RESUMO
Pulmonary arterial hypertension (PAH) is a chronic, progressive disease characterized by an increase in blood pressure in the lungs' arteries. It can occur in a variety of species, including humans, dogs, cats, and horses. To date, PAH has a high mortality rate in both veterinary and human medicine, often due to complications such as heart failure. The complex pathological mechanisms of PAH involve multiple cellular signalling pathways at various levels. IL-6 is a powerful pleiotropic cytokine that regulates several phases of immune response, inflammation, and tissue remodelling. The hypothesis of this study was that the use of an IL-6 antagonist in PAH could interrupt or mitigate the cascade of events that leads to the progression of the disease and the worsening of clinical outcome, as well as tissue remodelling. In this study, we used two pharmacological protocols with an IL-6 receptor antagonist in a monocrotaline-induced PAH model in rats. Our results showed that the use of an IL-6 receptor antagonist had a significant protective effect, ameliorating both haemodynamic parameters, lung and cardiac function, tissue remodelling, and the inflammation associated with PAH. The results of this study suggest that the inhibition IL-6 could be a useful pharmacological strategy in PAH, in both human and veterinary medicine.
Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Animais , Humanos , Ratos , Citocinas/metabolismo , Modelos Animais de Doenças , Hipertensão Pulmonar/tratamento farmacológico , Inflamação/patologia , Interleucina-6 , Hipertensão Arterial Pulmonar/tratamento farmacológico , Artéria Pulmonar , Receptores de Interleucina-6/uso terapêuticoRESUMO
Perfluorinated and polyfluorinated alkyl substances (PFAS), more than 4700 in number, are a group of widely used man-made chemicals that accumulate in living things and the environment over time. They are known as "forever chemicals" because they are extremely persistent in our environment and body. Because PFAS have been widely used for many decades, their presence is evident globally, and their persistence and potential toxicity create concern for animals, humans and environmental health. They can have multiple adverse health effects, such as liver damage, thyroid disease, obesity, fertility problems, and cancer. The most significant source of living exposure to PFAS is dietary intake (food and water), but given massive industrial and domestic use, these substances are now punctually present not only domestically but also in the outdoor environment. For example, livestock and wildlife can be exposed to PFAS through contaminated water, soil, substrate, air, or food. In this review, we have analyzed and exposed the characteristics of PFAS and their various uses and reported data on their presence in the environment, from industrialized to less populated areas. In several areas of the planet, even in areas far from large population centers, the presence of PFAS was confirmed, both in marine and terrestrial animals (organisms). Among the most common PFAS identified are undoubtedly perfluorooctanesulfonate (PFOS) and perfluorooctanoic acid (PFOA), two of the most widely used and, to date, among the most studied in terms of toxicokinetics and toxicodynamics. The objective of this review is to provide insights into the toxic potential of PFAS, their exposure, and related mechanisms.
Assuntos
Ácidos Alcanossulfônicos , Fluorocarbonos , Animais , Humanos , Ácidos Alcanossulfônicos/toxicidade , Poluição da Água , Fluorocarbonos/toxicidade , ÁguaRESUMO
BACKGROUND/AIMS: Respiratory diseases are the world's biggest cause of mortality and disability. Specific nutrients have been proposed to positively affect disease progression as novel therapy alternatives to glucocorticosteroids. There has been a lot of attention in the possible health advantages of dietary assumption of Açai Seeds, popular native fruit found in the Amazon region which is rich in bioactive compounds. Until today nobody investigated the beneficial property of Açai Seeds administration in lung disease. METHODS: In our study we use two model of lung disease: for acute lung disease we use an intrapleural injection of Carrageenan; for chronic disease we used an intratracheal instillation of bleomycin. Açai Seeds was administered orally dissolved in saline. RESULTS: We found that Açai Seeds was able to reduce histological alteration, cells infiltration, pro inflammatory cytokine release, inflammation, and oxidative stress in both acute and chronic model of lung disease. CONCLUSION: Our data clearly demonstrate for the first time that Açai Seeds administration was useful against lung disease by the reduction of NF-κB nuclear translocation and by the stimulation of Nrf2/ARE pathways promoting the physiological antioxidant defense.
