Azienda Ospedaliera di Perugia

Perugia, Italy

Azienda Ospedaliera di Perugia

Perugia, Italy
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Fiorucci S.,University of Perugia | Zampella A.,University of Naples Federico II | Distrutti E.,Azienda Ospedaliera di Perugia
Current Topics in Medicinal Chemistry | Year: 2012

The farnesoid-x-receptor (FXR), the constitute-androstane-receptor (CAR) and the pregnane-x-receptor (PXR) are ligand regulated nuclear receptors highly expressed in the liver and intestine supervising essential steps in the metabolism of xeno and endo-biotics in entero-hepatic tissues. Primary and secondary bile acids function as receptor agonists/activators for these receptors. Activation of FXR by steroidal and non steroidal ligands promotes bile acids secretion by activating bile acids transporters in the apical membrane of hepatocytes. These effects are coordinated with a reduction in bile acids uptake at the basolateral membrane. However, FXR agonists interfere with the regulatory activity of CAR on hepatocyte's basolateral transporters. Because these effects might worsen liver injury in a subset of patients with obstructive cholestasis, development of FXR antagonists might be of clinical relevance. Structure-activity relationship studies have shown that available FXR antagonists are poorly specific for FXR, however specific FXR antagonists that are currently used in pre-clinical models of liver injury have been identified from marine organisms. PXR agonists are endowed with a wide array of biological activities but their effects on the expression/activity of phase I and II metabolizing enzymes is likely to limit their pharmacological development. Nevertheless a combination between FXR agonists and CAR and PXR agonists might hold utility in treating subset of patients with liver disorders. In addition, development of tissue specific FXR antagonists is an attractive opportunity to target subsets of genes in the intestine and liver avoiding side-effects linked to FXR activation. © 2012 Bentham Science Publishers.


Cipriani S.,University of Perugia | Mencarelli A.,University of Perugia | Bruno A.,University of Perugia | Renga B.,University of Perugia | And 4 more authors.
British Journal of Pharmacology | Year: 2013

Background and Purpose Low doses of aspirin (acetylsalicylic acid; ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of gastrointestinal bleeding. GPBAR1 is a bile acid receptor expressed in the gastrointestinal tract. Here, we have investigated whether GPBAR1 was required for mucosal protection in models of gastrointestinal injury caused by ASA and NSAIDs. Experimental Approch GPBAR1+/+ and GPBAR1-/- mice were given ASA (10-50 mg.kg-1) or naproxen. Gastric and intestinal mucosal damage was assessed by measuring lesion scores. Key Results Expression of GPBAR1, mRNA and protein, was detected in mouse stomach. Mice lacking GPBAR1 were more sensitive to gastric and intestinal injury caused by ASA and NSAIDs and exhibited a markedly reduced expression of cystathionine-γ-liase (CSE), cystathionine-β-synthase (CBS) and endothelial NOS enzymes required for generation of H2S and NO, in the stomach. Treating GPBAR1 +/+ mice with two GPBAR1 agonists, ciprofloxacin and betulinic acid, rescued mice from gastric injury caused by ASA and NSAIDs. The protective effect of these agents was lost in GPBAR1-/- mice. Inhibition of CSE by DL-propargylglycine completely reversed protection afforded by ciprofloxacin in wild type mice, whereas treating mice with an H2S donor restored the protective effects of ciprofloxacin in GPBAR1-/- mice. Deletion of GPBAR1 altered the morphology of the small intestine and increased sensitivity to injury caused by naproxen. Conclusion and Implications GPBAR1 is essential to maintain gastric and intestinal mucosal integrity. GPBAR1 agonists protect against gastrointestinal injury caused by ASA and NSAIDs by a COX-independent mechanism. © 2012 The British Pharmacological Society.


