1,721,011 research outputs found
Disruption of Eph-ephrin B signaling pathways mitigates inflammation in a murine model of Crohn’s disease
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Multi-target-directed ligands: new histamine H3 receptor antagonists with anticholinesterase activity
No full textLithocholic acid competitively inhibitis EphA2-ephrinA1 binding: pharmacological and structural considerations.
No full textIntestinal Hypoxia and reperfusion: role for Eph-ephrin system
No full textBackground and aim: Mesenteric ischemia-reperfusion (I/R) is a life-threatening clinical problem consisting in the temporary deprivation of blood flow to the gut. The ensuing local organ damage is followed by the development of a systemic inflammatory response, eventually leading to multiple organ failure. Several neuronal, paracrine and plasmatic messengers are involved in mesenteric I/R injury. However, up to now, no studies have been performed on Eph receptors, the largest family of tyrosine kinase receptors, and their cell-bound ephrin ligands, whose role in cell adhesion-based processes during inflammation and immunity is growingly emerging. Eph-ephrin interaction generates a bidirectional signaling affecting both the receptor bearing (forward signaling) and the ligand bearing cells (reverse signaling). Our aim was therefore to investigate the effects produced by unidirectional activation of forward signaling (administration of chimeric protein ephrinA1-Fc; 50, 100, 200microg/kg), of reverse signaling (EphA2-Fc; 180microg/kg), or inhibition of both signals (monomeric EphA2 at equimolar doses of ephrinA1-Fc) on the inflammatory responses caused by mesenteric I/R in mice. Methods: Eph-ephrin proteins were intravenously administered to Swiss mice 5 min prior to 45 min occlusion of the superior mesenteric artery (SMA) followed by 5h reperfusion: intestinal and lung myeloperoxidase (MPO) activity, index of neutrophil recruit- ment, gut malondialdehyde (MDA) levels, marker of lipoperoxidation, and edema, index of increased vascular permeability, were compared to those of control I/R mice, receiving only vehicle, and of sham operated (SO) mice, subjected to the same manipulation without SMA occlusion and receiving vehicle. All experiments were performed according to the guidelines for the Care and Use of Animals (DL26/2014). Results: I/R mice displayed increased gut (45.3±4.7 vs 0.8±0.5 U/g, P<0.001) and lung (289.9±21.0vs 144.6±45.1 U/g, P<0.05) MPO activity and higher MDA levels (595.0±87.3 vs 203.4±62.6 nmol/g dry tissue, P<0.05) and edema (4.4±0.1 vs 3.4±0.3 wet to dry weight ratio, P<0.01) compared to SO. EphrinA1- Fc markedly reduced leukocyte infiltration in the gut (24.9±2.9 U/g) at 100microg/kg and in the lung (128.0±19.1 U/g) at 200microg/kg, while monomeric EphA2 significantly lowered intestinal edema formation (3.9±0.1g/g, P<0.05 vs I/R) at the highest dose. Neither EphA2- Fc nor equimolar doses of IgG-Fc alone were effective in modifying I/R-induced inflammatory responses. Conclusions: These preliminary findings indicate that pharmacological modula- tion of Eph-ephrin system may be advantageous in limiting the inflammatory responses elicited by mesenteric I/R: forward signaling activation attenuates local and systemic leuko- cytes enrolment and reverse signaling silencing contrasts local changes in vascular perme- ability
Brain Pharmacokinetics of Non-Imidazole Biphenyl H3 Receptor Antagonists: a Liquid Chromatography/Electrospray-Mass Spectrometry and ex vivo Binding Study in Rats
No full textIn the present article, we report on the kinetics of brain penetration in rats of the H3R antagonist
1,1’-[1,1’-biphenyl-4,4’-diylbis(methylene)]bis-[piperidine] (1), which had shown a favorable in vitro
pharmacological profile and in vivo potency in preventing scopolamine-induced amnesia. Two different
approaches were employed: high-performance liquid chromatography/electrospray-mass spectrometry
(HPLC/ESI-MS) and ex vivo binding against the labeled agonist [3H]-(R)-a-methylhistamine
([3H]RAMHA). Starting from the structure of 1, the rigid piperidine ring was replaced by a flexible
dipropylamino group (see 2) or by a morpholino ring (see 3), endowed with lower basicity. The effect of
replacement on rat plasma and brain disposition in the 24 h after administration was analyzed. High (mm)
and persistent concentrations of 1 were found in rat plasma, while plasma levels were significantly lower
(range: 0–200 nm) for the other two derivatives. This could be explained, among other factors, by the
higher stability, observed for 1, to liver metabolic cleavage. The applied chemical modulation had an
important effect on in vivo brain disposition, as, despite the comparable physico-chemical properties, 2
did not show the tendency to accumulate within the brain, as stated by its brain vs. plasma concentration
ratios, if compared to 1. These structure-property relationships should be taken into account in the
pharmacokinetic optimization of new series of H3 receptor antagonist
Lithocholic acid competitively inhibits EphA2-ephrinA1 binding: pharmacological and structural considerations.
