RESUMEN
PURPOSE: Metabolic syndrome (MS) is a major public health issue worldwide and fructose consumption has been associated with MS development. Recently, we showed that the dietary polyphenol chrysin is an effective inhibitor of fructose uptake by human intestinal epithelial cells. Therefore, our aim was to investigate if chrysin interferes with the development of MS induced by fructose in an animal model. METHODS: Adult male Sprague-Dawley rats (220-310 g) were randomly divided into four groups: (A) tap water (control), (B) tap water and a daily dose of chrysin (100 mg/kg) by oral administration (chrysin) (C) 10% fructose in tap water (fructose), and (D) 10% fructose in tap water and a daily dose of chrysin (100 mg/kg) by oral administration (fructose + chrysin). All groups were fed ad libitum with standard laboratory chow diet and dietary manipulation lasted 18 weeks. RESULTS: Fructose-feeding for 18 weeks induced an increase in serum triacylglycerols, insulin and angiotensin II levels and in hepatic fibrosis and these changes did not occur in fructose + chrysin rats. Moreover, the increase in both systolic and diastolic blood pressure which was found in fructose-fed animals from week 14th onwards was not observed in fructose + chrysin animals. In contrast, the increase in energy consumption, liver/body, heart/body and right kidney/body weight ratios, serum proteins, serum leptin and liver triacylglycerols observed in fructose-fed rats was not affected by chrysin. CONCLUSIONS: Chrysin was able to protect against some of the MS features induced by fructose-feeding.
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Dieta/métodos , Flavonoides/farmacología , Fructosa/administración & dosificación , Síndrome Metabólico/metabolismo , Síndrome Metabólico/prevención & control , Animales , Modelos Animales de Enfermedad , Flavonoides/metabolismo , Masculino , Polifenoles/metabolismo , Polifenoles/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Intake of fructose-containing sugars is epidemiological and experimentally linked to metabolic syndrome (MS). We recently verified that the dietary polyphenol chrysin was able to abolish some of the metabolic changes induced by fructose-feeding in the rat. Because the role of the intestine upon fructose-induced MS is poorly understood, we decided to investigate the influence of fructose, in vivo, on the intestinal environment and the ability of chrysin to interfere with the putative observed changes. For this, adult male Sprague-Dawley rats were treated for 18 weeks as follows: (A) tap water (CONT), (B) tap water and chrysin (100 mg kg-1 day-1) (CHRY), (C) 10% fructose in tap water (FRUCT), and (D) 10% fructose in tap water and chrysin (100 mg kg-1 day-1) (FRUCT + CHRY). Our findings show that the relative expression of SGLT1 and GLUT2 mRNA were not affected by fructose-feeding and/or chrysin. In contrast, GLUT5 mRNA expression was markedly increased in fructose-fed animals, and this effect was reduced by chrysin. However, the apparent permeability to 14C-FRUCT was markedly and similarly decreased in FRUCT, CHRY and FRUCT + CHRY rats. Jejunal villus width and crypt depth were significantly higher in FRUCT and FRUCT + CHRYS rats, respectively. Finally, chrysin did not alter gut microbiota composition, but fructose significantly increased Lactobacillus and E. coli. Moreover, FRUCT + CHRY rats had an increase on the Firmicutes to Bacteroidetes ratio. This is the first report showing that chrysin is able to interfere with the effects of fructose at the intestinal level, which may contribute to the fructose-induced MS features.