Distrutti E.,Azienda Ospedaliera di Perugia | Bifulco G.,University of Salerno | D'Auria M.V.,University of Naples Federico II | Zampella A.,University of Naples Federico II
Trends in Pharmacological Sciences | Year: 2012

Nuclear receptors (NRs) are a large family of evolutionarily conserved and ligand-regulated transcription factors. The farnesoid X receptor (FXR) and the pregnane X receptor (PXR) are two bile-acid-activated receptors highly expressed in enterohepatic tissues essential for bile acids and xenobiotic metabolism. More than 1600 new steroidal structures have been isolated from marine organisms. Chemical, structural, and pharmacological characterization of sponge steroid libraries has allowed the identification of steroids that regulate FXR and PXR: selective FXR antagonists, FXR modulators, FXR antagonists endowed with PXR agonism, and selective PXR agonists. Selective FXR antagonists (theonellasterol) have proven effective in protecting against liver injury in models of cholestasis. Selective PXR agonists (natural and synthetic solomonsterols) have been effective in reducing nuclear factor (NF)-κB activity and intestinal inflammation. Identification of marine steroids endowed with dual FXR and PXR agonism-antagonism probably reflects the common identity of the unique ancestral precursor of these NRs. These findings pave the way to the development of novel FXR and PXR agonists and antagonists to target human diseases. © 2012 Elsevier Ltd. All rights reserved.


Mencarelli A.,University of Perugia | Distrutti E.,Azienda Ospedaliera di Perugia | Renga B.,University of Perugia | D'Amore C.,University of Perugia | And 3 more authors.
PLoS ONE | Year: 2011

Background: Adipocytes from mesenteric white adipose tissue amplify the inflammatory response and participate in inflammation-driven immune dysfunction in Crohn's disease by releasing proinflammatory mediators. Peroxisome proliferator-activated receptors (PPAR)-α and -γ, pregnane x receptor (PXR), farnesoid x receptor (FXR) and liver x-receptor (LXR) are ligand-activated nuclear receptor that provide counter-regulatory signals to dysregulated immunity and modulates adipose tissue. Aims: To investigate the expression and function of nuclear receptors in intestinal and adipose tissues in a rodent model of colitis and mesenteric fat from Crohn's patients and to investigate their modulation by probiotics. Methods: Colitis was induced by TNBS administration. Mice were administered vehicle or VSL#3, daily for 10 days. Abdominal fat explants obtained at surgery from five Crohn's disease patients and five patients with colon cancer were cultured with VSL#3 medium. Results: Probiotic administration attenuated development of signs and symptoms of colitis, reduced colonic expression of TNFα, IL-6 and IFNγ and reserved colonic downregulation of PPARγ, PXR and FXR caused by TNBS. Mesenteric fat depots isolated from TNBS-treated animals had increased expression of inflammatory mediators along with PPARγ, FXR, leptin and adiponectin. These changes were prevented by VSL#3. Creeping fat and mesenteric adipose tissue from Crohn's patients showed a differential expression of PPARγ and FXR with both tissue expressing high levels of leptin. Exposure of these tissues to VSL#3 medium abrogates leptin release. Conclusions: Mesenteric adipose tissue from rodent colitis and Crohn's disease is metabolically active and shows inflammation-driven regulation of PPARγ, FXR and leptin. Probiotics correct the inflammation-driven metabolic dysfunction. © 2011 Mencarelli et al.


Fiorucci S.,University of Perugia | Mencarelli A.,University of Perugia | Distrutti E.,Azienda Ospedaliera di Perugia | Zampella A.,University of Naples Federico II
Future Medicinal Chemistry | Year: 2012

The farnesoid X receptor (FXR) is a bile sensor that acts in coordination with other nuclear receptors to regulate essential steps in bile acid uptake, metabolism and excretion. In addition, FXR is an ancillary receptor involved in lipid and glucose homeostasis. Steroidal and non-steroidal FXR ligands are currently available. Both groups have shown limitations in the preclinical studies regarding absorption, metabolism, specificity of target and intrinsic toxicity. FXR ligands endowed with agonistic activity are under development for the treatment of cholestatic liver diseases, including primary biliary cirrhosis and metabolic disorders linked to insulin resistance. Despite the fact that results from preclinical models are encouraging, targeting FXR holds potential for side effects (i.e., impaired cholesterol disposal and cholestasis). Thus, results from FXR gene-ablated mice and mice administered an FXR antagonist support a role for FXR antagonists or modulators (i.e., FXR agonists that selectively activate specific subsets of FXR target genes in a tissue) or co-regulator-specific manner. © 2012 Future Science Ltd.