Assuntos
Euterpe , Pneumopatias , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Euterpe/química , Frutas/química , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Pulmão/metabolismo , Pneumopatias/tratamento farmacológico , Fator 2 Relacionado a NF-E2/análise , NF-kappa B/análise , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , SementesRESUMO
Endometriosis (EMS) is a gynecological disease characterized by inflammation, oxidative stress, and apoptosis dysregulation. This study aims to evaluate the effect of Boswellia serrata gum resin extract (BS) on the endometriotic lesions in a rat model of endometriosis. We divided female rats into three groups, including Sham, EMS, EMS + BS. In the EMS and EMS + BS groups, pathology was induced and after 7 days by the abdominal high-frequency ultrasound (hfUS) analysis the presence of the endometriotic lesions was confirmed. Subsequently, the EMS + BS group was administered with BS (100 mg/Kg) daily for another 7 days. At the end of the experiment, the hfUS analysis was repeated and the animals were sacrificed to evaluate the size and histoarchitecture of the endometriotic implants. Pelvic ultrasound showed increased size of the endometriotic lesions in the Endo group, while BS administration reduced the lesion size. The macroscopic analysis confirmed the reduced area and volume of the endometriotic lesions of the EMS + BS group. The histological analysis showed reduced characteristic of ectopic stroma and glands in the animals treated with BS. Western blot analyses were conducted to evaluate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. BS increases the expression of Nfr2 in the nucleus and the expression of its downstream antioxidant proteins NQO-1 and HO-1. Moreover, it reduced lipid peroxidation and increased glutathione (GSH) levels, and glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities. BS administration also restored the impaired apoptotic pathway in the lesions by reducing Bcl-2 expression and increasing Bax and cleaved caspase 9 levels. The BS apoptotic effect was also confirmed by the cleavage of PARP, another specific marker of apoptosis, and by the TUNEL assay. Our results show that BS administration resulted in an effective and coordinated suppression of Endo owing to its antioxidant and antiapoptotic activities.
Assuntos
Endometriose , Estresse Oxidativo , Humanos , Ratos , Feminino , Animais , Resinas Vegetais/farmacologia , Apoptose , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Endometriose/patologia , Glutationa/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
Vinclozolin is one of the most used fungicides in the control of fungi in fruits, vegetables, and ornamental plants. The effects of its exposure on different organs have been described, but information regarding its relevance to vinclozolin-induced nephrotoxicity is largely missing. This study focuses on the potential mechanism of vinclozolin-induced nephrotoxicity. CD1 male mice were administered vinclozolin (100 mg/kg) by oral gavage for 28 days. Vinclozolin administration decreased body weight over the treatment period and at the end of the experiment, increased the ratio of kidney weight to body weight and increased serum urea nitrogen and creatinine contents. Vinclozolin also induced histopathological alterations, including tubular dilatation and necrosis and impaired the integrity of the renal-tubular architecture and kidney fibrosis. The analyses conducted showed that vinclozolin administration altered the mRNA levels of mitochondrial function-related proteins (SIRT3, SIRT1, PGC-1α, TFAM, NRF1, VDAC-1, and Cyt c) and oxidative stress (increased lipid peroxidation and decreased total antioxidative capacity, catalase, and superoxide dismutase activities, glutathione levels, and glutathione peroxidase activity) in the kidneys. Furthermore, vinclozolin induced toxicity that altered Nrf2 signalling and the related proteins (HO-1 and NQO-1). Vinclozolin administration also affected both the extrinsic and intrinsic apoptotic pathways, upregulating the expression of proapoptotic factors (Bax, Caspase 3, and FasL) and downregulating antiapoptotic factor (Bcl-2) levels. This study suggests that vinclozolin induced nephrotoxicity by disrupting the transcription of mitochondrial function-related factors, the Nrf2 signalling pathway, and the extrinsic and intrinsic apoptotic pathways.