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Flavonoides/administración & dosificación , Microbioma Gastrointestinal/efectos de los fármacos , Intestinos/microbiología , Síndrome Metabólico/tratamiento farmacológico , Animales , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Fructosa/efectos adversos , Fructosa/metabolismo , Transportador de Glucosa de Tipo 2/genética , Transportador de Glucosa de Tipo 2/metabolismo , Humanos , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/microbiología , Ratas , Ratas Sprague-Dawley , Transportador 1 de Sodio-Glucosa/genética , Transportador 1 de Sodio-Glucosa/metabolismoRESUMEN
The worldwide incidence of bone disorders is raising, mainly due to aging population. The lack of effective treatments is pushing the development of synthetic bone substitutes (SBSs). Most ceramic-based SBSs commercially available display limited handling properties. Attempting to solve these issues and achieve wider acceptance by the clinicians, granular ceramics have been associated with hydrogels (HGs) to produce injectable/moldable SBSs. Dextrin, a low-molecular-weight carbohydrate, was used to develop a fully resorbable and injectable HG. It was first oxidized with sodium periodate and then cross-linked with adipic acid dihydrazide. The in vivo biocompatibility and safety of the dextrin-based HG was assessed by subacute systemic toxicity and skin sensitization tests, using rodent models. The results showed that the HG did not induce any systemic toxic effect, skin reaction, or genotoxicity, neither impaired the bone repair/regeneration process. Then, the HG was successfully combined with granular bone substitute, registered as Bonelike (250-500 µm) to obtain a moldable/injectable SBS, which was implanted in tibial fractures in goats for 3 and 6 weeks. The obtained results showed that HG allowed the stabilization of the granules into the defect, ensuring effective handling, and molding properties of the formulation, as well as an efficient cohesion of the granules. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1678-1689, 2019.
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Sustitutos de Huesos/farmacología , Dextrinas/toxicidad , Hidrogeles/toxicidad , Pruebas de Toxicidad , Animales , Femenino , Cobayas , Implantes Experimentales , Inyecciones , Masculino , Mutágenos/toxicidad , Oxidación-Reducción , Ratas Wistar , Fracturas de la Tibia/diagnóstico por imagen , Microtomografía por Rayos XRESUMEN
BACKGROUND: In birds there are reports of intracranial lesions but not of the clinical, computed tomographic and histopathologic features of acute intraparenchymal cerebral haemorrhage in Iberian golden eagle. CASE PRESENTATION: The following report describes a case of a 30-year-old Iberian golden eagle (Aquila chrysaetos homeyeri) with no history of trauma, presented with acute opisthotonus, left head tilt and circling, anisocoria, positional nystagmus, and ataxia. The main differential diagnosis were hypovitaminosis B or E and intracranial disease due to trauma, infection, toxins or masses. A computed tomography (CT) of the head was performed with an 8-slices scanner and evidenced a hyperdense (63-65 HU) non-enhancing homogeneous well delineated round area in the midbrain, with 6 mm in its highest diameter. The attenuation values and the non-enhancing nature of the lesion strongly suggested the diagnosis of acute intraparenchymal haemorrhage, which was histologically confirmed after necropsy. CONCLUSIONS: In birds with a central neurological dysfunction, the diagnosis of acute brain haemorrhage should be considered when the CT evidences a non-enhancing, homogeneous, well circumscribed hyperattenuated round area.
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Enfermedades de las Aves/diagnóstico , Hemorragia Cerebral/veterinaria , Águilas , Animales , Animales de Zoológico , Enfermedades de las Aves/diagnóstico por imagen , Enfermedades de las Aves/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/diagnóstico por imagen , Hemorragia Cerebral/patología , Neuroimagen/veterinaria , Tomografía Computarizada por Rayos X/veterinariaRESUMEN
Endocrine-disrupting chemicals such as p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), are bioaccumulated in the adipose tissue (AT) and have been implicated in the obesity and diabetes epidemic. Thus, it is hypothesized that p,p'-DDE exposure could aggravate the harm of an obesogenic context. We explored the effects of 12 weeks exposure in male Wistar rats' metabolism and AT biology, assessing a range of metabolic, biochemical and histological parameters. p,p'-DDE -treatment exacerbated several of the metabolic syndrome-accompanying features induced by high-fat diet (HF), such as dyslipidaemia, glucose intolerance and hypertension. A transcriptome analysis comparing mesenteric visceral AT (vAT) of HF and HF/DDE groups revealed a decrease in expression of nervous system and tissue development-related genes, with special relevance for the neuropeptide galanin that also revealed DNA methylation changes at its promoter region. Additionally, we observed an increase in transcription of dipeptidylpeptidase 4, as well as a plasmatic increase of the pro-inflammatory cytokine IL-1ß. Our results suggest that p,p'-DDE impairs vAT normal function and effectively decreases the dynamic response to energy surplus. We conclude that p,p'-DDE does not merely accumulate in fat, but may contribute significantly to the development of metabolic dysfunction and inflammation. Our findings reinforce their recognition as metabolism disrupting chemicals, even in non-obesogenic contexts.
