RESUMEN
Diet is the primary factor affecting host nutrition and metabolism, with excess food intake, especially high-calorie diets, such as high-fat and high-sugar diets, causing an increased risk of obesity and related disorders. Obesity alters the gut microbial composition and reduces microbial diversity and causes changes in specific bacterial taxa. Dietary lipids can alter the gut microbial composition in obese mice. However, the regulation of gut microbiota and host energy homeostasis by different polyunsaturated fatty acids (PUFAs) in dietary lipids remains unknown. Here, we demonstrated that different PUFAs in dietary lipids improved host metabolism in high-fat diet (HFD)-induced obesity in mice. The intake of the different PUFA-enriched dietary lipids improved metabolism in HFD-induced obesity by regulating glucose tolerance and inhibiting colonic inflammation. Moreover, the gut microbial compositions were different among HFD and modified PUFA-enriched HFD-fed mice. Thus, we have identified a new mechanism underlying the function of different PUFAs in dietary lipids in regulating host energy homeostasis in obese conditions. Our findings shed light on the prevention and treatment of metabolic disorders by targeting the gut microbiota.
Asunto(s)
Dieta Alta en Grasa , Grasas de la Dieta , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , Grasas de la Dieta/farmacología , Obesidad/metabolismo , Ácidos Grasos Insaturados/efectos adversos , Inflamación/metabolismo , Ratones Endogámicos C57BL , Metabolismo de los LípidosRESUMEN
BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. IBS is characterized by recurrent chronic abdominal pain and altered bowel habits in the absence of organic damage. Although there are reviews and guidelines for treating IBS, the complexity and diversity of IBS presentation make treatment difficult. Treatment of IBS focuses on relieving symptoms as mild signs and symptoms can often be controlled by managing stress and by making changes in diet and lifestyle. The use of nutraceutical compounds has been advocated as a possible alternative treatment in patients with IBS. COLONIR® (Omega Pharma Srl, Milan, Italy) may be an alternative or adjuvant treatment in patients with gastrointestinal symptoms. This study aimed to evaluate the effect of this new nutraceutical formulation in inducing symptoms remission and improve gastrointestinal habits. METHODS: An initial cohort of 1004 consecutive patients referred to 25 different Units of Internal Medicine a/o Gastroenterology in Italy to perform colonoscopy for intestinal symptoms was asked to participate. Patients were treated for 2 months with two doses of nutraceuticals/day during meals namely COLONIR®. Patients were assessed at baseline and after 2 months to evaluate the frequency and severity of gastrointestinal symptoms in the past seven days with a questionnaire based on ROMA IV criteria. RESULTS: After 2 months, 899 patients completed the follow-up. COLONIR® achieved a statistically significant reduction of severity of symptoms in the study population without any documented side effects. CONCLUSIONS: These promising results, here reported, need to be confirmed, valuating the efficacy of COLONIR® in relieving gastrointestinal symptoms in IBS patients in further studies.
Asunto(s)
Dolor Crónico , Esencias Florales , Enfermedades Gastrointestinales , Glycyrrhiza , Síndrome del Colon Irritable , Mentha , Probióticos , Humanos , Síndrome del Colon Irritable/complicaciones , Síndrome del Colon Irritable/tratamiento farmacológico , Carbón Orgánico , Triptófano , Manzanilla , Suplementos Dietéticos , Dolor Abdominal/tratamiento farmacológico , Dolor Abdominal/etiologíaRESUMEN
Alternative or complementary treatments to a gluten-free diet are urgently needed for Celiac Disease. By exploiting the health-promoting properties of polyphenols on a transgenic mouse model of Celiac Disease enteropathy, this study provides the first in vivo evidence regarding the ability of 1 mg day-1 doses of green tea catechins and grape seed procyanidins to ameliorate some of the most characteristic histological changes of gliadin-treated DQ8 mice, including villus flattening, crypt hyperplasia, and infiltration of intraepithelial lymphocytes. Mechanistically, polyphenols were found to increase the intestinal nucleophilic tone of DQ8 mice by orchestrating an adaptive antioxidant response characterized by enhanced GSR enzyme activity and GSH content. Taken together, this work constitutes a highly relevant breakthrough as it provides the fundamental basis concerning the significance of natural polyphenols to be used in, for instance, the development of innovative functional foods aimed at CD individuals.