Assuntos
Fungicidas Industriais , Sirtuína 3 , Animais , Antioxidantes/farmacologia , Apoptose , Peso Corporal , Caspase 3/metabolismo , Catalase/metabolismo , Creatinina/metabolismo , Fibrose , Fungicidas Industriais/farmacologia , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Rim/metabolismo , Camundongos , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Nitrogênio/metabolismo , Oxazóis , Estresse Oxidativo , RNA Mensageiro/metabolismo , Sirtuína 1/metabolismo , Sirtuína 3/metabolismo , Superóxido Dismutase/metabolismo , Ureia/farmacologia , Proteína X Associada a bcl-2/metabolismoRESUMO
Endocrine-disrupting substances (EDS) are common and pervasive in our environment and pose a serious risk to both human and animal health. Endocrine-disrupting compounds (EDCs) have been associated with a variety of detrimental human health effects, including respiratory issues, as a result of their ability to disrupt cell physiology. Vinclozolin ((RS)-3-(3,5-Dichlorophenyl)-5-methyl-5-vinyloxazolidine-2,4-dione) is a common dicarboximide fungicide used to treat plant diseases. Several studies have analyzed the effects of vinclozolin exposure on the reproductive system, but less is known about its effect on other organs such as the lung. Mice were exposed for 28 days to orally administered vinclozolin at a dose of 100 mg/kg. Vinclozolin exposure induced histological alterations and collagen depositions in the lung. Additionally, vinclozolin induced inflammation and oxidative stress that led to lung apoptosis. Our study demonstrates for the first time that the toxicological effects of vinclozolin are not limited to the reproductive system but also involve other organs such as the lung.
Assuntos
Disruptores Endócrinos , Fungicidas Industriais , Animais , Disruptores Endócrinos/toxicidade , Fungicidas Industriais/toxicidade , Humanos , Pulmão/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2 , NF-kappa B , Oxazóis/toxicidadeRESUMO
Low back pain (LBP) management is an important clinical issue. Inadequate LBP control has consequences on the mental and physical health of patients. Thus, acquiring new information on LBP mechanism would increase the available therapeutic tools. Resveratrol is a natural compound with many beneficial effects. In this study, we investigated the role of resveratrol on behavioral changes, inflammation and oxidative stress induced by LBP. Ten microliters of Complete Freund's adjuvant (CFA) was injected in the lumbar intervertebral disk of Sprague Dawley rats to induce degeneration, and resveratrol was administered daily. Behavioral analyses were performed on day zero, three, five and seven, and the animals were sacrificed to evaluate the molecular pathways involved. Resveratrol administration alleviated hyperalgesia, motor disfunction and allodynia. Resveratrol administration significantly reduced the loss of notochordal cells and degenerative changes in the intervertebral disk. From the molecular point of view, resveratrol reduced the 5th/6th lumbar (L5-6) spinal activation of the WNT pathway, reducing the expression of WNT3a and cysteine-rich domain frizzled (FZ)8 and the accumulation of cytosolic and nuclear ß-catenin. Moreover, resveratrol reduced the levels of TNF-α and IL-18 that are target genes strictly downstream of the WNT/ß-catenin pathway. It also showed important anti-inflammatory activities by reducing the activation of the NFkB pathway, the expression of iNOS and COX-2, and the levels of PGE2 in the lumbar spinal cord. Moreover, resveratrol reduced the oxidative stress associated with inflammation and pain, as shown by the observed reduced lipid peroxidation and increased GSH, SOD, and CAT activities. Therefore, resveratrol administration controlled the WNT/ß-catenin pathway and the related inflammatory and oxidative alterations, thus alleviating the behavioral changes induced by LBP.
Assuntos
Dor Lombar , beta Catenina , Animais , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/etiologia , Inflamação/tratamento farmacológico , Dor Lombar/tratamento farmacológico , Dor Lombar/etiologia , Ratos , Ratos Sprague-Dawley , Resveratrol/uso terapêutico , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
Traumatic brain injury (TBI) disrupts the blood-brain barrier (BBB). Vascular endothelial growth factor (VEGF) is believed to play a key role in TBI and to be overexpressed in the absence of apolipoprotein E (ApoE). Bevacizumab, a VEGF inhibitor, demonstrated neuroprotective activity in several models of TBI. However, the effects of bevacizumab on Apo-E deficient mice are not well studied. The present study aimed to evaluate VEGF expression and the effects of bevacizumab on BBB and neuroinflammation in ApoE-/- mice undergoing TBI. Furthermore, for the first time, this study evaluates the effects of bevacizumab on the long-term consequences of TBI, such as atherosclerosis. The results showed that motor deficits induced by controlled cortical impact (CCI) were accompanied by increased brain edema and VEGF expression. Treatment with bevacizumab significantly improved motor deficits and significantly decreased VEGF levels, as well as brain edema compared to the control group. Furthermore, the results showed that bevacizumab preserves the integrity of the BBB and reduces the neuroinflammation induced by TBI. Regarding the effects of bevacizumab on atherosclerosis, it was observed for the first time that its ability to modulate VEGF in the acute phase of head injury prevents the acceleration of atherosclerosis. Therefore, the present study demonstrates not only the neuroprotective activity of bevacizumab but also its action on the vascular consequences related to TBI.