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Diclorodifenil Dicloroetileno/administración & dosificación , Disruptores Endocrinos/administración & dosificación , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Obesidad/metabolismo , Animales , Citocinas/metabolismo , Expresión Génica , Inflamación/inducido químicamente , Inflamación/metabolismo , Lipólisis , Masculino , Neuropéptidos/metabolismo , Obesidad/inducido químicamente , Ratas Wistar , TranscriptomaRESUMEN
Anterior cruciate ligament (ACL) reconstructive surgeries are the most frequent orthopedic procedures in the knee. Currently, existing strategies fail in completely restoring tissue functionality and have a high failure rate associated, presenting a compelling argument towards the development of novel materials envisioning ACL reinforcement. Tendons and ligaments, in general, have a strong demand in terms of biomechanical features of developed constructs. We have previously developed polylactic acid (PLA)-based biodegradable films reinforced either with graphene nanoplatelets (PLA/GNP) or with carboxyl-functionalized carbon nanotubes (PLA/CNT-COOH). In the present study, we comparatively assessed the biological performance of PLA, PLA/GNP, and PLA/CNT-COOH by seeding human dermal fibroblasts (HFF-1) and studying cell viability and proliferation. In vivo tests were also performed by subcutaneous implantation in 6-week-old C57Bl/6 mice. Results showed that all formulations studied herein did not elicit cytotoxic responses in seeded HFF-1, supporting cell proliferation up to 3 days in culture. Moreover, animal studies indicated no physiological signs of severe inflammatory response after 1 and 2 weeks after implantation. Taken together, our results present a preliminary assessment on the compatibility of PLA reinforced with GNP and CNT-COOH nanofillers, highlighting the potential use of these carbon-based nanofillers for the fabrication of reinforced synthetic polymer-based structures for ACL reinforcement. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2182-2190, 2017.
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Materiales Biocompatibles/química , Fibroblastos/citología , Grafito/química , Nanotubos de Carbono/química , Poliésteres/química , Implantes Absorbibles , Animales , Ligamento Cruzado Anterior/cirugía , Línea Celular , Proliferación Celular , Supervivencia Celular , Humanos , Ligamentos/cirugía , Ratones , Ratones Endogámicos C57BL , Nanocompuestos/química , Procedimientos de Cirugía Plástica , Tendones/cirugíaRESUMEN
Type 2 diabetes mellitus (T2DM) is a chronic disease characterized by metabolic disturbances in specific tissues. The present work aimed to analyze the effects of xanthohumol (XN) and 8-prenylnaringenin (8PN), two beer-derived polyphenols, in liver and skeletal muscle lipid and glycolytic metabolism in T2DM mice model. Thirty C57Bl/6 mice were randomly divided into five groups: standard diet (control), high-fat diet (DM), high-fat diet plus ethanol (DM-Ethanol), high-fat diet plus 10 mg/L XN (DM-XN) and high-fat diet plus 10 mg/L 8PN (DM-8PN) during 20 weeks. Fasting blood glucose and insulin tolerance tests were performed 1 week before sacrifice. At the end of the study, blood, liver and skeletal muscle were collected. Both XN and 8PN treatments prevented body weight gain; decreased glycemia, triglyceride, cholesterol and alkaline phosphatase levels; and improved insulin sensitivity. Polyphenols promoted hepatic and skeletal muscle AMP-activated protein kinase (AMPK) activation, diminishing the expression of target lipogenic enzymes (sterol regulatory element binding protein-1c and fatty acid synthase) and acetyl-CoA carboxylase activity. Moreover, both XN and 8PN treatments decreased VEGFR-1/VEGFB pathway, involved in fatty acid uptake, and increased AS160 expression, involved in GLUT4 membrane translocation. Presented data demonstrated that both XN and 8PN treatment resulted in AMPK signaling pathway activation, thus suppressing lipogenesis. Their consumption prevented body weight gain and improved plasma lipid profile, with significant improvement of insulin resistance and glucose tolerance. XN- or 8PN-enriched diet could ameliorate diabetic-associated metabolic disturbances by regulating glucose and lipid pathways.