Asunto(s)
Biflavonoides/uso terapéutico , Catequina/uso terapéutico , Enfermedad Celíaca/tratamiento farmacológico , Enfermedades Intestinales/tratamiento farmacológico , Proantocianidinas/uso terapéutico , Semillas/química , Té/química , Vitis/química , Animales , Antioxidantes/uso terapéutico , Biflavonoides/química , Catequina/química , Modelos Animales de Enfermedad , Gliadina/uso terapéutico , Mucosa Intestinal , Masculino , Ratones , Ratones Transgénicos , Proantocianidinas/químicaRESUMEN
Polyunsaturated fatty acids (PUFA) are fundamental building materials for cells and play crucial function as signaling molecules. When PUFA are used as substrates for non-enzymatic or enzymatic reactions and gut microbiota metabolism, they can generate electrophilic derivatives (called Reactive Lipid Species, RLS) that promptly form adducts with nucleophilic molecules. RLS participate in several signaling pathways, including the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, which is the key mechanism in the maintenance of redox, metabolic and protein homeostasis, as well as the regulation of inflammation. Recent studies have provided insights on the localization of enzymes that synthesise reactive oxygen or nitrogen species (ROS or RNS respectively) in plasma membrane compartments (raft/caveolae) which also harbour PUFA esters, from which free acid forms can be released by phospholipase A2 activity (PLA2), and the complex of Nrf2 with the inhibitory protein Kelch-like ECH-associated Protein 1(Keap1). Additional investigations have indicated that dietary PUFA insertion into specific plasma membrane microdomains may alter the lipid environment and thereby influence caveolar composition and cell signaling. Given that PUFA-originated RLS attack such a complex and promote the release of active Nrf2, it cannot be excluded that all the biochemical machinery for Nrf2 activation is present in caveolae, where it triggers the Nrf2-mediated adaptive response for rescuing or maintaining cellular redox homeostasis. Here, we specifically aimed to summarize current information with regard to the roles of dietary PUFA and RLS in Nrf2-mediated redox homeostasis, namely 1) their role as Nrf2 activators, 2) the significance of the in vivo conversion of PUFA into RLS and 3) the caveolar involvement in cell signaling for redox homeostasis.
Asunto(s)
Grasas Insaturadas en la Dieta/farmacología , Ácidos Grasos Insaturados/metabolismo , Ácidos Grasos Insaturados/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Microbioma Gastrointestinal , Homeostasis , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Metabolismo de los Lípidos , Oxidación-Reducción , Proteínas Quinasas/metabolismoRESUMEN
SCOPE: Polyphenols exhibit their antioxidant activity downstream the activation of the nuclear factor erythroid 2-related factor 2 pathway (Nrf2), but the connection between lipid metabolism and the Nrf2 pathway is still unknown. Flavonoid-rich concentrated extract from Prunus mahaleb (mahaleb concentrated fruit extract; MCFE) may act on oxido-reductive homeostasis and hepatic lipid metabolism via Nrf2. METHODS & RESULTS: MCFE ability to enhance the activity of Nrf2-mediated antioxidant/detoxifying enzymes is investigated in liver and colon of BALB/c mice. After a 4-week supplementation, macroscopic, histological, and biochemical signs of colitis are examined in mouse colon pulsed with 5% (w/v) dextran sodium sulfate (DSS). Untreated or DSS-supplemented mice are used as negative or positive control. MCFE effect on liver lipid metabolism and its possible link with the Nrf2 pathway is investigated. MCFE intake increases antioxidant defenses in mice colon and its pretreatment blunts pathological signs of colitis, as compared to positive control. In the liver, the increase in antioxidant defenses is associated with enhanced oxidative metabolism and with higher levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and of hemeoxygenase-1 (HO-1), in comparison with negative controls. CONCLUSION: Cytoprotective and hypolipidemic effect produced by MCFE intake results, at least in part, by the activation of the Nrf2 pathway.