Assuntos
Aterosclerose , Edema Encefálico , Lesões Encefálicas Traumáticas , Animais , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Barreira Hematoencefálica/metabolismo , Edema Encefálico/tratamento farmacológico , Edema Encefálico/etiologia , Lesões Encefálicas Traumáticas/metabolismo , Modelos Animais de Doenças , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Endometriosis is usually associated with inflammation and chronic pelvic pain. This paper focuses the attention on the anti-inflammatory, anti-oxidant and analgesic effects of cannabidiol (CBD) and on its potential role in endometriosis. We employed an in vivo model of endometriosis and administered CBD daily by gavage. CBD administration strongly reduced lesions diameter, volume and area. In particular, it was able to modify lesion morphology, reducing epithelial glands and stroma. CBD showed anti-oxidant effects reducing lipid peroxidation, the expression of Nox-1 and Nox-4 enzymes. CBD restored the oxidative equilibrium of the endogenous cellular defense as showed by the SOD activity and the GSH levels in the lesions. CBD also showed important antifibrotic effects as showed by the Masson trichrome staining and by downregulated expression of MMP-9, iNOS and TGF-ß. CBD was able to reduce inflammation both in the harvested lesions, as showed by the increased Ikb-α and reduced COX2 cytosolic expressions and reduced NFkB nuclear localization, and in the peritoneal fluids as showed by the decreased TNF-α, PGE2 and IL-1α levels. CBD has important analgesic effects as showed by the reduced mast cells recruitment in the spinal cord and the reduced release of neuro-sensitizing and pro-inflammatory mediators. In conclusion, the collected data showed that CBD has an effective and coordinated effects in endometriosis suppression.
Assuntos
Canabidiol , Endometriose , Analgésicos , Antioxidantes/metabolismo , Canabidiol/metabolismo , Canabidiol/farmacologia , Canabidiol/uso terapêutico , Endometriose/tratamento farmacológico , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Estresse OxidativoRESUMO
Acute lung injury (ALI) is a group of lung illnesses characterized by severe inflammation, with no treatment. The fatty acid amide hydrolase (FAAH) enzyme is an integral membrane protein responsible for the hydrolysis of the main endocannabinoids, such as anandamide (AEA). In pre-clinical pain and inflammation models, increasing the endogenous levels of AEA and other bioactive fatty acid amides (FAAs) via genetic deletion or the pharmacological inhibition of FAAH produces many analgesic benefits in several different experimental models. To date, nobody has investigated the role of FAAH inhibition on an ALI mouse model. Mice were subjected to a carrageenan injection and treated orally 1 h after with the FAAH inhibitor URB878 dissolved in a vehicle consisting of 10% PEG-400, 10% Tween-80 and 80% saline at different doses: The inhibition of FAAH activity was able to counteract not only the CAR-induced histological alteration, but also the cascade of related inflammatory events. URB878 clears the way for further studies based on FAAH inhibition in acute lung pathologies.
Assuntos
Lesão Pulmonar Aguda , Amidoidrolases , Lesão Pulmonar Aguda/tratamento farmacológico , Amidoidrolases/metabolismo , Animais , Endocanabinoides/metabolismo , Inflamação/tratamento farmacológico , Camundongos , Dor/patologia , Alcamidas Poli-Insaturadas/metabolismoRESUMO
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.
Assuntos
Atrazina/efeitos adversos , Encefalopatias/metabolismo , Encéfalo/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Administração por Inalação , Animais , Atrazina/farmacologia , Bleomicina/efeitos adversos , Bleomicina/farmacologia , Encéfalo/patologia , Encefalopatias/etiologia , Encefalopatias/patologia , Masculino , Camundongos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/complicações , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologiaRESUMO
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-1ß, 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.
Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Teste do Labirinto Aquático de Morris , Estresse Oxidativo/fisiologia , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND/AIMS: Atrazine (ATR) is the second most widely used herbicide, after glyphosate, that is used to stop pre- and post-emergence broadleaf and grassy weeds. In 2007, it was included in the class of endocrine disruptors due to the impact its exposure had on human health. Occasional ATR exposure at work has been linked to an increased risk of respiratory problems, but the molecular mechanisms underlying this relationship has not yet been fully elucidated. METHODS: Mice were exposed to an aerosol containing ATR. In particular ATR aerosol was prepared by dissolving 250 mg of ATR in a vehicle made with saline and 10% DMSO. Seven days after the aerosol exposure, the mice were sacrificed and lung tissue, bronchoalveolar lavage fluid (BALF), and blood samples were collected for histology and biochemical analysis. RESULTS: ATR inhalation induces a generalized state of oxidative/nitrosative stress that leads to an increase in cytokines production and to a physiologically unstable antioxidant defense response evaluated by the alteration of Nrf-2 pathways. Moreover, it stimulates autophagy through Beclin 1/Lc3 expressions and increases lipid peroxidation and apoptosis. All these effects culminate in serious alterations in the tissue architecture of the lungs and to an increase in mucus production and mast cells degranulation. CONCLUSION: Our study shows, for the first time, the impact of ATR inhalation on lung tissue. This could represent the first step to also recognize this substance as a problematic air pollutant as well as a soil and water contaminant.
Assuntos
Atrazina , Herbicidas , Pneumonia , Animais , Atrazina/toxicidade , Proteína Beclina-1 , Herbicidas/toxicidade , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia/induzido quimicamenteRESUMO
Inflammatory bowel disease (IBD) is a chronic disorder characterized by inflammation of the gastrointestinal (GI) tract, and it is associated with different neurological disorders. Recent evidence has demonstrated that the gut-brain-axis has a central function in the perpetuation of IBS, and for this reason, it can be considered a possible therapeutic target. N-Palmitoylethanolamine-oxazoline (PEA-OXA) possesses anti-inflammatory and potent neuroprotective effects. Although recent studies have explained the neuroprotective properties of PEA-OXA, nothing is known about its effects on the gut-brain axis during colitis. The aim of this study is to explore the mechanism and the effect of PEA-OXA on the gut-brain axis in rats subjected to experimental colitis induced by oral administration of dextran sulfate sodium (DSS). Daily oral administration of PEA-OXA (10 mg/kg daily o.s.) was able to decrease the body weight loss, macroscopic damage, colon length, histological alteration, and inflammation after DSS induction. Additionally, PEA-OXA administration enhanced neurotrophic growth factor release and decreased the astroglial and microglial activation induced by DSS. Moreover, PEA-OXA restored intestinal permeability and tight junctions (TJs) as well as reduced apoptosis in the colon and brain. In our work, we demonstrated, for the first time, the action of PEA-OXA on the gut-brain axis in a model of DSS-induced colitis and its implication on the "secondary" effects associated with colonic disturbance.
Assuntos
Amidas/uso terapêutico , Etanolaminas/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Oxazóis/uso terapêutico , Ácidos Palmíticos/uso terapêutico , Animais , Peso Corporal/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/metabolismo , Sulfato de Dextrana/toxicidade , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imuno-Histoquímica , Doenças Inflamatórias Intestinais/induzido quimicamente , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Selectina-P/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: During contrast enhanced ultrasound (CEUS), the features of the regions of interest (ROI) can affect the value of the perfusion-related parameters obtained from a time intensity curve (TIC). In veterinary medicine, conflicting have been reported on the influence of ROI size and location on renal CEUS. There are some disagreeing evidences regarding the optimal method for selecting ROI in quantitative analysis of renal perfusion using CEUS. The aim of this study was to evaluate the effect of the size and location of ROIs in the spleen of conscious dogs on perfusion variables determined using sulphur hexafluoride contrast-enhanced ultrasounds. RESULTS: A prospective observational study on 15 client-owned mixed-breed adult dogs was performed using a system equipped with contrast-tuned imaging technology. Qualitative and quantitative assessments of the spleen enhancement pattern were carried out. Three square ROIs (0.05 cm2) were manually drawn in a row and spaced 1 mm apart, placing adjacent ROIs at three different depths. Three medium rectangular ROIs (0.3 cm2) include the 3 smallest ROIs in each row, indicated by the letters A, B and C, and a single large square ROI (1 cm2) was drawn containing all previous ROIs. Software analysis of time-intensity curves generated within each ROI allowed us to calculate the perfusion-related parameters: peak enhancement, time to peak, regional blood flow, mean transit time and regional blood volume. The coefficient of variation for all blood-related parameters was always lower in the larger ROI than in the other smaller ROIs. ROI A and B, positioned proximally and medially, levels respectively, showed similar coefficients of variation to the largest ROI. The analysis of variance model exhibited a significant effect of location and size of the ROIs in the quantitative analysis of canine spleen perfusion, with a reduction of perfusion-related parameters in the distal ROI. CONCLUSIONS: The recommendation for a quantitative CEUS examination of a dog's spleen is to analyze splenic perfusion by drawing a sufficiently large ROI proximal to the ultrasound beam on the splenic parenchyma. This may be of clinical relevance in the diagnosis of splenic diseases.