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Diabetes Mellitus Tipo 2/metabolismo , Flavanonas/farmacología , Flavonoides/farmacología , Propiofenonas/farmacología , Acetil-CoA Carboxilasa/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/prevención & control , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/prevención & control , Dieta Alta en Grasa/efectos adversos , Glucólisis/efectos de los fármacos , Resistencia a la Insulina , Lípidos/sangre , Masculino , Ratones Endogámicos C57BL , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismo , Receptor fas/metabolismoRESUMEN
Erectile dysfunction (ED) is a complication of diabetes, condition responsible for causing endothelial dysfunction (EDys) and hampering repair mechanisms. However, scarce information is available linking vasculogenesis mediated by Endothelial Progenitor Cells (EPCs) and diabetes-associated ED. Furthermore, it remains to be elucidated if glycemic control plays a role on EPCs functions, EPCs modulators, and penile vascular health. We evaluated the effects of diabetes and insulin therapy on bone marrow (BM) and circulating EPCs, testosterone, and systemic/penile Stromal Derived Factor-1 alpha (SDF-1α) expression. Male Wistar rats were divided into groups: age-matched controls, 8-weeks streptozotocin-induced type 1 diabetics, and insulin-treated 8-weeks diabetics. EPCs were identified by flow cytometry for CD34/CD133/VEGFR2/CXCR4 antigens. Systemic SDF-1α and testosterone levels were evaluated by ELISA. Penile SDF-1α protein expression was assessed, in experimental and human diabetic cavernosal samples, by immunohistochemical techniques. Diabetic animals presented a reduction of BM-derived EPCs and an increase in putative circulating endothelial cells (CECs) sloughed from vessels wall. These alterations were rescued by insulin therapy. In addition, glycemic control promoted an increase in systemic testosterone and SDF-1α levels, which were significantly decreased in animals with diabetes. SDF-1α protein expression was reduced in experimental and human cavernosal diabetic samples, an effect prevented by insulin in treated animals. Insulin administration rescued the effects of diabetes on BM function, CECs levels, testosterone, and plasmatic/penile SDF-1α protein expression. This emphasizes the importance of glycemic control in the prevention of diabetes-induced systemic and penile EDys, by the amelioration of endothelial damage, and increase in protective pathways. J. Cell. Biochem. 118: 82-91, 2017. © 2016 Wiley Periodicals, Inc.
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Quimiocina CXCL12/sangre , Complicaciones de la Diabetes/sangre , Diabetes Mellitus Experimental/sangre , Impotencia Vasculogénica/sangre , Testosterona/sangre , Animales , Complicaciones de la Diabetes/terapia , Diabetes Mellitus Experimental/terapia , Impotencia Vasculogénica/prevención & control , Masculino , Ratas , Ratas WistarRESUMEN
SCOPE: Imbalance in kidney and heart neovascularization is common in type2 diabetes (T2DM) patients. Nevertheless, the mechanisms governing this angiogenic paradox have not been elucidated. Xanthohumol (XN) and 8-prenylnaringenin (8PN) beer polyphenols modulate angiogenesis, being thus targets for T2DM-related complications. Our work examined whether polyphenols consumption affects angiogenic paradox and metabolism in a T2DM mouse model. METHODS AND RESULTS: An increase in kidney and a reduction in left ventricle (LV) microvessels of diabetic C57Bl/6 mice were observed. XN consumption reduced angiogenesis, VEGFR-2 expression/activity, VEGF-A and phosphofructokinase-2/fructose-2,6-bisphosphatase-3 enzyme expression, a metabolic marker present in endothelial tip cells in T2DM mice kidney. 8PN had opposite effects in T2DM mice LV. These XN and 8PN effects were dependent on VEGF levels as revealed by in vitro assays. These findings were accompanied by tissue and plasma reduced expression levels of VEGF-B and its receptors, VEGFR1 and neuropilin-1, by both polyphenols. CONCLUSION: Beer polyphenols modulate T2DM angiogenic paradox in a tissue-dependent manner. We also show for the first time that both polyphenols decreased VEGF-B pathway, which is implicated in endothelial-to-tissue lipid metabolism. Altogether, the effects of these polyphenols in the crosstalk between angiogenesis and metabolism render them potent agents for novel diabetic therapeutic interventions.
