41 results on '"Raffaella Maria Gadaleta"'
Search Results
2. Psychobiotic Properties of Lactiplantibacillus plantarum in Neurodegenerative Diseases
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Mariagiovanna Di Chiano, Fabio Sallustio, Daniela Fiocco, Maria Teresa Rocchetti, Giuseppe Spano, Paola Pontrelli, Antonio Moschetta, Loreto Gesualdo, Raffaella Maria Gadaleta, and Anna Gallone
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microbiota ,microbiome ,neurological disorders ,Lactiplantibacillus plantarum ,gut–brain axis ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Neurodegenerative disorders are the main cause of cognitive and physical disabilities, affect millions of people worldwide, and their incidence is on the rise. Emerging evidence pinpoints a disturbance of the communication of the gut–brain axis, and in particular to gut microbial dysbiosis, as one of the contributors to the pathogenesis of these diseases. In fact, dysbiosis has been associated with neuro-inflammatory processes, hyperactivation of the neuronal immune system, impaired cognitive functions, aging, depression, sleeping disorders, and anxiety. With the rapid advance in metagenomics, metabolomics, and big data analysis, together with a multidisciplinary approach, a new horizon has just emerged in the fields of translational neurodegenerative disease. In fact, recent studies focusing on taxonomic profiling and leaky gut in the pathogenesis of neurodegenerative disorders are not only shedding light on an overlooked field but are also creating opportunities for biomarker discovery and development of new therapeutic and adjuvant strategies to treat these disorders. Lactiplantibacillus plantarum (LBP) strains are emerging as promising psychobiotics for the treatment of these diseases. In fact, LBP strains are able to promote eubiosis, increase the enrichment of bacteria producing beneficial metabolites such as short-chain fatty acids, boost the production of neurotransmitters, and support the homeostasis of the gut–brain axis. In this review, we summarize the current knowledge on the role of the gut microbiota in the pathogenesis of neurodegenerative disorders with a particular focus on the benefits of LBP strains in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, autism, anxiety, and depression.
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- 2024
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3. Low Adherence to Mediterranean Diet Characterizes Metabolic Patients with Gastrointestinal Cancer
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Carlo De Matteis, Lucilla Crudele, Raffaella Maria Gadaleta, Ersilia Di Buduo, Fabio Novielli, Stefano Petruzzelli, Marica Cariello, and Antonio Moschetta
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gastrointestinal cancer ,Mediterranean diet ,Chrono Med Diet Score ,nutrition ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Background. Gastrointestinal (GI) cancers are one of the most relevant causes of death globally, frequently associated with poor dietary patterns. The Mediterranean Diet (MedDiet) contributes to cancer prevention. To assess adherence to MedDiet, our research group validated a new score, the Chrono Med Diet Score (CMDS), that captures increased visceral adiposity. Methods. We enrolled 401 subjects who underwent an evaluation for metabolic diseases and specific screening procedures according to current guidelines and were asked to answer CMDS. A total of 71 new cancer cases were recorded, including 40 GI and 31 non-gastrointestinal (NON-GI) cancers. Results. We found that CMDS was reduced in subjects who were diagnosed with cancers. Patients who reported a CMDS score of 12 or less had an over three times increased risk of being diagnosed with GI cancers and presented increased waist circumference and triglycerides and reduced HDL cholesterol compared to adherent subjects. Conclusions. Low CMDS values capture the risk for cancer diagnosis, especially for GI cancers. Thus, CMDS, along with waist circumference, can be considered as a bona fide marker for increased risk of cancer, requiring anticipated screening procedures for the detection of premalignant and early stage GI cancers in patients with low adherence to MedDiet.
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- 2024
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4. The central role of the gut in intensive care
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Alberto Corriero, Raffaella Maria Gadaleta, Filomena Puntillo, Francesco Inchingolo, Antonio Moschetta, and Nicola Brienza
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Microbiota ,Microbiome ,Intensive care ,Dysbiosis ,Probiotics ,Prebiotics ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
Abstract Critically ill patients undergo early impairment of their gut microbiota (GM) due to routine antibiotic therapies and other environmental factors leading to intestinal dysbiosis. The GM establishes connections with the rest of the human body along several axes representing critical inter-organ crosstalks that, once disrupted, play a major role in the pathophysiology of numerous diseases and their complications. Key players in this communication are GM metabolites such as short-chain fatty acids and bile acids, neurotransmitters, hormones, interleukins, and toxins. Intensivists juggle at the crossroad of multiple connections between the intestine and the rest of the body. Harnessing the GM in ICU could improve the management of several challenges, such as infections, traumatic brain injury, heart failure, kidney injury, and liver dysfunction. The study of molecular pathways affected by the GM in different clinical conditions is still at an early stage, and evidence in critically ill patients is lacking. This review aims to describe dysbiosis in critical illness and provide intensivists with a perspective on the potential as adjuvant strategies (e.g., nutrition, probiotics, prebiotics and synbiotics supplementation, adsorbent charcoal, beta-lactamase, and fecal microbiota transplantation) to modulate the GM in ICU patients and attempt to restore eubiosis.
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- 2022
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5. Total serum FGF-21 levels positively relate to visceral adiposity differently from its functional intact form
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Lucilla Crudele, Oihane Garcia-Irigoyen, Marica Cariello, Marilidia Piglionica, Natasha Scialpi, Marilina Florio, Giuseppina Piazzolla, Patrizia Suppressa, Carlo Sabbà, Raffaella Maria Gadaleta, and Antonio Moschetta
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visceral obesity ,HDL cholesterol ,intact FGF21 ,waist circumference ,vitamin D ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
ObjectiveIncreased Fibroblast Growth Factor-21 (FGF-21) circulating levels have been described in obesity. In this observational study, we analysed a group of subjects with metabolic disorders to unravel the putative link between visceral adiposity and FGF-21 serum levels.MethodsTotal and intact serum FGF-21 concentration was measured with an ELISA assay respectively in 51 and 46 subjects, comparing FGF-21 levels in dysmetabolic conditions. We also tested Spearman’s correlations between FGF-21 serum levels and biochemical and clinical metabolic parameters.ResultsFGF-21 was not significantly increased in high-risk conditions such as visceral obesity, Metabolic Syndrome, diabetes, smoking, and atherosclerosis. Waist Circumference (WC), but not BMI, positively correlated with total FGF-21 levels (r=0.31, p
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- 2023
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6. Identification of a Novel Score for Adherence to the Mediterranean Diet That Is Inversely Associated with Visceral Adiposity and Cardiovascular Risk: The Chrono Med Diet Score (CMDS)
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Carlo De Matteis, Lucilla Crudele, Stefano Battaglia, Tiziana Loconte, Arianna Rotondo, Roberta Ferrulli, Raffaella Maria Gadaleta, Giuseppina Piazzolla, Patrizia Suppressa, Carlo Sabbà, Marica Cariello, and Antonio Moschetta
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nutrition ,Mediterranean diet ,biomarkers ,score ,cardiovascular risk ,visceral adiposity ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Adherence to the Mediterranean diet (MedDiet) leads to reduction of mortality from all causes, especially in subjects with cardiovascular disease, obesity, and diabetes. Numerous scores have been proposed to evaluate the adherence to MedDiet, mainly focused on eating habits. In this study, we verified whether existing validated MedDiet scores, namely, MEDI-LITE and the Mediterranean Diet Score (MDS), could be associated with visceral adiposity. Failing to find a significant association with adiposity, we proposed the validation of a new, easy-to-use adherence questionnaire, the Chrono Med-Diet score (CMDS). CMDS contains eleven food categories, including chronobiology of dietary habits and physical activity. Compared to the MEDI-LITE score and MDS, low values of CMDS are linked to increased waist circumference (WC) and dysmetabolic conditions. CMDS was also inversely correlated with cardiovascular risk (CVR), as well as Fatty Liver Index (FLI). In conclusion, the CMDS is a novel questionnaire to study the adherence to the MedDiet that, focusing on type and timing of carbohydrates intake, has the peculiar capability of capturing subjects with abdominal obesity, thus being an easy-to-use instrument of personalized medicine.
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- 2023
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7. Bile Salt Hydrolase-Competent Probiotics in the Management of IBD: Unlocking the 'Bile Acid Code'
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Raffaella Maria Gadaleta, Marica Cariello, Lucilla Crudele, and Antonio Moschetta
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bile acids ,BSH-competent bacteria ,gut microbiota ,intestinal inflammation ,probiotics ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Bile acid (BA) species and the gut microbiota (GM) contribute to intestinal mucosa homeostasis. BAs shape the GM and, conversely, intestinal bacteria with bile salt hydrolase (BSH) activity modulate the BA pool composition. The mutual interaction between BAs and intestinal microorganisms also influences mucosal barrier integrity, which is important for inflammatory bowel disease (IBD) pathogenesis, prevention and therapy. High levels of secondary BAs are detrimental for the intestinal barrier and increase the intestinal inflammatory response and dysbiosis. Additionally, a lack of BSH-active bacteria plays a role in intestinal inflammation and BA dysmetabolism. Thus, BSH-competent bacteria in probiotic formulations are being actively studied in IBD. At the same time, studies exploring the modulation of the master regulator of BA homeostasis, the Farnesoid X Receptor (FXR), in intestinal inflammation and how this impacts the GM are gaining significant momentum. Overall, the choice of probiotic supplementation should be a peculiar issue of personalized medicine, considering not only the disease but also the specific BA and metabolic signatures of a given patient.
