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1.
Pharmacol Res ; 197: 106948, 2023 Nov.
Article in English | MEDLINE | ID: mdl-37806602

ABSTRACT

The most recent and promising therapeutic strategies for inflammatory bowel disease (IBD) have engaged biologics targeting single effector components involved in major steps of the immune-inflammatory processes, such as tumor necrosis factor, interleukins or integrins. Nevertheless, these molecules have not yet met expectations regarding efficacy and safety, resulting in a significant percentage of refractory or relapsing patients. Thus, novel treatment options are urgently needed. The minor isoform of the complement inhibitor C4b-binding protein, C4BP(ß-), has been shown to confer a robust anti-inflammatory and immunomodulatory phenotype over inflammatory myeloid cells. Here we show that C4BP(ß-)-mediated immunomodulation can significantly attenuate the histopathological traits and preserve the intestinal epithelial integrity in dextran sulfate sodium (DSS)-induced murine colitis. C4BP(ß-) downregulated inflammatory transcripts, notably those related to neutrophil activity, mitigated circulating inflammatory effector cytokines and chemokines such as CXCL13, key in generating ectopic lymphoid structures, and, overall, prevented inflammatory immune cell infiltration in the colon of colitic mice. PRP6-HO7, a recombinant curtailed analogue with only immunomodulatory activity, achieved a similar outcome as C4BP(ß-), indicating that the therapeutic effect is not due to the complement inhibitory activity. Furthermore, both C4BP(ß-) and PRP6-HO7 significantly reduced, with comparable efficacy, the intrinsic and TLR-induced inflammatory markers in myeloid cells from both ulcerative colitis and Crohn's disease patients, regardless of their medication. Thus, the pleiotropic anti-inflammatory and immunomodulatory activity of PRP6-HO7, able to "reprogram" myeloid cells from the complex inflammatory bowel environment and to restore immune homeostasis, might constitute a promising therapeutic option for IBD.


Subject(s)
Colitis , Inflammatory Bowel Diseases , Animals , Humans , Mice , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Colitis/chemically induced , Colitis/drug therapy , Immunomodulation , Inflammation , Inflammatory Bowel Diseases/chemically induced , Inflammatory Bowel Diseases/drug therapy , Myeloid Cells
2.
J Membr Biol ; 246(3): 215-30, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23188062

ABSTRACT

Cell-attached and inside-out patch clamp recording was used to compare the functional expression of membrane ion channels in mouse and human embryonic stem cells (ESCs). Both ESCs express mechanosensitive Ca²âº permeant cation channels (MscCa) and large conductance (200 pS) Ca²âº-sensitive K⁺ (BK(Ca²âº)) channels but with markedly different patch densities. MscCa is expressed at higher density in mESCs compared with hESCs (70 % vs. 3 % of patches), whereas the BK(Ca²âº) channel is more highly expressed in hESCs compared with mESCs (~50 % vs. 1 % of patches). ESCs of both species express a smaller conductance (25 pS) nonselective cation channel that is activated upon inside-out patch formation but is neither mechanosensitive nor strictly Ca²âº-dependent. The finding that mouse and human ESCs express different channels that sense membrane tension and intracellular [Ca²âº] may contribute to their different patterns of growth and differentiation in response to mechanical and chemical cues.


Subject(s)
Calcium Channels/metabolism , Embryonic Stem Cells/physiology , Mechanotransduction, Cellular/physiology , Animals , Humans , Membrane Potentials/physiology , Mice , Patch-Clamp Techniques
3.
J Biol Chem ; 283(16): 10949-57, 2008 Apr 18.
Article in English | MEDLINE | ID: mdl-18283106

ABSTRACT

During exocytosis, the fusion pore expands to allow release of neurotransmitters and hormones to the extracellular space. To understand the process of synaptic transmission, it is of outstanding importance to know the properties of the fusion pore and how these properties affect the release process. Many proteins have been implicated in vesicle fusion; however, there is little evidence for proteins involved in fusion pore expansion. Myosin II has been shown to participate in the transport of vesicles and, surprisingly, in the final phases of exocytosis, affecting the kinetics of catecholamine release in adrenal chromaffin cells as measured by amperometry. Here, we have studied single vesicle exocytosis in chromaffin cells overexpressing an unphosphorylatable form (T18AS19A RLC-GFP) of myosin II that produces an inactive protein by patch amperometry. This method allows direct determination of fusion pore expansion by measuring its conductance, whereas the release of catecholamines is recorded simultaneously by amperometry. Here we demonstrated that the fusion pore is of critical importance to control the release of catecholamines during single vesicle secretion in chromaffin cells. We proved that myosin II acts as a molecular motor on the fusion pore expansion by hindering its dilation when it lacks the phosphorylation sites.


Subject(s)
Exocytosis , Myosin Type II/physiology , Animals , Biological Transport , Catecholamines/metabolism , Cell Membrane Permeability , Chromaffin Cells/chemistry , Chromaffin Cells/metabolism , Green Fluorescent Proteins/metabolism , Membrane Fusion , Models, Biological , Monte Carlo Method , Myosin Type II/chemistry , Phosphorylation , Rats , Rats, Sprague-Dawley , Recombinant Fusion Proteins/chemistry
4.
Brain Res Brain Res Rev ; 49(2): 406-15, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16111567

ABSTRACT

During the last decade a wealth of new information about the properties of the exocytotic fusion pore is changing our current view of exocytosis. The exocytotic fusion pore, a necessary stage before the full merging of the vesicle membrane with the plasma membrane, is becoming a key cellular structure that might critically control the amount of neurotransmitter released into the synaptic cleft and that can be subjected to control by second messengers and phosphorylated proteins. Fusion pores form, expand to fully merge membranes, or can close leaving an intact and identical synaptic vesicle in place for a new round of exocytosis. Transient formation of fusion pores is the mechanistic representation of the "kiss-and-run" hypothesis of transmitter release and offers new alternatives for synaptic vesicle recycling besides to the classical mechanism mediated by clathrin coat endocytosis. For vesicle recycling transient fusion pores ensures a fast mechanism for maintaining an active pool of synaptic vesicles. The size reached by transient fusion pores and the time spent on the open state can determine the release of subquantal synaptic transmission, which could be a mechanism of synaptic potentiation. In this review we will described the electrophysiological and fluorescence methods that contribute to further explore the biophysical properties of the exocytotic fusion pore and the relevant experiments obtained by these methods.


Subject(s)
Membrane Fusion/physiology , Nerve Endings/cytology , Neurotransmitter Agents/metabolism , Synaptic Vesicles/physiology , Animals , Diagnostic Imaging/methods , Electrophysiology/methods , Endocytosis/physiology , Exocytosis/physiology , Synaptic Vesicles/ultrastructure
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