Renga B.,University of Perugia | Migliorati M.,University of Perugia | Mencarelli A.,University of Perugia | Cipriani S.,University of Perugia | And 3 more authors.
Biochimica et Biophysica Acta - Gene Regulatory Mechanisms | Year: 2011

Multidrug resistance protein-4 (MRP4) is a member of the multidrug resistance associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive up-regulation in response to cholestatic injury or bile acid feeding. In this study we demonstrate that farnesoid X receptor (FXR) regulates MRP4 in vivo and in vitro. In vivo deletion of FXR induces MRP4 gene expression. In vitro treatment of HepG2 cells with FXR ligands, chenodeoxycholic acid (CDCA), cholic acid (CA) and the synthetic ligand GW-4064 suppresses basal mRNA level of the MRP4 gene as well as the co-treatment with CDCA and 6-(4-Chlorophenyl)imidazo[2,1- b][1,3]thiazole-5-carbaldehyde- O-(3,4-dichlorobenzyl)oxime (CITCO), an activator of constitutive androstane receptor (CAR). We found in the human MRP4 promoter a CAR responsive element (CARE) embedded within an FXR responsive element (FXRE). We cloned this region and found that FXR suppresses CAR activity in luciferase assay. Finally, we demonstrated that FXR competes with CAR for binding to this overlapping binding site. Our results support the view that FXR activation in obstructive cholestasis might worsen liver injury by hijacking a protective mechanism regulated by CAR and provides a new molecular explanation to the pathophysiology of cholestasis. © 2011 Elsevier B.V.


Fiorucci S.,University of Perugia | Distrutti E.,Azienda Ospedaliera di Perugia
Trends in Molecular Medicine | Year: 2015

The composition of the bile acid pool is a function of the microbial metabolism of bile acids in the intestine. Perturbations of the microbiota shape the bile acid pool and modulate the activity of bile acid-activated receptors (BARs) even beyond the gastrointestinal tract, triggering various metabolic axes and altering host metabolism. Bile acids, in turn, can also regulate the composition of the gut microbiome at the highest taxonomic levels. Primary bile acids from the host are preferential ligands for the farnesoid X receptor (FXR), while secondary bile acids from the microbiota are ligands for G-protein-coupled bile acid receptor 1 (GPBAR1). In this review, we examine the role of bile acid signaling in the regulation of intestinal microbiota and how changes in bile acid composition affect human metabolism. Bile acids may offer novel therapeutic modalities in inflammation, obesity, and diabetes. © 2015 Elsevier Ltd.


Fiorucci S.,University of Perugia | Cipriani S.,University of Perugia | Mencarelli A.,University of Perugia | Renga B.,University of Perugia | And 2 more authors.
Current Molecular Medicine | Year: 2010

In addition to their role in dietary lipid absorption bile acids are signaling modules activating nuclear receptors and at least one G-protein coupled receptor named the TGR5. With a different rank of potency primary and secondary bile acids activate a subset of nuclear receptors including the farnesoid-X-receptor (FXR, NR1H4); the constitutive androstane receptor (CAR, NR1H3), the pregnane-x-receptor (PXR, NR1H2), and the vitamin D receptor (VDR, NR1H1). Originally, these receptors were characterized for their role as bile acid and xenobiotic sensors, emerging evidence, however, indicates that FXR, PXR and VDR and their ligands are important for the modulation of immune and inflammatory reactions in entero-hepatic tissues. The immune phenotype FXR deficient mice indicates that these receptors are essential for the maintenance of immune homeostasis. A common theme of all bile acid-activated receptor is their ability to counter-regulate effector activities of cells of innate immunity establishing that signals generated by these receptors and their ligands function as braking signals for inflammation in entero-hepatic tissues. In this review, we will spotlight the molecular mechanisms of receptor/ligand function and how bile acid-activated receptors regulate the innate immunity in the gastrointestinal tract and liver. The ability of these receptors to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in immune-mediated diseases. © 2010 Bentham Science Publishers Ltd.