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- 2022
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8. Intestinal FXR Activation via Transgenic Chimera or Chemical Agonism Prevents Colitis-Associated and Genetically-Induced Colon Cancer
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Marica Cariello, Roberta Zerlotin, Emanuela Pasculli, Elena Piccinin, Claudia Peres, Emanuele Porru, Aldo Roda, Raffaella Maria Gadaleta, and Antonio Moschetta
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Farnesoid X Receptor (FXR) ,colitis ,colon cancer ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The Farnesoid X Receptor (FXR) is the master regulator of Bile Acids (BA) homeostasis orchestrating their synthesis, transport and metabolism. Disruption of BA regulation has been linked to gut-liver axis diseases such as colorectal cancer (CRC). In this study, firstly we examined the role of constitutive activation of intestinal FXR in CRC; then we pre-clinically investigated the therapeutic potential of a diet enriched with a synthetic FXR agonist in two models of CRC (chemically-induced and genetic models). We demonstrated that mice with intestinal constitutive FXR activation are protected from AOM/DSS-induced CRC with a significant reduction of tumor number compared to controls. Furthermore, we evaluated the role of chemical FXR agonism in a DSS model of colitis in wild type (WT) and FXRnull mice. WT mice administered with the FXR activating diet showed less morphological alterations and decreased inflammatory infiltrates compared to controls. The FXR activating diet also protected WT mice from AOM/DSS-induced CRC by reducing tumors’ number and size. Finally, we proved that the FXR activating diet prevented spontaneous CRC in APCMin/+ mice via an FXR-dependent modulation of BA homeostasis. Our results demonstrate that intestinal FXR activation prevented both inflammation- and genetically-driven colorectal tumorigenesis by modulating BA pool size and composition. This could open new avenues for the therapeutic management of intestinal inflammation and tumorigenesis.
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- 2022
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9. let-7e downregulation characterizes early phase colonic adenoma in APCMin/+ mice and human FAP subjects.
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Annalisa Contursi, Maria Arconzo, Marica Cariello, Marilidia Piglionica, Simona D'Amore, Michele Vacca, Giusi Graziano, Raffaella Maria Gadaleta, Rosa Valanzano, Renato Mariani-Costantini, Gaetano Villani, Antonio Moschetta, and Elena Piccinin
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Medicine ,Science - Abstract
The crypt-villus axis represents the essential unit of the small intestine, which integrity and functions are fundamental to assure tissue and whole-body homeostasis. Disruption of pathways regulating the fine balance between proliferation and differentiation results in diseases development. Nowadays, it is well established that microRNAs (miRNAs) play a crucial role in the homeostasis maintenance and perturbation of their levels may promote tumor development. Here, by using microarray technology, we analysed the miRNAs differentially expressed between the crypt and the villus in mice ileum. The emerged miRNAs were further validated by Real Time qPCR in mouse model (ApcMin/+), human cell lines and human tissue samples (FAP) of colorectal cancer (CRC). Our results indicated that miRNAs more expressed in the villi compartment are negatively regulated in tumor specimens, thus suggesting a close association between these microRNAs and the differentiation process. Particularly, from our analysis let-7e appeared to be a promising target for possible future therapies and a valuable marker for tumor staging, being upregulated in differentiated cells and downregulated in early-stage colonic adenoma samples.
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- 2021
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10. Corrigendum to ‘Fibroblast growth factor 19 modulates intestinal microbiota and inflammation in presence of farnesoid x receptor’
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Raffaella Maria Gadaleta, Oihane Garcia-Irigoyen, Marica Cariello, Natasha Scialpi, Claudia Peres, Stefania Vetrano, Gionatha Fiorino, Silvio Danese, Brian Ko, Jian Luo, Emanuele Porru, Aldo Roda, Carlo Sabbá, and Antonio Moschetta
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Medicine ,Medicine (General) ,R5-920 - Published
- 2020
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11. Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor
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Raffaella Maria Gadaleta, Oihane Garcia-Irigoyen, Marica Cariello, Natasha Scialpi, Claudia Peres, Stefania Vetrano, Gionatha Fiorino, Silvio Danese, Brian Ko, Jian Luo, Emanuele Porru, Aldo Roda, Carlo Sabbà, and Antonio Moschetta
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: Disruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver axis is the main site for the regulation of BA synthesis and BA pool size via the combined action of the nuclear Farnesoid X Receptor (FXR) and the enterokine Fibroblast Growth Factor 19 (FGF19). Increasing evidence have linked derangement of BA metabolism with dysbiosis and mucosal inflammation. Thus, here we aimed to investigate the potential action of an FGF19 analogue on intestinal microbiota and inflammation. Methods: A novel engineered non-tumorigenic variant of the FGF19 protein, M52-WO 2016/0168219 was generated. WT and FXRnull mice were injected with AAV-FGF19-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis. Findings: FGF19-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response and modulation of microbiota composition. Interestingly, FGF19-M52-driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR)null mice, thus underscoring the need of FXR to guarantee enterocytes’ fitness and complement FGF19 anti-inflammatory activity. To provide a translational perspective, we also show that circulating FGF19 levels are reduced in patients with Crohn's disease. Interpretation: Reactivation of the FXR-FGF19 axis in a murine model of intestinal inflammation could bona fide provide positive changes in BA metabolism with consequent reduction of intestinal inflammation and modulation of microbiota. These results point to the therapeutic potential of FGF19 in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis. Funding: A. Moschetta is funded by MIUR-PRIN 2017
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- 2020
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12. Extra-Virgin Olive Oil from Apulian Cultivars and Intestinal Inflammation
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Marica Cariello, Annalisa Contursi, Raffaella Maria Gadaleta, Elena Piccinin, Stefania De Santis, Marilidia Piglionica, Ada Fiorenza Spaziante, Carlo Sabbà, Gaetano Villani, and Antonio Moschetta
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olive oil ,inflammatory bowel disease ,intestinal inflammation ,animal experimentation ,mouse model ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Inflammatory bowel disease (IBD) is a multifactorial intestinal disorder characterized by chronic intestinal inflammation. The etiology of IBD is still unclear, although genetic, environmental and host factors have been associated to the disease. Extra-virgin olive oil (EVO) is a central component of the Mediterranean diet and it decreases chronic inflammation by interfering with arachidonic acid and NF-κB signaling pathways. Specifically, the different components of EVO are able to confer advantages in terms of health in their site of action. For instance, oleic acid displays a protective effect in liver dysfunction and gut inflammation, whereas phenolic compounds protect colon cells against oxidative damage and improve the symptoms of chronic inflammation in IBD. Given the biological properties of EVO, we investigated whether its administration is able to confer protection in a mouse model of dextrane sodium sulfate (DSS)-induced colitis. Four EVO cultivars from the Apulian Region of Italy, namely Ogliarola (Cima di Bitonto), Coratina, Peranzana and Cima di Mola, respectively, were used. Administration of EVO resulted in reduced body weight loss in our colitis model. Furthermore, mice treated with Ogliarola, Coratina and Cima di Mola EVO displayed a reduction of rectal bleeding and IL-1β, TGFβ, IL-6 gene expression levels. Furthermore, Ogliarola, Coratina and Peranzana EVO administration ameliorated intestinal permeability and histopathological features of inflammation. Our data further validate the well-known positive effects of EVO supplementation in promoting human health and suggest the bona fide contribution of EVO in preventing onset and reducing progression of intestinal inflammation.