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Inductores de la Angiogénesis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Flavanonas/farmacología , Flavonoides/farmacología , Propiofenonas/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Complicaciones de la Diabetes/tratamiento farmacológico , Humanos , Ratones , Neovascularización Patológica/metabolismo , Polifenoles/farmacología , Transducción de Señal , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
This study aimed to validate the antihypertensive activity of the angiotensin-converting enzyme (ACE)-inhibitor whey protein hydrolysate (WPH) obtained through the action of proteolytic enzymes from Cynara Cardunculus. The antihypertensive activity of WPH fractions containing peptides with molecular weight below 3kDa (Whey<3kDa) and 1kDa (Whey<1kDa) along with the antihypertensive activity of three potent ACE-inhibitory peptide sequences (DKVGINYW, DAQSAPLRVY and KGYGGVSLPEW), previously identified in WPH, were also investigated. In parallel, the influence of KGYGGVSLPEW (the most potent ACE-inhibitory peptide sequence) on AT1 receptors (a common pharmacological target of antihypertensive therapies beyond ACE), was evaluated. The effect of WPH and fractions (300mg/kg) and peptide sequences (5mg/kg) on systolic, diastolic and mean blood pressure was evaluated by telemetry on spontaneously hypertensive rats (SHR), after single oral administration. Despite their ACE-inhibitory effect in vitro, neither WPH, Whey <3kDa, Whey <1kDa or peptide sequences exhibited antihypertensive activity. In addition, KGYGGVSLPEW was not only devoid of AT1 receptor antagonism but, on the contrary, had a similar effect to that of Ang II by facilitating the noradrenaline release from sympathetic nerve terminals. In vitro ACE blockade does not always correlate with antihypertensive activity and food-derived peptides cannot be classified as antihypertensive agents based exclusively on in vitro assays. The absence of an antihypertensive effect may also be a result of the interaction of these compounds with other components of the systems involved in the blood pressure control.
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Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Cynara/química , Tejido Nervioso/metabolismo , Norepinefrina/metabolismo , Oligopéptidos/farmacología , Proteínas de Plantas/farmacología , Receptor de Angiotensina Tipo 1/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Oligopéptidos/química , Proteínas de Plantas/química , Ratas , Ratas Endogámicas SHRRESUMEN
The aim of this study was to understand whether high folic acid (HFA) exposure during the perigestational period induces metabolic dysfunction in the offspring, later in life. To do this, female Sprague-Dawley rats (G0) were administered a dose of folic acid (FA) recommended for pregnancy (control, C, 2âmg FA/kg of diet, n=5) or a high dose of FA (HFA, 40âmg FA/kg of diet, n=5). Supplementation began at mating and lasted throughout pregnancy and lactation. Body weight and food and fluid intake were monitored in G0 and their offspring (G1) till G1 were 13 months of age. Metabolic blood profiles were assessed in G1 at 3 and 13 months of age (3M and 13M respectively). Both G0 and G1 HFA females had increased body weight gain when compared with controls, particularly 22 (G0) and 10 (G1) weeks after FA supplementation had been stopped. G1 female offspring of HFA mothers had increased glycemia at 3M, and both female and male G1 offspring of HFA mothers had decreased glucose tolerance at 13M, when compared with matched controls. At 13M, G1 female offspring of HFA mothers had increased insulin and decreased adiponectin levels, and G1 male offspring of HFA mothers had increased levels of leptin, when compared with matched controls. In addition, feeding of fructose to adult offspring revealed that perigestational exposure to HFA renders female progeny more susceptible to developing metabolic unbalance upon such a challenge. The results of this work indicate that perigestational HFA exposure the affects long-term metabolic phenotype of the offspring, predisposing them to an insulin-resistant state.