No full textIn vitro pharmacology at human histamine H(3) receptors and brain access of non-imidazole alkylpiperidine derivatives.
No full textDistinct Roles of α4β2 and α7 Nicotinic Receptors in the Modulation of Inflammatory Responses in TNBS-Induced Colitis
No full textBackground and aim: Accumulating evidence indicates that vagus nerve signaling through nicotinic receptors (nAChRs) negatively modulates the inflammatory and immune responses in various clinical and experimental conditions, such as Inflammatory Bowel Disease (IBD), purportedly through a spleen-dependent pathway. Our aims were: 1)to pharmacologically investigate the role played by α4β2 and α7 nAChRs in the modulation of local and systemic inflammatory responses in 2,4,6-TriNitroBenzene Sulfonic acid (TNBS)-colitis in mice; 2)to assess the involvement of the spleen in nicotinic responses. Methods: Colitis was induced in Swiss mice by enema (i.r.) administration of 5mg/mouse TNBS 6 days after skin sensitiza- tion. Mice were randomly assigned to: CTR: saline (0.9% NaCl) 10 ml/kg TC: α4β2 agonist TC2403 5mg/kg DBE: α4β2 antagonist Dihydro-βErythroidine 1.5mg/kg AR-R: α7 agonist AR-R17779 1.5mg/kg MLA: α7 antagonist MethylLycAconitine 1mg/kg Pharmacological treatments started 8h after TNBS enema and were administered subcutaneously (s.c.) twice daily for 3 days. Normal mice (N) received saline 50 μL i.r. and 10 ml/kg s.c.. In a second series of experiments, mice subjected to splenectomy (SPX), performed 14 days before colitis induction, were administered with saline (SPX-CTR) or with AR-R17779 1.5mg/kg (SPX- AR). We determined clinical outcome as Disease Activity Index (DAI), colonic damage as Macroscopic Score (MS) and thickness and colonic and lung myeloperoxidase (MPO) activity.
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Splenic and mesenteric lymph nodes (MLN) CD3 T cells were counted by flow cytometry.
All animal experiments were performed according to the guidelines for the use and care of laboratory animals (DL 26/2014). Results: Compared to N, CTR mice showed markedly higher DAI (P<0.001), MS (p<0.001), colonic thickness (p<0.01), colonic (P<0.001) and
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lungMPO(p<0.01);CD3 Tcellswereincreasedinthespleen(P<0.01)andslightlydecreased
in MLN. Compared to CTR, TC improved only DAI (p<0.01), while DBE significantly reduced colonic MPO and DAI (p<0.05). AR-R significantly ameliorated MS (p<0.05), colonic MPO and thickness (p<0.05), while MLA slightly augmented MS and lung MPO but did not affect the other markers. In SPX-AR mice, α7 agonist lost efficacy in decreasing MS and MPO and worsened DAI but reduced colonic thickness (p<0.01); no effects were produced on T cells, either with or without SPX.Conclusions: The weak and seemingly contradictory effects shown by α4β2 agents indicated a controversial role of this nAChR subtype in TNBS colitis, thus requiring further investigations. On the contrary,α7 nAChRs, either tonically activated by the cholinergic anti-inflammatory reflex or exogenously stimu- lated, play a protective role against the inflammatory responses triggered by TNBS: this effect, not involving changes in T cells trafficking, does not rely exclusively on the splee
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