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- 2020
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13. Low HDL-cholesterol levels predict hepatocellular carcinoma development in individuals with liver fibrosis
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Lucilla Crudele, Carlo De Matteis, Elena Piccinin, Raffaella Maria Gadaleta, Marica Cariello, Ersilia Di Buduo, Giuseppina Piazzolla, Patrizia Suppressa, Elsa Berardi, Carlo Sabbà, and Antonio Moschetta
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Hepatology ,Gastroenterology ,Internal Medicine ,Immunology and Allergy - Abstract
Dysmetabolic conditions could drive liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), increasing susceptibility to hepatocellular carcinoma (HCC). We therefore aimed to identify novel predictive biomarkers of HCC in patients with and without liver fibrosis.A total of 1,234 patients with putative metabolic conditions and NAFLD were consecutively assessed in our outpatient clinic. Clinical and biochemical data were recorded, and then liver ultrasonography was performed annually for 5 years to detect HCC onset. For the analysis, the population was first divided according to HCC diagnosis; then a further subdivision of those who did not develop HCC was performed based on the presence or absence of liver fibrosis at time 0.Sixteen HCC cases were recorded in 5 years. None of our patients had been diagnosed with cirrhosis before HCC was detected. Compared to patients who did not develop HCC, those who did had higher liver transaminases and fibrosis scores at time 0 (This study identifies HDL-c as aVisceral adiposity and its associated conditions, such as chronic inflammation and insulin resistance, may play a pivotal role in hepatocellular carcinoma development in patients with non-alcoholic fatty liver disease. We provide new insights on the underlying mechanisms of its pathogenesis, shedding light on the involvement of low levels of "good" HDL-cholesterol. We recommend integrating dietary regimens and advice on healthy lifestyles into the clinical management of non-alcoholic fatty liver disease, with the goal of reducing the incidence of hepatocellular carcinoma.
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- 2022
14. Liver X Receptors (LXR)s and testicular function
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Antonio Moschetta, Damien A. Leach, Catherine Williamson, Charlotte L. Bevan, Robert Winston, Raffaella Maria Gadaleta, Emmanuelle Claude, Sheba Jarvis, and Lee A. Gethings
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medicine.medical_specialty ,Testicular function ,Endocrinology ,Chemistry ,Internal medicine ,medicine ,Liver X receptor - Published
- 2021
15. Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver
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Raffaella Maria Gadaleta and Antonio Moschetta
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Carcinoma, Hepatocellular ,Hepatology ,business.industry ,Liver Neoplasms ,FGF19 ,Cell Differentiation ,Fibroblast growth factor receptor 4 ,medicine.disease ,Fibroblast growth factor ,Clinical trial ,Liver ,Hepatocellular carcinoma ,medicine ,Cancer research ,Humans ,Receptor, Fibroblast Growth Factor, Type 4 ,Steatohepatitis ,Liver cancer ,business ,Receptor - Abstract
Summary Fibroblast growth factor (FGF) receptor 4 (FGFR4) and its cognate ligand, FGF19, are implicated in a range of cellular processes, including differentiation, metabolism and proliferation. Indeed, their aberrant activation has been associated with the development of hepatic tumours. Despite great advances in early diagnosis and the development of new therapies, liver cancer is still associated with a high mortality rate, owing primarily to high molecular heterogeneity and unclear molecular targeting. The development of FGFR4 inhibitors is a promising tool in patients with concomitant supraphysiological levels of FGF19 and several clinical trials are testing these treatments for patients with advanced hepatocellular carcinoma (HCC). Conversely, using FGF19 analogues to activate FGFR4-KLOTHO β represents a novel therapeutic strategy in patients presenting with cholestatic liver disorders and non-alcoholic steatohepatitis, which could potentially prevent the development of metabolic HCC. Herein, we provide an overview of the currently available therapeutic options for targeting FGFR4 in HCC and other liver diseases, highlighting the need to carefully stratify patients and personalise therapeutic strategies.
- Published
- 2021
16. Suppression of Hepatic Bile Acid Synthesis by a non-tumorigenic FGF19 analogue Protects Mice from Fibrosis and Hepatocarcinogenesis
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Natasha Scialpi, Antonio Moschetta, Raffaella Maria Gadaleta, Brian Ko, Claudia Peres, Emanuele Porru, Marica Cariello, Aldo Roda, Carlo Sabbà, and Jian Luo
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Liver Cirrhosis ,0301 basic medicine ,Carcinoma, Hepatocellular ,medicine.drug_class ,lcsh:Medicine ,Cholesterol 7 alpha-hydroxylase ,Fibroblast growth factor ,Article ,Bile Acids and Salts ,Mice ,03 medical and health sciences ,Gastrointestinal Agents ,Fibrosis ,medicine ,Animals ,lcsh:Science ,Mice, Knockout ,Biological Products ,Multidisciplinary ,Bile acid ,Chemistry ,lcsh:R ,FGF19 ,medicine.disease ,Fibroblast Growth Factors ,Disease Models, Animal ,Treatment Outcome ,030104 developmental biology ,Cancer research ,Mutant Proteins ,Farnesoid X receptor ,lcsh:Q ,Hepatic fibrosis ,Homeostasis - Abstract
Critical regulation of bile acid (BA) pool size and composition occurs via an intensive molecular crosstalk between the liver and gut, orchestrated by the combined actions of the nuclear Farnesoid X receptor (FXR) and the enterokine fibroblast growth factor 19 (FGF19) with the final aim of reducing hepatic BA synthesis in a negative feedback fashion. Disruption of BA homeostasis with increased hepatic BA toxic levels leads to higher incidence of hepatocellular carcinoma (HCC). While native FGF19 has anti-cholestatic and anti-fibrotic activity in the liver, it retains peculiar pro-tumorigenic actions. Thus, novel analogues have been generated to avoid tumorigenic capacity and maintain BA metabolic action. Here, using BA related Abcb4−/− and Fxr−/− mouse models of spontaneous hepatic fibrosis and HCC, we explored the role of a novel engineered variant of FGF19 protein, called FGF19-M52, which fully retains BA regulatory activity but is devoid of the pro-tumoral activity. Expression of the BA synthesis rate-limiting enzyme Cyp7a1 is reduced in FGF19-M52-treated mice compared to the GFP-treated control group with consequent reduction of BA pool and hepatic concentration. Treatment with the non-tumorigenic FGF19-M52 strongly protects Abcb4−/− and Fxr−/− mice from spontaneous hepatic fibrosis, cellular proliferation and HCC formation in terms of tumor number and size, with significant reduction of biochemical parameters of liver damage and reduced expression of several genes driving the proliferative and inflammatory hepatic scenario. Our data bona fide suggest the therapeutic potential of targeting the FXR-FGF19 axis to reduce hepatic BA synthesis in the control of BA-associated risk of fibrosis and hepatocarcinoma development.
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- 2018
17. let-7e downregulation characterizes early phase colonic adenoma in APCMin/+ mice and human FAP subjects
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Antonio Moschetta, Marilidia Piglionica, Maria Arconzo, Gaetano Villani, Annalisa Contursi, Marica Cariello, Giusi Graziano, Rosa Valanzano, Elena Piccinin, Michele Vacca, Raffaella Maria Gadaleta, Renato Mariani-Costantini, and Simona D'Amore
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Male ,0301 basic medicine ,Colorectal cancer ,Cellular differentiation ,Biochemistry ,Mice ,0302 clinical medicine ,Gastrointestinal Cancers ,Medicine and Health Sciences ,Cyclin D1 ,Multidisciplinary ,Cell Differentiation ,Animal Models ,Adenomas ,Nucleic acids ,medicine.anatomical_structure ,Oncology ,Experimental Organism Systems ,Adenomatous Polyposis Coli ,030220 oncology & carcinogenesis ,Medicine ,Anatomy ,Colorectal Neoplasms ,Research Article ,Adenoma ,Colon ,Transgene ,Science ,Adenomatous Polyposis Coli Protein ,Crypt ,Down-Regulation ,Mouse Models ,Mice, Transgenic ,Gastroenterology and Hepatology ,Biology ,Research and Analysis Methods ,Proto-Oncogene Proteins c-myc ,03 medical and health sciences ,Model Organisms ,Downregulation and upregulation ,Cell Line, Tumor ,microRNA ,Genetics ,medicine ,Animals ,Humans ,Non-coding RNA ,Colorectal Cancer ,Natural antisense transcripts ,Biology and life sciences ,Cancers and Neoplasms ,medicine.disease ,Small intestine ,Gene regulation ,Gastrointestinal Tract ,Mice, Inbred C57BL ,MicroRNAs ,030104 developmental biology ,Animal Studies ,Gene chip analysis ,Cancer research ,RNA ,Gene expression ,Digestive System ,Developmental Biology - Abstract
The crypt-villus axis represents the essential unit of the small intestine, which integrity and functions are fundamental to assure tissue and whole-body homeostasis. Disruption of pathways regulating the fine balance between proliferation and differentiation results in diseases development. Nowadays, it is well established that microRNAs (miRNAs) play a crucial role in the homeostasis maintenance and perturbation of their levels may promote tumor development. Here, by using microarray technology, we analysed the miRNAs differentially expressed between the crypt and the villus in mice ileum. The emerged miRNAs were further validated by Real Time qPCR in mouse model (ApcMin/+), human cell lines and human tissue samples (FAP) of colorectal cancer (CRC). Our results indicated that miRNAs more expressed in the villi compartment are negatively regulated in tumor specimens, thus suggesting a close association between these microRNAs and the differentiation process. Particularly, from our analysis let-7e appeared to be a promising target for possible future therapies and a valuable marker for tumor staging, being upregulated in differentiated cells and downregulated in early-stage colonic adenoma samples.
