Hormonal regulation of bicarbonate secretion in the biliary epithelium.

Bicarbonate excretion in bile is a major function of the biliary epithelium. It is driven by the apically located Cl-/HCO3- exchanger which is functionally coupled with a cAMP-dependent Cl- channel (CFTR). A number of hormones and/or neuropeptides with different mechanisms and at different intracellular levels regulate, in concert, the processes underlying bicarbonate excretion in the biliary epithelium. Secretin induces a bicarbonate rich choleresis by stimulating the activity of the Cl-/HCO3- exchanger by cAMP and protein kinase A mediated phosphorylation of CFTR regulatory domain. Protein phosphatase 1/2A are involved in the run-down of secretory stimulus after secretin removal. Acetylcholine potentiates secretin-choleresis by inducing a Ca(++)-calcineurin mediated "sensitization" of adenyl cyclase to secretin. Bombesin and vasoactive intestinal peptide also enhance the Cl-/HCO3- exchanger activity, but the intracellular signal transduction pathway has not yet been defined. Somatostatin and gastrin inhibit basal and/or secretin-stimulated bicarbonate excretion by down-regulating the secretin receptor and decreasing cAMP intracellular levels induced by secretin

UniPR1331, a small molecule targeting Eph/ephrin interaction, prolongs survival in glioblastoma and potentiates the effect of antiangiogenic therapy in mice

Glioblastoma multiforme (GBM) is the most malignant brain tumor, showing high resistance to standard therapeutic approaches that combine surgery, radiotherapy, and chemotherapy. As opposed to healthy tissues, EphA2 has been found highly expressed in specimens of glioblastoma, and increased expression of EphA2 has been shown to correlate with poor survival rates. Accordingly, agents blocking Eph receptor activity could represent a new therapeutic approach. Herein, we demonstrate that UniPR1331, a pan Eph receptor antagonist, possesses significant in vivo anti-angiogenic and anti-vasculogenic properties which lead to a significant anti-tumor activity in xenograft and orthotopic models of GBM. UniPR1331 halved the final volume of tumors when tested in xenografts (p<0.01) and enhanced the disease-free survival of treated animals in the orthotopic models of GBM both by using U87MG cells (40 vs 24 days of control, p<0.05) or TPC8 cells (52 vs 16 days, p<0.01). Further, the association of UniPR1331 with the anti-VEGF antibody Bevacizumab significantly increased the efficacy of both monotherapies in all tested models. Overall, our data promote UniPR1331 as a novel tool for tackling GBM

Meccanismi fisiopatologici implicati in modelli sperimentali di colestasi

Dottorato di ricerca in fisiopatologia epato-digestiva. 11. ciclo. Coordinatore Lajos Okolicsanyi. Tutore Livio CapocacciaConsiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal

Synthesis of amino and ammonium resorcin[4]arenes as potential receptors

Starting from the tetrabromide la (cone conformation) a number of resorcin[4]arene derivatives (3a, 4a, 5a, 6a) containing an amino function in the side chains have been prepared. Preliminary investigations, including UV, NMR, and NIS analyses, of mixtures of the resorcinarene and its potential guests, such as metal cations or amino acids, evidenced promising new properties, depending on the nature of the substituents. Notably, treatment of 1a with pyridine gave readily the corresponding pyridinium salt 7a, capable of interacting with Ga(III) salts in aqueous solution. The same results have been obtained starting from the tetrabromide 1b (1,2alternate conformation) for two of the above reactions, giving derivatives 3b and 7b

Reaction of Nitrosonium Cation with Resorc[4]​arenes Activated by Supramolecular Control: Covalent Bond Formation

Resorc[4]​arenes 1 and 2, which previously proved to entrap NO+ cation within their cavities under conditions of host-​to-​guest excess, were treated with a 10-​fold excess of NOBF4 salt in chloroform. Kinetic and spectral UV-​visible analyses revealed the formation of isomeric 1:2 complexes as a direct evolution of the previously obsd. event. Accordingly, three-​body 1-​(NO+)​2 and 2-​(NO+)​2 adducts were built by MM and fully optimized by DFT calcns. at the B3LYP​/6-​31G(d) level of theory. Notably, covalent nitration products 4, 5 and 6, 7 were obtained by reaction of NOBF4 salt with host 1 and 2, resp., involving macrocycle ring-​opening and insertion of a nitro group in one of the four arom. rings. In particular, compds. 4 and 6, both contg. a trans-​double bond in the place of the methine bridge, were oxidized to aldehydes 5 and 7, resp., after addn. of water to the reaction mixt. Calcn. of the charge and frontier orbitals of the arom. donor (HOMO) and the NO+ acceptor (LUMO) clearly suggests an ipso electrophilic attack by a first NO+ unit on the resorcinol ring, mediated by the second NO+ unit

The function of alkaline phosphatase in the liver: Regulation of intrahepatic biliary epithelium secretory activities in the rat

We studied the effects of alkaline phosphatase (AP) on the secretory processes of the rat intrahepatic biliary epithelium as well as the role of the intrahepatic biliary epithelium in the uptake and biliary secretion of exogenous AP. The effects of acute and chronic administration of AP on bile secretory parameters were investigated in vivo in normal and bile duct ligated (BDL) rats and in vitro in isolated rat bile duct units (IBDU), In vivo, acute AP administration decreased bile now and biliary bicarbonate excretion and abolished secretin choleresis in BDL rats but not in normal rats. On the contrary, the AP inhibitor, levamisole, increased in BDL rat bile flow and biliary bicarbonate excretion. In vitro, basal and secretin-stimulated Cl(-)/HCO(3)(-) exchanger activity in IBDU was immediately inhibited by AP intraluminal microinjection (apical exposure) but only after a prolonged exposure to the basolateral pole. Levamisole increased the Cl(-)/HCO(3)(-) exchanger activity of IBDU, A significant basolateral uptake of AP occurs in IBDU with a progressive transport to the apical domain. AP chronic treatment increased AP and gamma-glutamyltranspeptidase (gamma-GT) activities in the intrahepatic bile ducts and hepatocyte canalicular pole, promoted enlargement of bile canaliculi, and decreased bile flow and biliary bicarbonate excretion. In conclusion, the intrahepatic biliary epithelium plays a role in the uptake and biliary secretion of serum AP. AP inhibits the secretory processes of the intrahepatic biliary epithelium and induces features of intrahepatic cholestasis after chronic administration. These findings indicate that AP plays an active role in down-regulating the secretory activities of the intrahepatic biliary epithelium