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Ácido Fólico/efectos adversos , Enfermedades Metabólicas/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Animales , Animales Recién Nacidos , Suplementos Dietéticos , Relación Dosis-Respuesta a Droga , Femenino , Ácido Fólico/administración & dosificación , Hiperfagia/inducido químicamente , Hiperfagia/metabolismo , Masculino , Enfermedades Metabólicas/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Aumento de Peso/efectos de los fármacosRESUMEN
Type 1 diabetes mellitus is responsible for metabolic dysfunction, accompanied by chronic inflammation, oxidative stress, and endothelium dysfunction, and is often associated with impaired wound healing. Phenol-rich food improves vascular function, contributing to diabetes prevention. This study has evaluated the effect of phenol-rich beverage consumption in diabetic rats on wound healing, through angiogenesis, inflammation, and oxidative stress modulation. A wound-healing assay was performed in streptozotocin-induced diabetic Wistar rats drinking water, 5% ethanol, and stout beer with and without 10 mg/L xanthohumol (1), for a five-week period. Wounded skin microvessel density was reduced to normal values upon consumption of 1 in diabetic rats, being accompanied by decreased serum VEGF-A and inflammatory markers (IL-1ß, NO, N-acetylglucosaminidase). Systemic glutathione and kidney and liver H2O2, 3-nitrotyrosine, and protein carbonylation also decreased to healthy levels after treatment with 1, implying an improvement in oxidative stress status. These findings suggest that consumption of xanthohumol (1) by diabetic animals consistently decreases inflammation and oxidative stress, allowing neovascularization control and improving diabetic wound healing.
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Inductores de la Angiogénesis/metabolismo , Flavonoides/farmacología , Estrés Oxidativo/efectos de los fármacos , Propiofenonas/farmacología , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Flavonoides/química , Glutatión/metabolismo , Peróxido de Hidrógeno/metabolismo , Inflamación/complicaciones , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Hígado/metabolismo , Masculino , Neovascularización Patológica/metabolismo , Fenoles/farmacología , Propiofenonas/química , Ratas , Ratas Wistar , Piel/efectos de los fármacos , Tirosina/análogos & derivados , Factor A de Crecimiento Endotelial Vascular/metabolismo , Cicatrización de Heridas/efectos de los fármacosRESUMEN
AIMS: Obesity and asthma are widely prevalent and associated disorders. Recent studies of our group revealed that Substance P (SP) is involved in pathophysiology of obese-asthma phenotype in mice through its selective NK1 receptor (NK1-R). Lymphangiogenesis is impaired in asthma and obesity, and SP activates contractile and inflammatory pathways in lymphatics. Our aim was to study whether NK1-R expression was involved in lymphangiogenesis on visceral (VAT) and subcutaneous (SAT) adipose tissues and in the lungs, in obese-allergen sensitized mice. MAIN METHODS: Diet-induced obese and ovalbumin (OVA)-sensitized Balb/c mice were treated with a selective NK1-R antagonist (CJ 12,255, Pfizer Inc., USA) or placebo. Lymphatic structures (LYVE-1+) and NK1-R expression were analyzed by immunohistochemistry. A semi-quantitative score methodology was used for NK1-R expression. KEY FINDINGS: Obesity and allergen-sensitization together increased the number of LYVE-1+ lymphatics in VAT and decreased it in SAT and lungs. NK1-R was mainly expressed on adipocyte membranes of VAT, blood vessel areas of SAT, and in lung epithelium. Obesity and allergen-sensitization combined increased the expression of NK1-R in VAT, SAT and lungs. NK1-R antagonist treatment reversed the effects observed in lymphangiogenesis in those tissues. SIGNIFICANCE: The obese-asthma phenotype in mice is accompanied by increased expression of NK1-R on adipose tissues and lung epithelium, reflecting that SP released during inflammation may act directly on these tissues. Blocking NK1-R affects lymphangiogenesis, implying a role of SP, with opposite physiological consequences in VAT, and in SAT and lungs. Our results provide a clue for a novel SP role in the obese-asthma phenotype.