- Published
- 2021
18. Corrigendum to ‘Fibroblast growth factor 19 modulates intestinal microbiota and inflammation in presence of farnesoid x receptor’
- Author
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Claudia Peres, Gionatha Fiorino, Carlo Sabbà, Jian Luo, Stefania Vetrano, Brian Ko, Marica Cariello, Aldo Roda, Emanuele Porru, Oihane Garcia-Irigoyen, Raffaella Maria Gadaleta, Natasha Scialpi, Silvio Danese, and Antonio Moschetta
- Subjects
lcsh:R5-920 ,business.industry ,lcsh:R ,lcsh:Medicine ,Inflammation ,General Medicine ,Fibroblast growth factor ,General Biochemistry, Genetics and Molecular Biology ,medicine ,Cancer research ,Farnesoid X receptor ,medicine.symptom ,business ,lcsh:Medicine (General) - Published
- 2020
19. Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor
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Stefania Vetrano, Raffaella Maria Gadaleta, Claudia Peres, Gionatha Fiorino, Antonio Moschetta, Brian Ko, Marica Cariello, Oihane Garcia-Irigoyen, Carlo Sabbà, Silvio Danese, Emanuele Porru, Natasha Scialpi, Aldo Roda, Jian Luo, Gadaleta, Raffaella Maria, Garcia-Irigoyen, Oihane, Cariello, Marica, Scialpi, Natasha, Peres, Claudia, Vetrano, Stefania, Fiorino, Gionatha, Danese, Silvio, Ko, Brian, Luo, Jian, Porru, Emanuele, Roda, Aldo, Sabbà, Carlo, and Moschetta, Antonio
- Subjects
0301 basic medicine ,Male ,Cytoplasmic and Nuclear ,Anti-Inflammatory Agents ,lcsh:Medicine ,Receptors, Cytoplasmic and Nuclear ,Intestinal inflammation ,Ulcerative ,Inbred C57BL ,Fibroblast growth factor ,Mice ,0302 clinical medicine ,Crohn Disease ,Nuclear receptors ,Receptors ,lcsh:R5-920 ,DSS-colitis ,Bile acid ,Chemistry ,General Medicine ,Colitis ,Recombinant Proteins ,Cell biology ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,lcsh:Medicine (General) ,Corrigendum ,medicine.drug_class ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Bile Acids and Salts ,03 medical and health sciences ,medicine ,Animals ,Humans ,lcsh:R ,FGF19 ,medicine.disease ,Bile acids ,Gastrointestinal Microbiome ,Fibroblast Growth Factors ,Mice, Inbred C57BL ,030104 developmental biology ,Nuclear receptor ,Enterokine ,Farnesoid X receptor ,Colitis, Ulcerative ,Peptides ,Dysbiosis - Abstract
Background: Disruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver axis is the main site for the regulation of BA synthesis and BA pool size via the combined action of the nuclear Farnesoid X Receptor (FXR) and the enterokine Fibroblast Growth Factor 19 (FGF19). Increasing evidence have linked derangement of BA metabolism with dysbiosis and mucosal inflammation. Thus, here we aimed to investigate the potential action of an FGF19 analogue on intestinal microbiota and inflammation. Methods: A novel engineered non-tumorigenic variant of the FGF19 protein, M52-WO 2016/0168219 was generated. WT and FXRnull mice were injected with AAV-FGF19-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis. Findings: FGF19-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response and modulation of microbiota composition. Interestingly, FGF19-M52-driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR)null mice, thus underscoring the need of FXR to guarantee enterocytes’ fitness and complement FGF19 anti-inflammatory activity. To provide a translational perspective, we also show that circulating FGF19 levels are reduced in patients with Crohn's disease. Interpretation: Reactivation of the FXR-FGF19 axis in a murine model of intestinal inflammation could bona fide provide positive changes in BA metabolism with consequent reduction of intestinal inflammation and modulation of microbiota. These results point to the therapeutic potential of FGF19 in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis. Funding: A. Moschetta is funded by MIUR-PRIN 2017
- Published
- 2019
20. Bile acids and colon cancer: Is FXR the solution of the conundrum?
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Raffaella Maria Gadaleta, Antonio Moschetta, and Oihane Garcia-Irigoyen
- Subjects
0301 basic medicine ,Receptors, Steroid ,medicine.medical_specialty ,Colon ,medicine.drug_class ,Colorectal cancer ,Clinical Biochemistry ,Receptors, Cytoplasmic and Nuclear ,Inflammation ,Biology ,Biochemistry ,Bile Acids and Salts ,03 medical and health sciences ,Risk Factors ,Internal medicine ,medicine ,Animals ,Humans ,Intestinal Mucosa ,Molecular Biology ,Constitutive Androstane Receptor ,Bile acid ,Pregnane X Receptor ,Cancer ,General Medicine ,medicine.disease ,Intestinal epithelium ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Endocrinology ,Liver ,Nuclear receptor ,Diet, Western ,Colonic Neoplasms ,Receptors, Calcitriol ,Molecular Medicine ,Farnesoid X receptor ,Animal studies ,medicine.symptom ,Signal Transduction - Abstract
Diet and lifestyle habits have a profound impact on the pathophysiology of many diseases. Colorectal cancer (CRC) is the third most common cancer worldwide and its etiology is strongly influenced by nutrition and high fat/high carbohydrate Western-style diet. Human epidemiological and animal studies have shown that colonic cancer risk is also related to faecal bile acid concentration. Abnormally high levels of bile acids (BA) trigger the colonic mucosa with a plethora of detrimental effects such as DNA oxidative damage, inflammation and hyperproliferation that highly promote CRC progression in post-initiation phase. The Farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally mediates the signalling activity of BAs. FXR regulates BA metabolism mainly maintaining BA concentrations within a physiological range, thereby preventing BA-induced cytotoxicity. In fact, loss of FXR is associated with higher BA concentrations and with a pro-tumorigenic phenotype. Here we explore the liaison connecting nutrition, intestinal epithelium renewal, BA and their nuclear receptor FXR in CRC. Moreover, we summarize evidence linking BA and CRC, as well as examine current understanding of the protumoral actions of BA and the bona fide antitumoral properties of FXR.
- Published
- 2017
21. Exploration of Inflammatory Bowel Disease in Mice: Chemically Induced Murine Models of Inflammatory Bowel Disease (IBD)
- Author
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Raffaella Maria Gadaleta, Antonio Moschetta, and Oihane Garcia-Irigoyen
- Subjects
0301 basic medicine ,Azoxymethane ,business.industry ,General Medicine ,Disease ,medicine.disease ,digestive system ,Inflammatory bowel disease ,Ulcerative colitis ,digestive system diseases ,Pathophysiology ,Pathogenesis ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,2,4,6-Trinitrobenzenesulfonic acid ,chemistry ,Immunology ,medicine ,Colitis ,business - Abstract
Inflammatory bowel disease (IBD) is a chronic multifactorial inflammatory disorder characterized by periods of activation and remission of intestinal inflammation, with potentially severe complications, that can lead to mortality. Experimental animal models of intestinal inflammation are crucial for understanding the pathogenesis of Crohn's disease (CD) and ulcerative colitis (UC), the two major human IBD phenotypes. Animal models have been instrumental in unveiling the molecular background of IBD, and although a single model is not able to capture the complexity of this disease, each of them provided valuable insight into its different aspects. Chemically induced models of intestinal inflammation, mainly dextran sodium sulfate (DSS)- and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis, are widely used. This article describes DSS- and TNBS-induced colitis models and their relevance to IBD pathophysiology and pre-clinical therapeutic management. © 2017 by John Wiley & Sons, Inc.
- Published
- 2017
22. The Enterokine Fibroblast Growth Factor 15/19 in Bile Acid Metabolism
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Marilidia Piglionica, Raffaella Maria Gadaleta, Antonio Moschetta, and Marica Cariello
- Subjects
0301 basic medicine ,FGF21 ,Bile acid ,Glycogen ,medicine.drug_class ,FGF19 ,Cholesterol 7 alpha-hydroxylase ,Fibroblast growth factor ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,chemistry ,030220 oncology & carcinogenesis ,medicine ,Glucose homeostasis ,Farnesoid X receptor - Abstract
The endocrine fibroblast growth factors (FGFs), FGF19, FGF21, and FGF23, play a key role in whole-body homeostasis. In particular, FGF19 is a postprandial hormone regulating glucose homeostasis, glycogen and protein synthesis, and primary bile acid (BA) metabolism. In the ileum, BA-dependent farnesoid X receptor (FXR) activation induces the production of FGF19, which reaches the liver through the portal system where it represses the expression of CYP7A1, the rate-limiting enzyme of hepatic de novo BAs synthesis. Dysregulation of BA levels associated with alteration in FGF19 level has been depicted in different pathological conditions of the gut-liver axis. Furthermore, FGF19 exploits strong anti-cholestatic and anti-fibrotic activities in the liver. However, native FGF19 seems to retain peculiar hepatic pro-tumorigenic actions. Recently engineered FGF19 analogues have been recently synthetized, with fully retained BA regulatory activity but without intrinsic pro-tumoral action, thus opening bona fide novel pharmacological strategy for the treatment of gut-liver axis diseases.
