) reported as the absolute value, progressively increased as exercise limitation did.Conclusions In conclusion, the last minute of 6MWT must be perceived as a maximal or even supramaximal exercise activity in patients with more severe HF. Our findings should influence the safety procedures needed for the 6MWT in HF

Protective Effect of Hydroxytyrosol Against Oxidative Stress Induced by the Ochratoxin in Kidney Cells: in vitro and in vivo Study

Ochratoxin-A (OTA) is a mycotoxin that is a common contaminant of food products for both humans and animals. This mycotoxin has several toxic effects. In particular, ochratoxin has significant nephrotoxic potential. In fact, OTA has been described as being responsible for naturally occurring animal and human kidney disorders. The toxicity of this mycotoxin involves the induction of the oxidative stress pathways. Therefore, in the present study, we wanted to evaluate the potential protective effects of hydroxytyrosol (HT), a phenolic constituent with potent antioxidant activity, of extra virgin olive oil in three different renal cell lines, the Madin-Darby canine kidney cell line (MDCK), a pig kidney cell line (LLC-PK1), and a rabbit kidney cell line (RK 13), and in rats. Our results clearly showed that renal cells respond to OTA exposure by reducing cell proliferation and the induction of oxidative stress. Pre-incubation of the cells with HT prevented the cellular cytotoxicity and increased reactive oxygen species (ROS) levels induced by OTA. In addition, the antioxidative activity of HT was studied by measuring malondialdehyde (MDA) and lactate dehydrogenase (LDH) levels and nitrosative stress. Finally, we investigated the capability of HT (20 mg/kg, intraperitoneally) to act in vivo. In rats, HT reduced oxidative stress and collagen accumulation in the kidney and counteracted the augmentations in AST, ALT, and creatinine levels following OTA induction (250 μg/kg for 90 days orally). In conclusion, our findings demonstrate that HT is able to protect three renal cell lines from the damage induced by OTA and protect the kidneys of rats. Therefore, the use of this compound could be an important strategy for the treatment and prevention of this type of kidney dysfunction

A novel composite formulation of palmitoylethanolamide and quercetin decreases inflammation and relieves pain in inflammatory and osteoarthritic pain models

Background: Osteoarthritis (OA) is a common progressive joint disease in dogs and cats. The goal of OA treatment is to reduce inflammation, minimize pain, and maintain joint function. Currently, non-steroidal anti-inflammatory drugs (e.g., meloxicam) are the cornerstone of treatment for OA pain, but side effects with long-term use pose important challenges to veterinary practitioners when dealing with OA pain. Palmitoylethanolamide (PEA) is a naturally-occurring fatty acid amide, locally produced on demand by tissues in response to stress. PEA endogenous levels change during inflammatory and painful conditions, including OA, i.e., they are typically increased during acute conditions and decreased in chronic inflammation. Systemic treatment with PEA has anti-inflammatory and pain-relieving effects in several disorders, yet data are lacking in OA. Here we tested a new composite, i.e., PEA co-ultramicronized with the natural antioxidant quercetin (PEA-Q), administered orally in two different rat models of inflammatory and OA pain, namely carrageenan paw oedema and sodium monoiodoacetate (MIA)-induced OA. Oral treatment with meloxicam was used as benchmark. Results: PEA-Q decreased inflammatory and hyperalgesic responses induced by carrageenan injection, as shown by: (i) paw oedema reduction, (ii) decreased severity in histological inflammatory score, (iii) reduced activity of myeloperoxidase, i.e., a marker of inflammatory cell infiltration, and (iv) decreased thermal hyperalgesia. Overall PEA-Q showed superior effects compared to meloxicam. In MIA-treated animals, PEA-Q exerted the following effects: (i) reduced mechanical allodynia and improved locomotor function, (ii) protected cartilage against MIA-induced histological damage, and (iii) counteracted the increased serum concentration of tumor necrosis factor alpha, interleukin 1 beta, metalloproteases 1, 3, 9 and nerve growth factor. The magnitude of these effects was comparable to, or even greater than, those of meloxicam. Conclusion: The present findings shed new light on some of the inflammatory and nociceptive pathways and mediators targeted by PEA-Q and confirm its anti-inflammatory and pain-relieving effects in rodent OA pain models. The translatability of these observations to canine and feline OA pain is currently under investigation