Assuntos
Meios de Contraste/metabolismo , Cães , Baço/metabolismo , Animais , Feminino , Masculino , Estudos Prospectivos , Baço/diagnóstico por imagem , Ultrassonografia/métodos , Ultrassonografia/veterináriaRESUMO
Treating postoperative (PO) pain is a clinical challenge. Inadequate PO pain management can lead to worse outcomes, for example chronic post-surgical pain. Therefore, acquiring new information on the PO pain mechanism would increase the therapeutic options available. In this paper, we evaluated the role of a natural substance, epigallocatechin-3-gallate (EGCG), on pain and neuroinflammation induced by a surgical procedure in an animal model of PO pain. We performed an incision of the hind paw and EGCG was administered for five days. Mechanical allodynia, thermal hyperalgesia, and motor dysfunction were assessed 24 h, and three and five days after surgery. At the same time points, animals were sacrificed, and sera and lumbar spinal cord tissues were harvested for molecular analysis. EGCG administration significantly alleviated hyperalgesia and allodynia, and reduced motor disfunction. From the molecular point of view, EGCG reduced the activation of the WNT pathway, reducing WNT3a, cysteine-rich domain frizzled (FZ)1 and FZ8 expressions, and both cytosolic and nuclear ß-catenin expression, and the noncanonical ß-catenin-independent signaling pathways, reducing the activation of the NMDA receptor subtype NR2B (pNR2B), pPKC and cAMP response element-binding protein (pCREB) expressions at all time points. Additionally, EGCG reduced spinal astrocytes and microglia activation, cytokines overexpression and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) pathway, downregulating inducible nitric oxide synthase (iNOS) activation, cyclooxygenase 2 (COX-2) expression, and prostaglandin E2 (PGE2) levels. Thus, EGCG administration managing the WNT/ß-catenin signaling pathways modulates PO pain related neurochemical and inflammatory alterations.
Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Catequina/análogos & derivados , Dor Pós-Operatória/tratamento farmacológico , Analgésicos/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Catequina/farmacologia , Catequina/uso terapêutico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Receptores Frizzled/genética , Receptores Frizzled/metabolismo , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismoRESUMO
Endometriosis is a common gynecological disease. Here, we aimed to investigate the anti-fibrotic, anti-inflammatory, and anti-oxidative role of the methyl ester of 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO-Me) on endometriosis. An endometriosis rat model was constructed by intraperitoneally injecting recipient rats with an equivalent of tissue from the uterus of a donor animal. Endometriosis was allowed to develop for seven days. CDDO-Me was administered on the 7th day and for the next 7 days. On day 14, rats were sacrificed, and peritoneal fluid and endometriotic implants were collected. CDDO-Me displayed antioxidant activity by activating the Nfr2 pathway and the expression of antioxidant mediators such as NQO-1 and HO-1. Moreover, it reduced lipid peroxidation and increased glutathione (GSH) levels and superoxide dismutase (SOD) activity. CDDO-Me also showed anti-inflammatory activity by decreasing the expression of pro-inflammatory cytokines in peritoneal fluids and NFkB activation. It, in turn, reduced cyclooxygenase-2 (COX-2) expression in the endometriotic loci and prostaglandin E2 (PGE2) levels in the peritoneal fluids, leading to increased apoptosis and reduced angiogenesis. The reduced oxidative stress and pro-inflammatory microenvironment decreased implants diameter, area, and volume. In particular, CDDO-Me administration reduced the histopathological signs of endometriosis and inflammatory cells recruitment into the lesions, as shown by toluidine blue staining and myeloperoxidase (MPO) activity. CDDO-Me strongly suppressed α-SMA and fibronectin expression and collagen deposition, reducing endometriosis-associated fibrosis. In conclusion, CDDO-Me treatment resulted in a coordinated and effective suppression of endometriosis by modulating the Nrf2 and NFkB pathways.