- Published
- 2019
23. Proteomics and Lipidomics in Inflammatory Bowel Disease Research: From Mechanistic Insights to Biomarker Identification
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Julia Hoeng, Kim Ekroos, Bjoern Titz, Nikolai V. Ivanov, Ashraf Elamin, Raffaella Maria Gadaleta, Giuseppe Lo Sasso, and Manuel C. Peitsch
- Subjects
0301 basic medicine ,Proteome ,Disease ,Computational biology ,Review ,Proteomics ,Inflammatory bowel disease ,Catalysis ,lcsh:Chemistry ,Inorganic Chemistry ,03 medical and health sciences ,proteomics ,inflammatory bowel disease ,Lipidomics ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,Biomarker discovery ,Precision Medicine ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,business.industry ,Research ,Organic Chemistry ,biomarkers ,General Medicine ,personalized medicine ,Omics ,medicine.disease ,Inflammatory Bowel Diseases ,Lipid Metabolism ,Ulcerative colitis ,digestive system diseases ,Computer Science Applications ,030104 developmental biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Metabolome ,lipidomics ,Personalized medicine ,business - Abstract
Inflammatory bowel disease (IBD) represents a group of progressive disorders characterized by recurrent chronic inflammation of the gut. Ulcerative colitis and Crohn′s disease are the major manifestations of IBD. While our understanding of IBD has progressed in recent years, its etiology is far from being fully understood, resulting in suboptimal treatment options. Complementing other biological endpoints, bioanalytical “omics” methods that quantify many biomolecules simultaneously have great potential in the dissection of the complex pathogenesis of IBD. In this review, we focus on the rapidly evolving proteomics and lipidomics technologies and their broad applicability to IBD studies; these range from investigations of immune-regulatory mechanisms and biomarker discovery to studies dissecting host–microbiome interactions and the role of intestinal epithelial cells. Future studies can leverage recent advances, including improved analytical methodologies, additional relevant sample types, and integrative multi-omics analyses. Proteomics and lipidomics could effectively accelerate the development of novel targeted treatments and the discovery of complementary biomarkers, enabling continuous monitoring of the treatment response of individual patients; this may allow further refinement of treatment and, ultimately, facilitate a personalized medicine approach to IBD.
- Published
- 2018
24. Uncoupling FoxO3A mitochondrial and nuclear functions in cancer cells undergoing metabolic stress and chemotherapy
- Author
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Enrico Garattini, Valentina Celestini, Tiziana Cocco, Domenico De Rasmo, L. Russo, Natasha Scialpi, Cristiano Simone, Gaetano Villani, Martina Lepore Signorile, Raffaella Maria Gadaleta, Mineko Terao, Giovanna Forte, Paola Sanese, Anna Signorile, Antonio Moschetta, Valentina Grossi, Alessia Peserico, Giovanna Longo, Candida Fasano, and Tugsan Tezil
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Cancer Research ,Apoptosis ,Foxo3A ,AMP-Activated Protein Kinases ,Mitochondrion ,Inbred C57BL ,Malignant transformation ,Mice ,Phosphorylation ,Extracellular Signal-Regulated MAP Kinases ,Gene Editing ,Tumor ,Genome ,lcsh:Cytology ,mitochondrial ,carcinogenesis ,Forkhead Box Protein O3 ,MAP Kinase Kinase Kinases ,Metformin ,Cell biology ,Gene Expression Regulation, Neoplastic ,mitochondria ,Fluorouracil ,Signal transduction ,Signal Transduction ,Mitochondrial DNA ,Cell Survival ,Physiological ,Immunology ,Antineoplastic Agents ,Biology ,Irinotecan ,Stress ,Article ,Cell Line ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Stress, Physiological ,Cell Line, Tumor ,medicine ,Animals ,Humans ,lcsh:QH573-671 ,Transcription factor ,Cell Nucleus ,Neoplastic ,Cancer ,Cell Biology ,CRISPR-Cas Systems ,Cisplatin ,Genome, Mitochondrial ,HEK293 Cells ,Mice, Inbred C57BL ,Mitochondria ,NIH 3T3 Cells ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Cancer cell - Abstract
While aberrant cancer cell growth is frequently associated with altered biochemical metabolism, normal mitochondrial functions are usually preserved and necessary for full malignant transformation. The transcription factor FoxO3A is a key determinant of cancer cell homeostasis, playing a dual role in survival/death response to metabolic stress and cancer therapeutics. We recently described a novel mitochondrial arm of the AMPK-FoxO3A axis in normal cells upon nutrient shortage. Here, we show that in metabolically stressed cancer cells, FoxO3A is recruited to the mitochondria through activation of MEK/ERK and AMPK, which phosphorylate serine 12 and 30, respectively, on FoxO3A N-terminal domain. Subsequently, FoxO3A is imported and cleaved to reach mitochondrial DNA, where it activates expression of the mitochondrial genome to support mitochondrial metabolism. Using FoxO3A−/− cancer cells generated with the CRISPR/Cas9 genome editing system and reconstituted with FoxO3A mutants being impaired in their nuclear or mitochondrial subcellular localization, we show that mitochondrial FoxO3A promotes survival in response to metabolic stress. In cancer cells treated with chemotherapeutic agents, accumulation of FoxO3A into the mitochondria promoted survival in a MEK/ERK-dependent manner, while mitochondrial FoxO3A was required for apoptosis induction by metformin. Elucidation of FoxO3A mitochondrial vs. nuclear functions in cancer cell homeostasis might help devise novel therapeutic strategies to selectively disable FoxO3A prosurvival activity.
- Published
- 2018
25. Tissue-specific actions of FXR in metabolism and cancer
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Carlo Sabbà, Marica Cariello, Antonio Moschetta, and Raffaella Maria Gadaleta
- Subjects
Receptors, Cytoplasmic and Nuclear ,Lipid metabolism ,Cell Biology ,Metabolism ,Biology ,Pathogenesis ,Structure-Activity Relationship ,Glucose ,Liver ,Biochemistry ,Transcription (biology) ,Neoplasms ,Animals ,Homeostasis ,Humans ,Farnesoid X receptor ,Intestinal Mucosa ,Molecular Biology ,Transcription factor ,Hormone - Abstract
The nuclear Farnesoid X Receptor (FXR) is a transcription factor critically involved in metabolic homeostasis in the gut-liver axis. FXR activity is mediated by hormonal and dietary signals and driven by bile acids (BAs), which are the natural FXR ligands. Given the great physiological importance in BA homeostasis, as well as in the regulation of glucose and lipid metabolism, FXR plays a pivotal role in the pathogenesis of a wide range of disease of the liver, biliary tract and intestine, including hepatic and colorectal cancer. In the last years several studies have shown the relative FXR tissue-specific importance, highlighting synergism and additive effects in the liver and intestine. Gain- and loss-of-FXR-function mouse models have been generated in order to identify the biological processes and the molecular FXR targets. Taking advantage of the knowledge on the structure-activity relationship of BAs for FXR, semi-synthetic and synthetic molecules have been generated to obtain more selective and powerful FXR activators than BAs. This article is part of a Special Issue entitled: Linking transcription to physiology in lipodomics.
- Published
- 2015
26. Corrigendum: Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ER alpha metastatic breast cancer
- Author
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Valentina Vircillo, Ylenia Perone, Andreas Trumpp, Massimo Saini, Giancarlo Pruneri, Saverio Minucci, Raffaella Maria Gadaleta, Pernette J Vershure, Giacomo Corleone, Mannus H Kempe, Sung Pil Hong, Gianmaria Frigè, Iros Barozzi, Marco Colleoni, Sonia Fabris, Giuseppe Viale, Simak Ali, Antonino Neri, Luca Magnani, and Imperial College London
- Subjects
Genetics & Heredity ,Aromatase inhibitor ,Science & Technology ,medicine.drug_class ,Mechanism (biology) ,Biology ,06 Biological Sciences ,medicine.disease ,Metastatic breast cancer ,Nat ,Genetics ,medicine ,Cancer research ,Life Sciences & Biomedicine ,11 Medical and Health Sciences ,Developmental Biology - Abstract
Nat. Genet.; 10.1038/ng.3773; corrected online 31 January 2017 In the version of this article initially published online, the names of authors Hermannus Kempe and Pernette J. Verschure were spelled incorrectly. These errors have been corrected in the print, PDF and HTML versions of this article.