Treatment With a Flavonoid-Rich Fraction of Bergamot Juice Improved Lipopolysaccharide-Induced Periodontitis in Rats

Objective: In this study, we investigated the effects of a flavonoid-rich fraction of Bergamot juice (BJe) in rats subjected to experimental periodontitis induced by a single intragingival injection of lipopolysaccharides (LPS).Main Methods: Periodontitis was induced by a single intragingival injection of 1 μl LPS (10 μg/μl) derived from Salmonella typhimurium in sterile saline solution. The injection was made in the mesolateral side at the interdental papilla between the first and the second molar. Fourteen days after LPS injection, we performed radiographic analyses and then we surgically removed the gingivomucosal tissue surrounding the mandibular first molar for histological, immunohistochemical and molecular analysis.Results: LPS significantly induced oedema, tissue damage and increased neutrophil infiltration. At molecular level, we found increased NF-κB translocation as well as raised both TNF-α and IL-1β expression, other than modulation of apoptosis-associated proteins. Moreover, the increased myeloperoxidase activity was associated with up-regulation of adhesion molecules. Immunohistochemical analysis for nitrotyrosine and poly ADP-ribose displayed an intense staining in the gingivomucosal tissue. Oral administration of BJe for 14 consecutive days reduced tissue injury and several markers of gingival inflammation including nuclear NF-κB translocation, cytokines expression, myeloperoxidase activity and the expression of some adhesion molecules such as ICAM and P-selectin. BJe also decreased both nitrosative stress and PARP positive staining. Moreover, it caused down-regulation of Bax and up-regulation of Bcl-2 expression.Conclusion: Our findings demonstrate that BJe improves LPS-induced periodontitis in rats by reducing the typical markers of inflammation, thus suggesting its potential in the treatment of periodontal diseases

Neuroprotective Effect of Artesunate in Experimental Model of Traumatic Brain Injury

Traumatic brain injuries (TBI) are an important public health challenge. In addition, subsequent events at TBI can compromise the quality of life of these patients. In fact, TBI is associated with several complications for both long and short term, some evidence shows how TBI is associated with a decline in cognitive functions such as the risk of developing dementia, cerebral atrophy, and Parkinson disease. After the direct damage from TBI, a key role in TBI injury is played by the inflammatory response and oxidative stress, that contributes to tissue damage and to neurodegenerative processes, typical of secondary injury, after TBI. Given the complex series of events that are involved after TBI injury, a multitarget pharmacological approach is needed. Artesunate is a more stable derivative of its precursor artemisin, a sesquiterpene lactone obtained from a Chinese plant Artemisia annua, a plant used for centuries in traditional Chinese medicine. artesunate has been shown to be a pluripotent agent with different pharmacological actions. therefore, in this experimental model of TBI we evaluated whether the treatment with artesunate at the dose of 30 mg\Kg, had an efficacy in reducing the neuroinflammatory process after TBI injury, and in inhibiting the NLRP3 inflammasome pathway, which plays a key role in the inflammatory process. We also assessed whether treatment with artesunate was able to exert a neuroprotective action by modulating the release of neurotrophic factors. our results show that artesunate was able to reduce the TBI-induced lesion, it also showed an anti-inflammatory action through the inhibition of Nf-kb, release of proinflammatory cytokines IL-1β and TNF-α and through the inhibition NLRP3 inflammasome complex, furthermore was able to reduce the activation of astrocytes and microglia (GFAP, Iba-1). Finally, our results show that the protective effects of artesunate also occur through the modulation of neurotrophic factors (BDNF, GDNF, NT-3) that play a key role in neuronal survival

protective effect of a new hyaluronic acid carnosine conjugate on the modulation of the inflammatory response in mice subjected to collagen induced arthritis