Mencarelli A.,University of Perugia | Cipriani S.,University of Perugia | Renga B.,University of Perugia | Bruno A.,University of Perugia | And 3 more authors.
PLoS ONE | Year: 2012

Background: Signals generated by the inflammed intestine are thought to contribute to metabolic derangement. The intestinal microbiota contributes to instructing the immune system beyond the intestinal wall and its modulation is a potential target for treating systemic disorders. Aims: To investigate the pathogenetic role of low grade intestinal inflammation in the development of steatohepatitis and atherosclerosis in a model of genetic dyslipidemia and to test the therapeutic potential of a probiotics intervention in protecting against development of these disorders. Results: ApoE-/- mice were randomized to receive vehicle or VSL#3, a mixture of eight probiotics, at the dose of 20×109 colony-forming units/kg/day for three months alone or in combination with 0.2% of dextran sulfate sodium (DSS) in drinking water. Administering DSS to ApoE-/- mice failed to induce signs and symptoms of colitis but increased intestinal permeability to dextran FITC and, while had no effect on serum lipids, increased the blood levels of markers of liver injury and insulin resistance. DSS administration associated with low level inflammation of intestinal and mesenteric adipose tissues, caused liver histopathology features of steatohepatitis and severe atherosclerotic lesions in the aorta. These changes were prevented by VSL#3 intervention. Specifically, VSL#3 reversed insulin resistance, prevented development of histologic features of mesenteric adipose tissue inflammation, steatohepatitis and reduced the extent of aortic plaques. Conditioned media obtained from cultured probiotics caused the direct transactivation of peroxisome proliferator-activated receptor-γ, Farnesoid-X-receptors and vitamin D receptor. Conclusions: Low grade intestinal inflammation drives a transition from steatosis to steatohepatitis and worsens the severity of atherosclerosis in a genetic model of dyslipidemia. VSL#3 intervention modulates the expression of nuclear receptors, corrects for insulin resistance in liver and adipose tissues and protects against development of steatohepatitis and atherosclerosis. © 2012 Mencarelli et al.


Mencarelli A.,University of Perugia | Migliorati M.,University of Perugia | Barbanti M.,Alfa Wassermann SpA | Cipriani S.,University of Perugia | And 4 more authors.
Biochemical Pharmacology | Year: 2010

The pregnane-X-receptor (PXR) is master gene overseeing detoxification of wide number of xenobiotics and is critical for maintenance of intestinal integrity. The intestinal expression of genes involved in cellular detoxification is down-regulated in patients with inflammatory bowel diseases (IBD). Rifaximin is a non-absorbable antibiotic endowed with a PXR agonistic activity. In the present study we have investigated whether rifaximin activates PXR in primary human colon epithelial cells and human colon biopsies and assessed whether this antibiotic antagonizes the effect of tumor necrosis factor (TNF)-α on expression of PXR and PXR-related genes. Present results demonstrate that primary colon epithelial cells express PXR and that their exposure to rifaximin induces the expression of genes involved in cellular detoxification. Exposure to TNFα reduces the expression of PXR mRNA as well as expression of its target genes. This inhibitory effect was prevented by that co-treatment with rifaximin. Knocking down the expression of PXR in colon epithelial cells by an anti-PXR siRNA, abrogated the counter-regulatory effects exerted by rifaximin on cell exposed to TNFα. Finally, ex vivo exposure of colon biopsies obtained from ulcerative colitis patients to rifaximin increased the expression of genes involved in xenobiotics metabolism. In aggregate, these data illustrate that rifaximin increases the expression of PXR and PXR-regulated genes involved in the metabolism and excretion of xenobiotics and antagonizes the effects of TNFα in intestinal epithelial cells and colon biopsies. These non-antibiotic effects of rifaximin could contribute to the maintenance of the intestinal barrier integrity against xenobiotics and products generated by luminal bacteria. © 2010 Elsevier Inc.

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