Asunto(s)
Colitis/prevención & control , Mitocondrias/efectos de los fármacos , Factor 2 Relacionado con NF-E2/fisiología , Extractos Vegetales/farmacología , Prunus , Animales , Sulfato de Dextran , Femenino , Frutas , Metabolismo de los Lípidos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Mitocondrias/metabolismo , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
Inflammation and oxidative stress play an important role in the pathogenesis of depressive disorders and nuclear erythroid related factor 2 (Nrf2), a regulator of RedOx homeostasis and inflammation, is a promising target for depression prevention/treatment. As fish oil (FO) and conjugated linoleic acid (CLA) are known Nrf2 inducers, their protective ability is comparatively evaluated in a murine model of depression (MRL/MpJ-Faslpr ). Oxidative stress, fatty acids content, and critical factors reflecting brain functioning-namely brain-derived neurotrophic factor (BDNF), synaptic markers, and cholinergic signaling-are preliminarily evaluated in the frontal cortex of 8-week (Young) and in 22-week old animals (Old), which are used as model of depression. These markers are measured in Old mice at the end of a 5-week pretreatment with FO or CLA (728 or 650 mg kg-1 , respectively). Old mice exhibit disrupted Redox homeostasis, compensatory Nrf2 hyperactivation, lower docosaheaxaenoic acid (DHA), and lower BDNF and synaptic function proteins compared to Young mice. FO and CLA treatment relieves almost all the pathophysiological hallmarks at a level comparable to Young mice. Presented data provide the first evidence for the comparable efficacy of FO or CLA supplementation in preventing depression signs in Old MRL/lpr mice, likely through their ability of improving Nrf2-mediated antioxidant defenses.
Asunto(s)
Encéfalo/efectos de los fármacos , Depresión/dietoterapia , Aceites de Pescado/farmacología , Ácidos Linoleicos Conjugados/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Envejecimiento , Animales , Antidepresivos/farmacología , Autoinmunidad/efectos de los fármacos , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Depresión/metabolismo , Depresión/patología , Suplementos Dietéticos , Ácidos Docosahexaenoicos/metabolismo , Elongasas de Ácidos Grasos/genética , Ácidos Grasos/metabolismo , Inflamación/dietoterapia , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones Endogámicos MRL lpr , Estrés Oxidativo/efectos de los fármacos , Estearoil-CoA Desaturasa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Oxidative stress is a key mediator of autoimmune/neurodegenerative disorders. The antioxidant/anti-inflammatory effect of a synthetic conjugated linoleic acid (CLA) mixture in MRL/MpJ-Fas lpr mice (MRL/lpr), an animal model of neuropsychiatric lupus, was previously associated with the improvement of nuclear factor-E2-related factor 2 (Nrf2) defenses in the spleen and liver. However, little is known about the neuroprotective ability of a CLA mixture. This study investigated the age-dependent progression of oxidative stress and the hyperactivation of redox-sensitive compensatory pathways (macroautophagy, Nrf2) in old/diseased MRL/lpr mice brains and examines the effect produced by dietary CLA supplementation. Disrupted redox homeostasis was evidenced in the blood, liver, and brain of 21- to 22-week-old MRL/lpr (Old) mice compared with 8- to 10-week-old MRL/lpr (Young) animals. This alteration was associated with significant hyperactivation of compensatory mechanisms (macroautophagy, Nrf2, and astrocyte activation) in the brains of Old mice. Five-week daily supplementation with CLA (650 mg/kg-1 body weight) of 16-week-old (CLA+Old) mice diminished all the pathological hallmarks at a level comparable to Young mice or healthy controls (BALB/c). Such data demonstrated that MRL/lpr mice can serve as a valuable model for the evaluation of the effectiveness of neuroprotective drugs. Notably, the preventive effect provided by CLA supplementation against age-associated neuronal damage and hyperactivation of compensatory mechanisms suggests that the activation of an adaptive response is at least in part accountable for its neuroprotective ability.
Asunto(s)
Modelos Animales de Enfermedad , Ácidos Linoleicos Conjugados/farmacología , Lupus Eritematoso Sistémico/prevención & control , Administración Oral , Factores de Edad , Animales , Femenino , Ácidos Linoleicos Conjugados/administración & dosificación , Masculino , Ratones , Ratones Endogámicos BALB C , Degeneración Nerviosa/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
The most recent trend in research on probiotic bacteria aims at the exploitation of bioactive bacterial compounds that are responsible for health-promoting effects and suitable for medical applications. Therefore, the main purpose of this study was to ascertain if the immunomodulatory effects of L. paracasei strains on dendritic cells (DCs) were caused by bacterial metabolites released in the culture medium. For that reason, bacterial strains were grown in two media generally used for the culture of DCs, and the effects of culture filtrates on the maturation of DCs and cytokine production were evaluated. Moreover, to reveal potential synergistic effects on the immunomodulation of DCs, an artichoke phenolic extract (APE) was added to the media before bacterial growth. The experiments pointed out an interesting anti-inflammatory activity of a culture filtrate obtained after growing a probiotic L. paracasei strain in one of the media supplemented with APE. Therefore, this culture filtrate-which combines the anti-inflammatory activity and the other well-known health-promoting properties of artichoke phenolic compounds-could represent the basis for future particular exploitations.