Abstract Several studies demonstrated the pharmacological actions of carnosine as well as hyaluronic acid (HA) during joint inflammation. In that regard, the aim of this study was to investigate the protective effect of a new HA -Carnosine conjugate (FidHycarn) on the modulation of the inflammatory response in mice subjected to collagen-induced arthritis (CIA). CIA was induced by two intradermal injections of 100 μl of an emulsion of collagen (CII) and complete Freund's adjuvant (CFA) at the base of the tail on day 0 and 21. At 35 day post CIA induction, the animals were sacrificed. CII injection caused erythema and edema in the hind paws, histological alterations with erosion of the joint cartilage as well as behavioral changes. Oral treatment with FidHycarn starting at the onset of arthritis (day 25) ameliorated the clinical signs, improved behavioral deficits as well as decreased histological and radiographic alterations. The degree of oxidative damage evaluated by inducible nitric oxide synthase (iNOS), nitrotyrosine, poly-ADP-ribose (PAR) expressions and malondialdehyde (MDA) levels, was also significantly reduced in Carnosine+HA association and FidHycarn treated mice. Moreover, the levels of proinflammatory cytokines and chemokines and cyclo-oxygenase COX-2 enzyme were also more significantly reduced by Carnosine+HA and FidHycarn compared to carnosine alone. However, interestingly, in some cases, the effects of FidHycarn were more important than Carnosine+HA association and not statistically different to methotrexate (MTX) used as positive control. Thus, the conjugation of Carnosine with HA (FidHycarn) could represent an interesting therapeutic strategy to combat arthritis disorders

Atrazine Inhalation Worsen Pulmonary Fibrosis Regulating the Nuclear Factor-Erythroid 2-Related Factor (Nrf2) Pathways Inducing Brain Comorbidities.

BACKGROUND/AIMS: Pulmonary fibrosis can be caused by genetic abnormalities, autoimmune disorders or exposure to environmental pollutants. All these causes have in common the excessive production of oxidative stress species that initiate a cascade of molecular mechanism underlying fibrosis in a variety of organs, including lungs. The chemical name of Atrazine (ATR) is 6-chloro-N-ethyl-N'-(1-methylethyl)-1,3,5-triazine-2,4-diamine, and it is the most commonly used broad-spectrum herbicide in agricultural crops. Additionally, Bleomycin is a chemotherapeutic agent often used for different lymphoma with a seriously pulmonary complication. The most accredited hypothesis that may explain the mechanism of toxicity induced by ATR or bleomycin is exactly the production of reactive oxygen species (ROS) that leads to an unbalance in the physiological anti-oxidant system. However, until today, nobody has investigated the effect of ATR exposure during pulmonary fibrosis. METHODS: Mice were subject to ATR exposure, to bleomycin injection or to both. At the end of experiment, the lungs and blood were collected. Additionally, we analyzed by different test such as open field, pole and rotarod test or other we investigated the effects of ATR or bleomycin exposure on behavior. RESULTS: Following ATR or bleomycin induction, we found a significant increase in lung damage, fibrosis, and oxidative stress. This condition was significantly worsened when the animals injected with bleomycin were also exposed to ATR. Additionally, we observed significant motor and non-motor impairment in animals exposed to ATR. CONCLUSION: Our study demonstrates that ATR exposure, decrease nuclear factor-erythroid 2-related factor (Nrf2) pathways in both lung and brain

Physiological and Biochemical Changes in NRF2 Pathway in Aged Animals Subjected to Brain Injury.

Background/Aims: Oxidative stress plays a key role in aging, which in turn represents a substantial risk factor for brain injuries. The aim of the present study was to investigate the differences in physiological and biochemical changes in the brain during injury-related inflammation and oxidative stress, comparing young and old mice. Methods: Young and old mice were subjected to focal cerebral ischemia induced by transient middle cerebral artery occlusion or to traumatic brain injury performed by a controlled cortical impactor. At the end of both experiments, mice were sacrificed 24h after injuries and brains were collected to perform biochemical analysis. Results: In both ischemic stroke and traumatic brain injury, aging has not only led to damage-induced worsening of motor function and behavioural changes but also increased of infarct area compared to young animals. Moreover, aged mice show increased evidence of oxidative stress and reduced antioxidant capacity when compared to younger animals, as demonstrated by Nrf2-Keap1 signalling pathway and lower expression of antioxidant enzymes, such as HO-1, SOD-1 and GSH-Px. Additionally, brain tissues collected from elderly mice showed an increased IκB-α degradation into the cytoplasm and consequently NF-κB translocation into the nucleus, compared to young mice subjected to same injuries. The elderly mice showed significantly higher levels of iNOS and CoX-2 expression than the young mice, as well as higher levels of inflammatory cytokines such as TNFα, IL-1β, and IL-6 after MCAO and TBI. Conclusion: Preserving and keeping the NRF-2 pathway active counteracts the onset of oxidative stress and consequent inflammation after ischemic and traumatic brain insult, particularly in the elderly. Not only that, NRF-2 pathway could represent a possible therapeutic target in the management of brain injuries