- Published
- 2017
27. Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer
- Author
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Simak Ali, Antonino Neri, Valentina Vircillo, Massimo Saini, Hermannus Kempe, Giacomo Corleone, Luca Magnani, Giancarlo Pruneri, Marco Colleoni, Giuseppe Viale, Gianmaria Frigè, Iros Barozzi, Sonia Fabris, Saverio Minucci, Pernette J. Verschure, Andreas Trumpp, Sung Pil Hong, Raffaella Maria Gadaleta, Ylenia Perone, Commission of the European Communities, Imperial College London, Cancer Research UK, Synthetic Systems Biology (SILS, FNWI), and Systems Biology
- Subjects
0301 basic medicine ,ANDROGEN RECEPTOR GENE ,endocrine system ,ESR1 MUTATIONS ,Antineoplastic Agents, Hormonal ,medicine.drug_class ,Estrogen receptor ,PROGRESSION ,Breast Neoplasms ,THERAPY ,Article ,Metastasis ,03 medical and health sciences ,Breast cancer ,Aromatase ,REVEALS ,Genetics ,medicine ,Humans ,11 Medical and Health Sciences ,Genetics & Heredity ,Aromatase inhibitor ,Science & Technology ,biology ,Aromatase Inhibitors ,Estrogen Receptor alpha ,06 Biological Sciences ,medicine.disease ,Metastatic breast cancer ,EVOLUTION ,3. Good health ,PROSTATE-CANCER ,GENOME ,030104 developmental biology ,Selective estrogen receptor modulator ,Drug Resistance, Neoplasm ,Immunology ,LIGAND-BINDING ,CELLS ,Cancer research ,biology.protein ,Female ,Neoplasm Recurrence, Local ,Estrogen receptor alpha ,Life Sciences & Biomedicine ,Developmental Biology - Abstract
Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, estrogen receptor (ERα) positive breast cancer (BCa) patients are treated with adjuvant endocrine therapy2 including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, over 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease4. Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases: in this study, 21.5% of AI-treated, relapsed patients had acquired CYP19A1 gene (aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer genes including ESR1 and CYP19A1. Strikingly, CYP19A1amp cells also emerge in vitro but only in AI resistant models. CYP19A1 amplification causes increased aromatase activity and estrogen-independent ERα binding to target genes resulting in CYP19A1amp cells displaying decreased sensitivity to AI treatment. Collectively these data suggest that AI treatment itself selects for acquired CYP19A1 amplification and promotes local autocrine estrogen signalling in AI resistant metastatic patients.
- Published
- 2016
28. P031 Effects of tobacco alkaloids on DSS-induced colitis mouse model
- Author
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Athanasios Kondylis, G Lo Sasso, Raffaella Maria Gadaleta, Blaine Phillips, Ashraf Elamin, Julia Hoeng, and Nikolai V. Ivanov
- Subjects
business.industry ,Disease progression ,Gastroenterology ,General Medicine ,Pharmacology ,medicine.disease ,Inflammatory bowel disease ,Nicotine ,Potable water ,medicine ,Cigarette smoke ,Colitis ,business ,medicine.drug - Published
- 2018
29. Nuclear receptors and chromatin: an inducible couple
- Author
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Luca Magnani and Raffaella Maria Gadaleta
- Subjects
Genome ,RNA, Untranslated ,Receptors, Cytoplasmic and Nuclear ,RNA ,Biology ,Chromatin ,humanities ,Epigenesis, Genetic ,Cell biology ,Histones ,Transactivation ,Endocrinology ,Histone ,Nuclear receptor ,Gene expression ,biology.protein ,Animals ,Humans ,Epigenetics ,human activities ,Molecular Biology ,Transcription factor - Abstract
The nuclear receptor (NR) family comprises 48 transcription factors (TFs) with essential and diverse roles in development, metabolism and disease. Differently from other TFs, NRs engage with well-defined DNA-regulatory elements, mostly after ligand-induced structural changes. However, NR binding is not stochastic, and only a fraction of the cognate regulatory elements within the genome actively engage with NRs. In this review, we summarize recent advances in the understanding of the interactions between NRs and DNA. We discuss how chromatin accessibility and epigenetic modifications contribute to the recruitment and transactivation of NRs. Lastly, we present novel evidence of the interplay between non-coding RNA and NRs in the mediation of the assembly of the transcriptional machinery.
- Published
- 2013
30. Discovery of 3α,7α,11β-Trihydroxy-6α-ethyl-5β-cholan-24-oic Acid (TC-100), a Novel Bile Acid as Potent and Highly Selective FXR Agonist for Enterohepatic Disorders
- Author
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Antimo Gioiello, Aldo Roda, Carolina Colliva, Paolo Filipponi, Andrea Carotti, Antonio Moschetta, Antonio Macchiarulo, Roberto Pellicciari, Placido Franco, Serena Mostarda, Daniela Passeri, Raffaella Maria Gadaleta, Francesca De Franco, Pellicciari, Roberto, Passeri, Daniela, De Franco, Francesca, Mostarda, Serena, Filipponi, Paolo, Colliva, Carolina, Gadaleta, Raffaella Maria, Franco, Placido, Carotti, Andrea, Macchiarulo, Antonio, Roda, Aldo, Moschetta, Antonio, and Gioiello, Antimo
- Subjects
0301 basic medicine ,Agonist ,Stereochemistry ,medicine.drug_class ,Hydroxylation ,Bile Acids ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery, Medicinal Chemistry, FXR, Bile Acids, Liver diseases, NASH ,Cholestasis ,In vivo ,Drug Discovery ,medicine ,Receptor ,Liver diseases ,Bile acid ,Drug Discovery3003 Pharmaceutical Science ,NASH ,medicine.disease ,G protein-coupled bile acid receptor ,Ursodeoxycholic acid ,030104 developmental biology ,FXR ,chemistry ,Biochemistry ,030220 oncology & carcinogenesis ,Molecular Medicine ,Medicinal Chemistry ,medicine.drug - Abstract
As a continuation of previous efforts in mapping functional hot spots on the bile acid scaffold, we here demonstrate that the introduction of a hydroxy group at the C11β position affords high selectivity for FXR. In particular, the synthesis and FXR/TGR5 activity of novel bile acids bearing different hydroxylation patterns at the C ring are reported and discussed from a structure-activity standpoint. The results obtained led us to discover the first bile acid derivative endowed with high potency and selectivity at the FXR receptor, 3α,7α,11β-trihydroxy-6α-ethyl-5β-cholan-24-oic acid (TC-100, 7) which also shows a remarkable physicochemical and pharmacological profile. Compound 7 combines the excellent physicochemical properties of hydrophilic bile acids such as ursodeoxycholic acid, with the distinct ability to specifically bind and regulate FXR activity in vivo, thus providing a bona fide novel therapeutic agent to treat enterohepatic disorders such as cholestasis, NASH, and inflammatory bowel disease.
- Published
- 2016
31. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease
- Author
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Giuseppe Penna, Raffaella Maria Gadaleta, Bas Oldenburg, Marguerite E.I. Schipper, Saskia W.C. van Mil, Stefania Murzilli, Gilles Laverny, Antonio Moschetta, Luciano Adorini, Silvio Danese, Peter D. Siersema, Leo W. J. Klomp, Karel J. van Erpecum, Willem Renooij, Ellen C.L. Willemsen, Gadaleta, Rm, van Erpecum, Kj, Oldenburg, B, Willemsen, Ecl, Renooij, W, Murzilli, S, Klomp, Lwj, Siersema, Pd, Schipper, Mei, Danese, S, Penna, G, Laverny, G, Adorini, L, Moschetta, A, and van Mil, Swc
- Subjects
medicine.medical_specialty ,Colon ,Drug Evaluation, Preclinical ,Receptors, Cytoplasmic and Nuclear ,Inflammation ,Bile acid ,Biology ,Chenodeoxycholic Acid ,Inflammatory bowel disease ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Ileum ,Internal medicine ,medicine ,Animals ,Humans ,Colitis ,030304 developmental biology ,0303 health sciences ,Goblet cell ,Reverse Transcriptase Polymerase Chain Reaction ,Tumor Necrosis Factor-alpha ,Dextran Sulfate ,Gastroenterology ,PostScript ,Inflammatory Bowel Diseases ,medicine.disease ,inflammatory bowel disorders ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,Intestinal Absorption ,Trinitrobenzenesulfonic Acid ,Cancer research ,Cytokines ,030211 gastroenterology & hepatology ,Farnesoid X receptor ,Cytokine secretion ,Caco-2 Cells ,Inflammation Mediators ,medicine.symptom - Abstract
Background & aims Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models. Methods Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types. Results INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor a secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD. Conclusions FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD. RI van Mil, Saskia/C-3751-2009
- Published
- 2011
32. P116 A computable, causal biological network model suite for mechanistic evaluation of ulcerative colitis
- Author
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Manuel C. Peitsch, Justyna Szostak, Raffaella Maria Gadaleta, Julia Hoeng, M Florian, and Marja Talikka
- Subjects
business.industry ,Suite ,Gastroenterology ,medicine ,General Medicine ,Computational biology ,medicine.disease ,business ,Ulcerative colitis ,Biological network - Published
- 2018
33. Chromatin and Epigenetic Determinants of Resistance to Aromatase Inhibitors
- Author
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Raffaella Maria Gadaleta and Luca Magnani
- Subjects
biology ,biology.protein ,Estrogen receptor ,Histone code ,Epigenetics ,Aromatase ,Estrogen receptor activity ,Reprogramming ,Chromatin remodeling ,Chromatin ,Cell biology - Abstract
Resistance to aromatase inhibitors (AI) involves extensive transcriptional reprogramming to overcome drug-mediated cell cycle arrest. Chromatin accessibility and epigenetic modifications play a crucial role in regulating gene expression in normal development and contribute to aberrant transcription commonly found in malignant cells. In this chapter we will discuss the latest research findings linking AI resistance to epigenetics. Initially we will examine the epigenetic regulation of the aromatase gene. The estrogen receptor activity is significantly influenced by the chromatin template and we will present evidence on how the estrogen receptor-chromatin crosstalk can contribute to the development of resistance. Next we will consider alternative survival pathways and how they are epigenetically regulated in response to AI treatment. Afterward, we will review the current state of epigenetic-based medicine in the context of endocrine therapies. Finally, we will offer some insights on future challenges and possible breakthroughs.