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Asma/metabolismo , Regulación de la Expresión Génica , Vasos Linfáticos/metabolismo , Obesidad/metabolismo , Receptores de Neuroquinina-1/biosíntesis , Animales , Asma/patología , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Pulmón/metabolismo , Pulmón/patología , Vasos Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Obesidad/patología , Fenotipo , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/patología , Grasa Subcutánea Abdominal/metabolismo , Grasa Subcutánea Abdominal/patologíaRESUMEN
AIM: A number of studies have shown an association between obesity and asthma. Controversy remains on the mechanisms supporting this association. In this study we aimed to assess neurogenic inflammation in a model of diet-induced obesity and allergen-challenged mice. METHODS: High fat diet-induced (HFD) obese Balb/c mice were sensitized and challenged with ovalbumin (OVA). Glucose, insulin, OVA-specific IgE and substance P (SP), and the main tachykinin involved in neurogenic inflammation, were quantified in sera. Cell counts were performed in bronchoalveolar lavage fluid (BALF). The extent of peribronchial infiltrates was estimated on lung tissue sections and inflammation was score based on inflammatory cell counts surrounding the bronchi. RESULTS: Obesity per se and allergen-sensitization per se increased serum SP (P = .027, P = .004, respectively). Further increased was observed in obese-sensitized mice (P = .007). Obese-sensitized mice also showed higher insulin (P = .0016), OVA-specific IgE (P = .016), peribronchial inflammatory score (P = .045), and tendency for higher glycemia. The interaction of obesity and asthma on SP levels was confirmed (P = .005, R(2) = 0.710). SP was positively correlated with metabolic (glycemia, r = 0.539, P = .007) and allergic inflammation parameters (BALF eosinophils, r = 0.445, P = 0.033; BALF mast cells, r = 0.574, P = .004; peribronchial inflammation score, r = 0.661, P < .001; and OVA-specific IgE, r = 0.714, P < .001). CONCLUSIONS: Our findings provide support to the neurogenic inflammation link between obesity and asthma in mice. These two conditions independently increased SP and the presence of both pathologies further increased this level. Neurogenic inflammation may be a previously unrecognized mechanism beyond the obese-asthma phenotype. Further studies are need to confirm this role of SP in human obesity-asthma association.
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Alérgenos/inmunología , Asma/inmunología , Asma/patología , Inflamación Neurogénica/inmunología , Inflamación Neurogénica/patología , Obesidad/inmunología , Obesidad/patología , Animales , Glucemia/inmunología , Glucemia/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Recuento de Células , Dieta Alta en Grasa , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Insulina/sangre , Insulina/inmunología , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Obesos , Ovalbúmina/inmunología , Sustancia P/sangre , Sustancia P/inmunología , Taquicininas/sangre , Taquicininas/inmunologíaRESUMEN
The bacterial cellulose (BC) secreted by Gluconacetobacter xylinus is a network of pure cellulose nanofibres which has high crystallinity, wettability and mechanical strength. These characteristics make BC an excellent material for tissue-engineering constructs, noteworthy for artificial vascular grafts. In this work, the in vivo biocompatibility of BC membranes produced by two G. xylinus strains was analyzed through histological analysis of long-term subcutaneous implants in the mice. The BC implants caused a mild and benign inflammatory reaction that decreased along time and did not elicit a foreign body reaction. A tendency to calcify over time, which may be related to the porosity of the BC implants, was observed, especially among the less porous BC-1 implants. In addition, the potential toxicity of BC nanofibres - obtained by chemical-mechanical treatment of BC membranes - subcutaneously implanted in mice was analysed through bone marrow flow cytometry and histological analyses. At 2 and 4 months post-implantation, the nanofibres implants were found to accumulate intracellularly, in subcutaneous foamy macrophages aggregates. Moreover, no differences were observed between the controls and implanted animals in thymocyte populations and in B lymphocyte precursors and myeloid cells in the bone marrow.