Asunto(s)
Cynara scolymus/química , Citocinas/metabolismo , Células Dendríticas/efectos de los fármacos , Lacticaseibacillus paracasei/metabolismo , Extractos Vegetales/farmacología , Polifenoles/farmacología , Probióticos , Células Dendríticas/metabolismo , Humanos , Lacticaseibacillus paracasei/crecimiento & desarrolloRESUMEN
PURPOSE: The beneficial effects of conjugated linoleic acid (CLA) mixture (cis9, trans11, c9; trans10, cis12, t10) against gliadin-induced toxicity in HLA-DQ8-transgenic mice (DQ8) have been associated with improved duodenal cytoprotective mechanisms [nuclear factor-E2-related factor-2, Nrf2; acylpeptide hydrolase (APEH)/proteasome]. The present study was aimed at investigating the ability of individual CLA isomers to improve the efficacy of these defensive mechanisms and to protect against duodenal injury caused by the combined administration of gliadin and indomethacin (GI). METHODS: Gluten-mediated enteropathy was induced in DQ8 mice by three intra-gastric administration of gliadin (20 mg kg(-1)/bw) and indomethacin (15 mg L(-1)) in drinking water for 10 days (GI). C9 or t10 CLA (520 mg kg(-1)/bw/day) were orally administered for 2 weeks. Pro-oxidant and toxic effects associated with GI treatment, anti-oxidant/detoxifying ability of c9 or t10-CLA and the protective effect induced by c9 pre-treatment (c9 + GI) were evaluated in DQ8 mice duodenum by combining enzymatic, immunoblotting, histological evaluation and quantitative real-time PCR assays. RESULTS: GI treatment produces the time-dependent decline of the considered detoxifying mechanisms thus leading to pro-apoptotic and pro-oxidant effects. APEH/proteasome pathway was not markedly affected by individual CLA isomers, but duodenal redox status and activity/mRNA levels of Nrf2-activated enzymes were significantly improved by c9 administration. c9 pre-treatment protects against GI-mediated accumulation of oxidative stress markers, and histological examination reveals the increase of goblet cells number in mouse duodenum but induces only a partial recovery of APEH/proteasome activity. CONCLUSIONS: The activation of and adaptive response by low doses of c9 supplementation prevents distinct signs of gliadin-induced enteropathy in DQ8 mice.
Asunto(s)
Enfermedad Celíaca/tratamiento farmacológico , Gliadina/efectos adversos , Ácidos Linoleicos Conjugados/administración & dosificación , Animales , Enfermedad Celíaca/inducido químicamente , Relación Dosis-Respuesta a Droga , Indometacina/efectos adversos , Ratones , Ratones Transgénicos , NAD(P)H Deshidrogenasa (Quinona)/genética , NAD(P)H Deshidrogenasa (Quinona)/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
SCOPE: The involvement of oxidative stress in gluten-induced toxicity has been evidenced in vitro and in clinical studies but has never been examined in vivo. We recently demonstrated the protective activity of conjugated linoleic acid (CLA), which functions by the activation of nuclear factor erythroid 2-related factor2 (Nrf2), a key transcription factor for the synthesis of antioxidant and detoxifying enzymes (phase 2). Here, we evaluate the involvement of nuclear factor erythroid 2-related factor2 in gliadin-mediated toxicity in human Caco-2 intestinal cells and in gliadin-sensitive human leukocyte antigen-DQ8 transgenic mice (DQ8) and the protective activity of CLA. METHODS AND RESULTS: Gliadin effects in differentiated Caco-2 cells and in DQ8 mice, fed with a gliadin-containing diet with or without CLA supplementation, were evaluated by combining enzymatic, immunochemical, immunohistochemical, and quantitative real-time PCR (qRT-PCR) assays. Gliadin toxicity was accompanied by downregulation of phase 2 and elevates proteasome-acylpeptide hydrolase activities in vitro and in vivo. Notably, gliadin was unable to generate severe oxidative stress extent or pathological consequences in DQ8 mice intestine comparable to those found in celiac patients and the alterations produced were hampered by CLA. CONCLUSION: The beneficial effects of CLA against the depletion of crucial intestinal cytoprotective defenses indicates a novel nutritional approach for the treatment of intestinal disease associated with altered redox homeostasis.