- Published
- 2015
34. 4 Nuclear bile acid receptor FXR and hepatobiliary transport systems
- Author
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Antonio Moschetta and Raffaella Maria Gadaleta
- Subjects
Biochemistry ,Chemistry ,G protein-coupled bile acid receptor - Published
- 2012
35. Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease
- Author
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Saskia W.C. van Mil, Leo W. J. Klomp, Peter D. Siersema, Karel J. van Erpecum, Bas Oldenburg, and Raffaella Maria Gadaleta
- Subjects
medicine.medical_specialty ,medicine.drug_class ,Gastrointestinal Diseases ,Receptors, Cytoplasmic and Nuclear ,Inflammation ,Biology ,Inflammatory bowel disease ,Bile Acids and Salts ,Internal medicine ,medicine ,Animals ,Bile ,Humans ,Regeneration ,Intestinal Mucosa ,Molecular Biology ,Enterohepatic circulation ,Gastrointestinal tract ,Bile acid ,Liver Diseases ,Cell Biology ,medicine.disease ,Intestines ,Endocrinology ,Nuclear receptor ,Liver ,Gastrointestinal disease ,Bacterial Translocation ,Cancer research ,Farnesoid X receptor ,medicine.symptom - Abstract
The nuclear receptor Farnesoid X Receptor (FXR) critically regulates nascent bile formation and bile acid enterohepatic circulation. Bile acids and FXR play a pivotal role in regulating hepatic inflammation and regeneration as well as in regulating extent of inflammatory responses, barrier function and prevention of bacterial translocation in the intestinal tract. Recent evidence suggests, that the bile acid-FXR interaction is involved in the pathophysiology of a wide range of diseases of the liver, biliary and gastrointestinal tract, such as cholestatic and inflammatory liver diseases and hepatocellular carcinoma, inflammatory bowel disease and inflammation-associated cancer of the colon and esophagus. In this review we discuss current knowledge of the role the bile acid-FXR interaction has in (patho)physiology of the liver, biliary and gastrointestinal tract, and proposed underlying mechanisms, based on in vitro data and experimental animal models. Given the availability of highly potent synthetic FXR agonists, we focus particularly on potential relevance for human disease.
- Published
- 2010
36. Deciphering the nuclear bile acid receptor FXR paradigm
- Author
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Antonio Moschetta, Raffaella Maria Gadaleta, and Salvatore Modica
- Subjects
Gastrointestinal Stromal Tumors ,Receptors, Cytoplasmic and Nuclear ,Hyperlipidemias ,Review ,Gallstones ,Biology ,Bile Acids and Salts ,03 medical and health sciences ,0302 clinical medicine ,Cholestasis ,Diabetes Mellitus ,medicine ,Animals ,Glucose homeostasis ,Receptor ,Liver X receptor ,Triglycerides ,030304 developmental biology ,0303 health sciences ,Liver Neoplasms ,General Medicine ,Atherosclerosis ,medicine.disease ,G protein-coupled bile acid receptor ,Liver regeneration ,Liver Regeneration ,Rats ,3. Good health ,Intestinal Diseases ,Glucose ,Gene Expression Regulation ,Nuclear receptor ,Biochemistry ,030220 oncology & carcinogenesis ,Farnesoid X receptor ,Transcription Factors - Abstract
Originally called retinoid X receptor interacting protein 14 (RIP14), the farnesoid X receptor (FXR) was renamed after the ability of its rat form to bind supra-physiological concentrations of farnesol. In 1999 FXR was de-orphanized since primary bile acids were identified as natural ligands. Strongly expressed in the liver and intestine, FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of conditions such as cholestasis, fatty liver disease, cholesterol gallstone disease, intestinal inflammation and tumors. Furthermore, given the importance of FXR in the gut-liver axis feedbacks regulating lipid and glucose homeostasis, FXR modulation appears to have great input in diseases such as metabolic syndrome and diabetes. Exciting results from several cellular and animal models have provided the impetus to develop synthetic FXR ligands as novel pharmacological agents. Fourteen years from its discovery, FXR has gone from bench to bedside; a novel nuclear receptor ligand is going into clinical use.
- Published
- 2010
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37. Pharmacological Activation of the Bile Acid Nuclear Farnesoid X Receptor Is Feasible in Patients with Quiescent Crohn's Colitis
- Author
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Peter D. Siersema, Karel J. van Erpecum, Bas Oldenburg, Raffaella Maria Gadaleta, Frank G. Schaap, Fiona D.M. van Schaik, Saskia W.C. van Mil, Surgery, RS: NUTRIM - R2 - Gut-liver homeostasis, and Tytgat Institute for Liver and Intestinal Research
- Subjects
Male ,LIVER ,lcsh:Medicine ,Receptors, Cytoplasmic and Nuclear ,Biochemistry ,Inflammatory bowel disease ,DISEASE ,Feces ,chemistry.chemical_compound ,Crohn Disease ,INTESTINE ,Chenodeoxycholic acid ,Drug Discovery ,Molecular Cell Biology ,Signaling in Cellular Processes ,lcsh:Science ,Multidisciplinary ,Bile acid ,Chemistry ,Clinical Pharmacology ,Gallbladder ,Middle Aged ,Nuclear Signaling ,FXR ,Medicine ,Female ,Biliary Disorders ,Research Article ,Biotechnology ,Signal Transduction ,Adult ,Drugs and Devices ,medicine.medical_specialty ,Drug Research and Development ,Clinical Research Design ,medicine.drug_class ,CHOLESTASIS ,Gastroenterology and Hepatology ,Chenodeoxycholic Acid ,Bile Acids and Salts ,Cholestasis ,Internal medicine ,DNA-binding proteins ,medicine ,Humans ,Clinical Trials ,RNA, Messenger ,Colitis ,Biology ,Aged ,IDENTIFICATION ,lcsh:R ,Inflammatory Bowel Disease ,Proteins ,FGF19 ,medicine.disease ,Fibroblast Growth Factors ,Endocrinology ,Gene Expression Regulation ,Nuclear receptor ,Case-Control Studies ,lcsh:Q ,Farnesoid X receptor ,Nuclear Receptor Signaling - Abstract
Background The bile acid-activated nuclear receptor Farnesoid X Receptor (FXR) is critical in maintaining intestinal barrier integrity and preventing bacterial overgrowth. Patients with Crohn's colitis (CC) exhibit reduced ileal FXR target gene expression. FXR agonists have been shown to ameliorate inflammation in murine colitis models. We here explore the feasibility of pharmacological FXR activation in CC. Methods Nine patients with quiescent CC and 12 disease controls were treated with the FXR ligand chenodeoxycholic acid (CDCA; 15 mg/kg/day) for 8 days. Ileal FXR activation was assessed in the fasting state during 6 hrs after the first CDCA dose and on day 8, by quantification of serum levels of fibroblast growth factor (FGF) 19. Since FGF19 induces gallbladder (GB) refilling in murine models, we also determined concurrent GB volumes by ultrasound. On day 8 ileal and cecal biopsies were obtained and FXR target gene expression was determined. Results At baseline, FGF19 levels were not different between CC and disease controls. After the first CDCA dose, there were progressive increases of FGF19 levels and GB volumes during the next 6 hours in CC patients and disease controls (FGF19: 576 resp. 537% of basal; GB volumes: 190 resp. 178% of basal) without differences between both groups, and a further increase at day 8. In comparison with a separate untreated control group, CDCA affected FXR target gene expression in both CC and disease controls, without differences between both groups. Conclusions Pharmacological activation of FXR is feasible in patients with CC. These data provide a rationale to explore the anti-inflammatory properties of pharmacological activation of FXR in these patients. Trial Registration TrialRegister.nl NTR2009
- Published
- 2012
38. Tu1883 Activation of the Nuclear Receptor FXR by Oral Chenodeoxycholic Acid in Patients With Crohn's Colitis: Potential Therapeutic Consequences for Inflammatory Bowel Disease
- Author