Asunto(s)
Celulosa , Gluconacetobacter xylinus , Nanofibras , Animales , Médula Ósea/patología , Médula Ósea/fisiología , Calcificación Fisiológica , Celulosa/química , Citometría de Flujo , Gluconacetobacter xylinus/química , Implantes Experimentales/efectos adversos , Masculino , Ensayo de Materiales , Membranas Artificiales , Ratones Endogámicos BALB C , Microscopía Electrónica de Rastreo , Nanofibras/química , Porosidad , Tejido Subcutáneo/irrigación sanguínea , Tejido Subcutáneo/patología , Tejido Subcutáneo/fisiología , Factores de TiempoRESUMEN
Angiogenesis and inflammation are two intermingled processes that play a role in wound healing. Nevertheless, whenever exacerbated, these processes result in nonhealing wounds. Xanthohumol (XN), a beer-derived polyphenol, inhibits these processes in many physiopathological situations. This study aimed at examining whether XN ingestion affects wound healing. Wistar rats drinking water, 5% ethanol, stout beer (SB) or stout beer supplemented with 10 mg/L XN (Suppl SB) for 4 weeks, were subjected to a 1.5 cm full skin-thickness longitudinal incision, and further maintained under the same beverage conditions for another week. No differences in beverage consumption or body weight were found throughout the study but food intake decreased in every group relative to controls. Consumption of Suppl SB resulted in decreased serum VEGF levels (18.42%), N-acetylglucosaminidase activity (27.77%), IL1ß concentration (9.07%), and NO released (77.06%), accompanied by a reduced redox state as observed by increased GSH/GSSG ratio (to 198.80%). Also, the number of blood vessels within the wound granulation tissue seems to reduce in animals drinking Suppl SB (23.08%). Interestingly, SB and primarily Suppl SB showed a tendency to increase adipocyte number (to 194.26% and 156.68%, respectively) and reduce adipocyte size (4.60% and 24.64%, respectively) within the granuloma. Liver function and metabolism did not change among the animal groups as analyzed by plasma biochemical parameters, indicating no beverage toxicity. This study shows that XN intake in its natural beer context reduced inflammation, oxidative stress, and angiogenesis, ameliorating the wound healing process, suggesting that this polyphenol may exert beneficial effect as a nutritional supplement.
Asunto(s)
Adipocitos/efectos de los fármacos , Cerveza , Flavonoides/farmacología , Inflamación/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Propiofenonas/farmacología , Cicatrización de Heridas/efectos de los fármacos , Acetilglucosaminidasa/metabolismo , Animales , Suplementos Dietéticos , Glutatión/sangre , Granuloma/metabolismo , Interleucina-1beta/metabolismo , Óxido Nítrico/metabolismo , Oxidación-Reducción/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , Piel/efectos de los fármacos , Piel/lesiones , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
Antimicrobial peptides (AMPs) are part of the innate immune system and are generally defined as cationic, amphipathic peptides, with less than 50 amino acids, including multiple arginine and lysine residues. The human cathelicidin antimicrobial peptide LL37 can be found at different concentrations in many different cells, tissues and body fluids and has a broad spectrum of antimicrobial and immunomodulatory activities. The healing of wound is a complex process that involves different steps: hemostasis, inflammation, remodeling/granulation tissue formation and re-epithelialization. Inflammation and angiogenesis are two fundamental physiological conditions implicated in this process. We have recently developed a new method for the expression and purification of recombinant LL37. In this work, we show that the recombinant peptide P-LL37 with a N-terminus proline preserves its immunophysiological properties in vitro and in vivo. P-LL37 neutralized the activation of macrophages by lipopolysaccharide (LPS). Besides, the peptide induced proliferation, migration and tubule-like structures formation by endothelial cells. Wound healing experiments were performed in dexamethasone-treated mice to study the effect of LL37 on angiogenesis and wound regeneration. The topical application of synthetic and recombinant LL37 increased vascularization and re-epithelialization. Taken together, these results clearly demonstrate that LL37 may have a key role in wound regeneration through vascularization.