Archives

  • 2018-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • The knowledge that piroxicam competes with ligands that bind

    2022-06-27

    The knowledge that piroxicam competes with ligands that bind to FPR may be of importance for a deeper understanding of the anti-inflammatory effects possessed by this NSAIDs. It has recently been reported that not only phagocytes but also platelets express FPR on their cell surface and that these receptors are partly responsible for the migratory capacity of the platelet [34]. An impaired platelet migration due to NSAID medication might be one of several factors that affect blood clotting. To summarize the results in relation to neutrophil function, piroxicam inhibits the cellular response induced by FPR ligands, and the reduced response is due to a binding competition, to FPR, between piroxicam and the receptor specific ligands.
    Introduction The G-protein-coupled receptors (GPCRs) comprise a large family of transmembrane proteins activated by a broad range of ligands and implicated in many patho-physiological processes [1]. In conventional GPCR signaling, receptors are localized to the plasma membrane and their stimulation with a specific agonist triggers the activation of G proteins [2] and, in turn, the activity of second messengers, ion topoisomerase or membrane-associated enzymes. However, a number of GPCRs, such as β-adrenergic, lysophosphatidic acid, gonadotropin releasing hormone type I, metabotropic glutamate, endothelin, platelet-activating factor, prostaglandin, angiotensin 2 type I, C-X-C 4 receptors, also localize to and signal at the nuclear membrane or within the nucleus [3], [4], [5], [6], [7], [8], [9], [10] in several cell types [11], [12], [13], [14]. Nuclear GPCRs represent distinctive signaling units that respond to specific intracellular agonists, by transducing nuclear transcription signals. They may be constitutively active or activated by endogenous produced non-secreted ligands, thus regulating a number of physiological processes, such as inflammatory responses, cell proliferation, DNA synthesis and transcription [8], [10], [15], [16], [17]. A GPCR may translocate from the plasma to nuclear membrane, constituting complexes that transduce distinctive signals in relation to the intracellular levels of their cognate agonists [13]. A full complement of downstream signal transduction components is present on the nuclear membranes and in the nucleoplasm including G proteins, enzyme effectors, ion channels, pumps and exchangers [14], [17], [18], [19], [20], [21]. Furthermore, several second messenger signaling cascades, such as ERKs, p38MAPK, PKB, PKA and PKC are activated upon binding of cognate agonists to nuclear GPCRs [4], [15], [22], [23], [24], [25]. Gα and Gβγ subunits are key regulators of cellular signaling events and are associated, or co-purificate, or co-immunoprecipitate with nuclear GPCRs [26]. Gβγ have also a role in the assembly and trafficking of receptor-based complexes in endoplasmic reticulum and Golgi apparatus [27], as well as in the regulation of nuclear histone deacetylase 5 [28] and transcriptional repressor AEBP1 [29]. Targeting of proteins to the nucleus requires a nuclear localization signal (NLS) embedded in the protein, which consist of mono- or bi-partite basic aminoacids residues, usually lysines and arginines, or glycine-arginine repeats [30]. Nuclear translocation is generally regulated by importins, which bind to the NLS motif, and by beta-arrestin, which plays a key role in receptor internalization. A NLS motif has been identified in the eighth helix of adenosine, growth hormone, motilin, purine, angiotensin, bradikinin and endothelin receptors or in the third intracellular loop of apelin receptor [31], even though several heterogenous sequences that do not resemble to classical basic NLS can promote nuclear import of several proteins [32]. The human Formyl-peptide Receptors 1, 2 and 3 (FPR1, FPR2 and FPR3) belong to GPCR family. They are all coupled to the Gi family of G proteins, as indicated by the total loss of cell response to their agonists upon exposure to pertussis toxin (PTX), and their activation by specific ligands triggers distinct signaling cascades in several cell types [33], [34], [35]. Many FPR2 agonists are peptides, with the exception of lipoxin A4 and of the synthetic small-molecular weight ligands isolated by compound library screens. Several FPR2 peptide ligands have been identified and purified from living organisms and a number of these peptides have been synthesized on the basis of the sequence of known proteins, but their physiological function and their presence in vivo has to be proven. FPR2 transduces the anti-inflammatory effects of lipoxin A4, but it can also mediate pro-inflammatory responses to serum amyloid A. WKYMVm, a modified peptide isolated by screening synthetic peptide libraries, binds FPR2 with high efficiency [36] and triggers several intracellular signaling pathways [33], [37]. In human fibroblasts, WKYMVm induces ERKs activation, p47phox translocation and NADPH-dependent superoxide generation [38], which requires the hexapeptide-dependent activation of PKCα and PKCδ [39]. In human lung cancer CaLu-6 cells, stimulation with WKYMVm induces EGFR tyrosine phosphorylation, which provide docking sites for recruitment and triggering of the STAT3 pathway [40]. Similarly, in PNT1A cell line, WKYMVm induces HGF receptor transactivation and triggers some of the molecular responses elicited by c-Met/HGF binding [41]. These results indicate that, despite FPR2 lacks intrinsic tyrosine kinase activity, tyrosine phosphorylation of tyrosine kinase receptors occurs in response to the binding of an FPR2 agonist and activates intracellular mitogenic cascades [42].