Asunto(s)
Gliadina/toxicidad , Intestinos/efectos de los fármacos , Intestinos/fisiología , Ácidos Linoleicos Conjugados/farmacología , Animales , Antioxidantes/metabolismo , Células CACO-2 , Enfermedad Celíaca/metabolismo , Diferenciación Celular/efectos de los fármacos , Enzimas/genética , Enzimas/metabolismo , Gliadina/efectos adversos , Antígenos HLA-DQ/genética , Humanos , Inactivación Metabólica , Ratones , Ratones Transgénicos , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Transglutaminasas/metabolismoRESUMEN
The current issue of the International Reviews of Immunology is dedicated entirely to Celiac Disease (CD). Recent development of additional biomarkers and diagnostics resulted in a sharp revision of the prevalence of this condition, with a previously unrecognized subclinical occurrence in the adult population. This was paralleled by groundbreaking progress in understanding its molecular pathogenesis: while gluten-derived peptides activate the innate immunity, post-translationally modified gluten elicits an adaptive immunity. These arms amplify each other, resulting in a self- perpetuating autoimmune condition, influenced by disturbances of the gut flora and mucus chemistry. The process evolves dramatically in a subset of patients with vulnerable immune homeostasis (eg. Treg cells) explaining the progressive, aggravating syndrome in the clinically overt version of CD. In depth understanding of the pathogenesis of CD thus creates the premises of developing novel, more accurate animal models that should support a rationale development of new prophylactic and therapeutic interventions.
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Biomarcadores/metabolismo , Enfermedad Celíaca/inmunología , Glútenes/inmunología , Inmunidad Adaptativa , Animales , Autoinmunidad , Terapia Biológica/tendencias , Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/epidemiología , Enfermedad Celíaca/terapia , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata , Patología Molecular/tendencias , PrevalenciaRESUMEN
Celiac disease (CD) is a gluten-sensitive enteropathy with an immune basis. We established the immune reactivity of the alcohol-soluble fraction from two minor cereals (tef and millet) and two pseudocereals (amaranth and quinoa) which are believed to be nontoxic based on taxonomy. Grains were examined in intestinal T-cell lines (iTCLs), cultures of duodenal explants from HLA-DQ2(+) CD patients and HLA-DQ8 transgenic mice for signs of activation. Our data indicated that tef, millet, amaranth, and quinoa did not show any immune cross-reactivity toward wheat gliadin, and therefore confirming their safety in the diet of CD patients.
Asunto(s)
Enfermedad Celíaca/etiología , Grano Comestible/inmunología , Proteínas de Plantas/inmunología , Alcoholes , Amaranthus/inmunología , Secuencia de Aminoácidos , Animales , Chenopodium quinoa/inmunología , Reacciones Cruzadas , Glútenes , Humanos , Interferón gamma/biosíntesis , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Panicum/inmunología , Extractos Vegetales/inmunología , Proteínas de Plantas/química , Alineación de SecuenciaRESUMEN
OBJECTIVE: The aim of this study is to compare the effect of medical and surgical treatment on the history of patients with Barrett esophagus (BE) and histologic evidence of low-grade dysplasia (LGD). SUMMARY BACKGROUND DATA: BE is a complication of severe gastroesophageal reflux. It is considered a major risk factor for esophageal adenocarcinoma, which may develop through stages from nondysplastic metaplasia to dysplasia (LGD and high-grade dysplasia). Presently, there are no recommended therapeutic guidelines for patients with LGD. METHODS: Between 1998 through 2003, 6592 patients underwent upper endoscopy; 327 of 6592 (5%) patients had BE, and 35 of 327 (10.7%) had LGD. Nineteen patients with LGD were treated with high-dose proton pump inhibitors, and 16 patients underwent laparoscopic Nissen fundoplication. Endoscopic and histologic follow-up was available in all patients after 18 months. We used multiple logistic regression to examine the effect of the 2 treatments on regression of LGD. RESULTS: LGD was predominant in men (male-to-female ratio: 1.7:1). Mean age was 58 +/- 13.5 years. Sixty percent of patients had no endoscopic evidence of esophagitis. A regression from LGD to BE was observed in 12 of 19 (63.2%) patients in the medical group and in 15 of 16 (93.8%) patients in the surgical group (statistically significant difference). Differences between the 2 groups were statistically significant (P = 0.03). CONCLUSION: The results of our study suggest that surgical treatment may be more effective than medical therapy to modify the natural history of LGD in patients with BE, perhaps because it not only controls acid but also biliopancreatic reflux into the esophagus.