Assuntos
Endometriose/tratamento farmacológico , Endometriose/patologia , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Ácido Oleanólico/análogos & derivados , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Microambiente Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Feminino , Fibrose , Inflamação/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Oxirredução , Estresse Oxidativo , Ratos Sprague-DawleyRESUMO
Endometriosis is a gynecological condition affecting patients in reproductive age. The aim of this paper was to assess the effects of the autophagy and mitophagy induction in a rat model of endometriosis. Endometriosis was induced by the injection of uterine fragments, and rapamycin (0. 5 mg/kg) was administered once per week. One week from the induction, rats were sacrificed, and laparotomy was performed to collect the endometriotic implants and to further process them for molecular analysis. Western blot analysis was conducted on explanted lesions to evaluate the autophagy pathway during the pathology. Elevated phospho-serine/threonine kinase (p-AKT) and mammalian target of rapamycin (mTOR) expressions were detected in vehicle-treated rats, while Beclin and microtubule-associated protein 1A/1B-light chain 3 II (LC3II) expressions were low. Additionally, samples collected from vehicle groups indicated low Bnip3, Ambra1, and Parkin expressions, demonstrating impaired autophagy and mitophagy. Rapamycin administration reduced p-AKT and mTOR expressions and increased Beclin and LC3II, Bnip3, Ambra1, and Parkin expressions, activating both mechanisms. We also evaluated the impact of the impaired autophagy and mitophagy pathways on apoptosis and angiogenesis. Rapamycin was administered by activating autophagy and mitophagy, which increased apoptosis (assessed by Western blot analysis of Bcl-2, Bax, and Cleaved-caspase 3) and reduced angiogenesis (assessed by immunohistochemical analysis of vascular endothelial grow factor (VEGF) and CD34) in the lesions. All of these mechanisms activated by the induction of the autophagy and mitophagy pathways led to the reduction in the lesions' volume, area and diameter.
Assuntos
Apoptose , Autofagia , Endometriose/patologia , Mitofagia , Serina-Treonina Quinases TOR/metabolismo , Animais , Endometriose/metabolismo , Feminino , Ratos , Ratos Sprague-DawleyRESUMO
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1ß, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Amidas/farmacologia , Citocinas/metabolismo , Etanolaminas/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Amidas/uso terapêutico , Animais , Etanolaminas/uso terapêutico , Imuno-Histoquímica , Inflamação/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Ácidos Palmíticos/uso terapêutico , Peroxidase/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Endometriosis is a common disease. Its pathogenesis still remains uncertain, but it is clear that cell proliferation, apoptosis and chronic inflammation play an important role in its development. This paper aimed to investigate the anti-proliferative and anti-inflammatory effects of a combined therapy with fotemustine and dexamethasone. Endometriosis was induced by intraperitoneal injections of uterine fragments from donor animals to recipient animals. Next, the pathology was allowed to develop for 7 days. On the seventh day, fotemustine was administered once and dexamethasone was administered daily for the next 7 days. On Day 14, the animals were sacrificed, and peritoneal fluids and lesions were explanted. In order to evaluate the gastrointestinal side effects of the drugs, stomachs were harvested as well. The combined therapy of fotemustine and dexamethasone reduced the proinflammatory mediator levels in the peritoneal fluid and reduced the lesions' area and diameter. In particular, fotemustine and dexamethasone administration reduced the heterogeneous development of endometrial stroma and glands (histological analysis of lesions) and hyperproliferation of endometriotic cells (immunohistochemical analysis of Ki67 and Western blot analysis of PCNA) through the mitogen-activated protein kinase (MAPK) signaling pathway. Combined fotemustine and dexamethasone therapy showed anti-inflammatory effects by inducing the synthesis of anti-inflammatory mediators at the transcriptional and post-transcriptional levels (Western blot analysis of NFκB, COX-2 and PGE2 expression). Fotemustine and dexamethasone administration had anti-apoptotic activity, restoring the impaired mechanism (TUNEL assay and Western blot analysis of Bax and Bcl-2). Moreover, no gastric disfunction was detected (histological analysis of stomachs). Thus, our data showed that the combined therapy of fotemustine and dexamethasone reduced endometriosis-induced inflammation, hyperproliferation and apoptosis resistance.