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Fiona D.M. van Schaik, Saskia W.C. van Mil, Bas Oldenburg, Frank G. Schaap, Raffaella Maria Gadaleta, Peter D. Siersema, and Karel J. van Erpecum
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Crohn's colitis ,Gastroenterology ,medicine.disease ,Inflammatory bowel disease ,chemistry.chemical_compound ,Endocrinology ,Nuclear receptor ,chemistry ,Internal medicine ,Chenodeoxycholic acid ,medicine ,In patient ,business - Published
- 2012
39. A Functional Variant of the Farnesoid X Receptor (FXR) Predisposes to Ileocolonic Localization of Crohn's Disease
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Christien J. van der Woude, Adriaan A. van Bodegraven, Bas Oldenburg, Gerard Dijkstra, Rian M. Nijmeijer, Saskia W.C. van Mil, J. Bart A. Crusius, Marguerite E.I. Schipper, Rinse K. Weersma, Raffaella Maria Gadaleta, Daniel W. Hommes, Cyriel Y. Ponsioen, Dirk J. de Jong, Karel J. van Erpecum, Hein W. Verspaget, and Cisca Wijmenga
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medicine.medical_specialty ,Crohn's disease ,Hepatology ,Internal medicine ,Philosophy ,Gastroenterology ,medicine ,Farnesoid X receptor ,medicine.disease - Abstract
A Functional Variant of the Farnesoid X Receptor (FXR) Predisposes to Ileocolonic Localization of Crohn's Disease Rian M. Nijmeijer, Raffaella Maria Gadaleta, Karel J. Van Erpecum, Adriaan A. van Bodegraven, J. Bart A. Crusius, Gerard Dijkstra, Daniel W. Hommes, Dirk J. De Jong, Cyriel Ponsioen, Hein W. Verspaget, Rinse K. Weersma, Christien J. van der Woude, Marguerite E. Schipper, Cisca Wijmenga, Saskia W. van Mil, Bas Oldenburg
- Published
- 2011
40. S1728 Intestinal Bile Salt Nuclear Receptor FXR Protects From Inflammatory Bowel Disease: Potential Therapeutic Implications
- Author
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Ellen C.L. Willemsen, Stefania Murzilli, Antonio Moschetta, Bas Oldenburg, Peter D. Siersema, Saskia W.C. van Mil, Karel J. van Erpecum, Raffaella Maria Gadaleta, and Leo W. J. Klomp
- Subjects
medicine.medical_specialty ,Intestinal permeability ,Hepatology ,FGF15 ,Gastroenterology ,medicine.disease ,Inflammatory bowel disease ,chemistry.chemical_compound ,Interleukin 10 ,Endocrinology ,chemistry ,Nuclear receptor ,Chenodeoxycholic acid ,Internal medicine ,medicine ,Farnesoid X receptor ,Colitis - Abstract
The bile salt nuclear receptor Farnesoid X Receptor (FXR) was recently implicated in intestinal antibacterial defense and barrier function. We aimed to study its role in pathogenesis of inflammatory bowel diseasE. colitis was induced in Wild Type (WT) and FXR knock-out (ko) mice (n=8 to 10 for each group) by Dextran Sodium Sulphate (DSS: 2.5% in drinking water, 10 days) with or without synthetic FXR ligand 6-Ethyl Chenodeoxycholic Acid (6ECDCA: 5 mg/kg/day, 13 days, starting 3 days before DSS). Colitis symptoms were checked daily and intestinal permeability (FITC-dextran assay), bile salt composition (HPLC), histology and colonic inflammatory gene expression (Q-PCR) determined. mRNA expression of FXR and target genes was determined in IBD patient biopsies. Underlying mechanisms were explored in complementary In Vitro experiments. 6ECDCA-treated WT but not FXR ko mice were protected from DSS-induced colitis, as shown by highly significant reduction of body weight loss, rectal bleeding, colonic shortening, normalization of intestinal permeability, 49% reduction in blinded histological score and 55% reduction in goblet cell loss. Only in 6ECDCA-treated WT mice, mRNA levels of pro-inflammatory genes (IL-1β, IL-6, IL10 and MCP-1) were strongly down-regulated while antibacterial defense gene iNOS was upregulated. 6ECDCA was enriched in bile of both WT and FXR ko mice (9.8% and 5.3% of total bile salts, respectively). However intestinal expression of FXR target genes FGF15 and SHP was increased 4.5and 19-fold with 6ECDCA treatment only in WT. In patients with quiescent Crohn colitis (n=17), mRNA expression of FXR and SHP was significantly altered compared to patients with ulcerative colitis (n=16) or healthy controls (n=17). In differentiated CaCo2 cells grown on trans-well plates, FXR activation by GW4064 prevented DSS-dependent loss of integrity of the monolayer. In differentiated HT29 cells, TNFαinduced 20-fold increase of IL-1β expression was abolished by GW4064-dependent FXR activation. In reporter assays, the FXR agonist GW4064 prevented TNFα-induced NF-κB activity in HEK293 cells transfected with WT FXR, but no effect was achieved with FXR mutant W469A (defective in Ligand Binding Domain), indicating FXR-mediated inhibition of NF-κB signalling. In conclusion, FXR activation protects against experimental murine colitis, supposedly by preserving the intestinal barrier and inhibitingNF-κB activity. Currently available potent synthetic FXR agonists may offer new therapeutic strategies for inflammatory bowel disease.
- Published
- 2010
41. Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine
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Saskia W.C. van Mil, Leo W.J. Klomp, Stefania Murzilli, Bas Oldenburg, Ellen C.L. Willemsen, Raffaella Maria Gadaleta, Peter D. Siersema, Maureen Spit, Karel J. van Erpecum, and Lorena Salvatore
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Male ,medicine.medical_specialty ,Receptors, Cytoplasmic and Nuclear ,Inflammation ,Biology ,Inflammatory bowel disease ,Cell Line ,Proinflammatory cytokine ,Bile Acids and Salts ,Mice ,Intestinal mucosa ,Mutual inhibition ,Internal medicine ,medicine ,Animals ,Humans ,Nuclear factor κB ,Intestinal Mucosa ,Molecular Biology ,Farnesoid X Receptor ,Reverse Transcriptase Polymerase Chain Reaction ,FGF15 ,NF-kappa B ,NFKB1 ,Cell biology ,Mice, Inbred C57BL ,Endocrinology ,Nuclear receptor ,Cytokines ,Molecular Medicine ,Farnesoid X receptor ,Inflammation Mediators ,Signal transduction ,medicine.symptom ,Signal Transduction - Abstract
Hyperactivation of NF-κB is a key factor in the pathophysiology of inflammatory bowel disease (IBD). We previously showed that the bile salt nuclear Farnesoid X Receptor (FXR) counter-regulates intestinal inflammation, possibly via repression of NF-κB. Here, we examine whether mutual antagonism between NF-κB and FXR exists. FXR and its target genes IBABP and FGF15/19 expression were determined in HT29 colon carcinoma cells and ex vivo in intestinal specimens of wild type (WT) and Fxr -ko mice, treated with/without FXR ligands (GW4064/INT-747) and inflammatory stimuli (TNFα/IL-1β). In addition, FXR activation was studied in vivo in WT and Fxr -ko mice with DSS-colitis. The involvement of NF-κB in decreasing FXR activity was investigated by reporter assays and Glutathione S-transferase pulldown assays. FXR target gene expression was highly reduced by inflammatory stimuli in all model systems, while FXR mRNA expression was unaffected. In line with these results, reporter assays showed reduced FXR transcriptional activity upon TNFα/IL-1β stimulation. We show that this reduction in FXR activity is probably mediated by NF-κB, since overexpression of NF-κB subunits p50 and/or p65 also lead to inhibition of FXR activity. Finally, we report that p65 and p50 physically interact with FXR in vitro . Conclusions : Together, these results indicate that intestinal inflammation strongly reduces FXR activation, probably via NF-κB-dependent tethering of FXR. Therefore, FXR not only inhibits inflammation, but also is targeted by the inflammatory response itself. This could result in a vicious cycle where reduced FXR activity results in less repression of inflammation, contributing to development of chronic intestinal inflammation. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
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