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Recent Cannabinoid Delivery Systems
Published in Betty Wedman-St Louis, Cannabis as Medicine, 2019
Natascia Bruni, Carlo Della Pepa, Simonetta Oliaro-Bosso, Daniela Gastaldi, Franco Dosio, Enrica Pessione
Although phytocannabinoids have similar chemical structures, they can elicit different pharmacological action. The identification of THC paved the way for the discovery, in 1988, of cannabinoid receptor type 1 (CB1) [4], and, later, of cannabinoid receptor type 2 (CB2) [5]. CB1 and CB2, belong to a family of seven transmembrane guanosine binding protein-coupled receptors, are widely expressed and distinguished by their specific functions, localization, and signaling mechanisms. They are one of the important endogenous lipid signaling pathways, named the “endocannabinoid system,” which consists of cannabinoid receptors, the endogenous ligands of cannabinoid receptors (endocannabinoids), and the enzymes that regulate the biosynthesis and inactivation of endocannabinoids. This lipid signaling system is involved in many important physiological functions in the central and peripheral nervous system and in the endocrine and immune systems [6,7].
Effects of chemical pollutants on spermatogenesis and implications in male infertility
Published in C. Yan Cheng, Spermatogenesis, 2018
In previous studies, exposure to PFOS resulted in increased expression of the arachidonic acid (AA)-metabolizing cytochrome P450 (CYP) isoforms, CYP2, and CYP4.173,174 These enzymes convert AA into hydroxyeicosa-tetraenoic acids (HETEs) or epoxyeicosatrienoic acids (EETs). It was proposed that the PFOS-mediated perturbation of fatty acid metabolism and the resulting physiological outcomes were due to the modulation of lipid signaling via dysregulation of the AA cascade.175 Interestingly, a study reported that certain endocrine-disrupting chemicals (i.e., BPA and phthalates) inhibited the prostaglandin (PG) signaling pathway in a mouse Sertoli cell line and in ex vivo rat testes.176 PGs are a group of lipid signaling mediators generated by the oxidation of AA. AA and the lipoxygenase-catalyzed products of the AA cascade play critical roles in steroidogenesis, early male sexual development, and masculinization.177–187 Interestingly, most lipid-mediators (i.e., PGs and HETEs) produced by this cascade are also agonists of PPARs.188,189Using primary mouse Sertoli cell cultures, PFOS treatment (10–20 μM) disrupted actin polymerization and bundling via affecting the levels and/or localization of cell adhesion proteins and activity of focal adhesion kinase at Sertoli cell BTB. Significant reductions of actin crossing linking proteins (filamin A, palladin), tight junctional proteins (zonula occludens-1, occludin), adherens junction proteins (β-catenin, N-cadherin), and the gap junction (GJ) protein connexin-43 (Cx43) were observed.190 The overexpression of Cx43 rescued PFOs-disrupted TJ barrier.191 Intriguingly, CX43 is known to be a downstream target of the lipid mediator PG. Therefore, further investigation is necessary to determine whether PFC exposure disrupts AA metabolism, and the PG signaling pathway in particular, resulting in male sexual dysfunction.
Trimeric Scaffold Ligand-Gated Ion Channels
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Xiao-Na Yang, Si-Yu Wang, Jin Wang, Ye Yu
In this aspect, researches on ASICs agonists are in front of P2X receptors. Besides proton activation, there are many ways to activate the ASIC family in direct or indirect manner. A small molecule compound GMQ (2-guanidine-4-methylquinazoline), lipid, and neurotoxin could activate AISCs directly (54,88–90); Zn2+ indirectly activates AISC1a/2a heterodimer (91); neuropeptide and bile acid modulate the acidic activation of ASIC (92,93). GMQ is the first nonproton ligand of AISC that directly activates ASIC3 under the condition of pH 7.4, probably via acting on E79 on the palm domain of rASIC3 to promote the channel to maintain a constantly activated state (90,94). Toxins as a flashpoint have been identified in recent years, a few of which can bind to ASIC, including two direct agonists of ASIC, PcTx1 and MitTx, with effects on sites related to the acidic pocket (54,88). Functioning both as agonist and inhibitor, PcTx1 activates rASIC1 via binding the whole toxin to the α5 helix of the thumb domain by virtue of two arginines to expand to the acidic pocket, which also depends on the subtype and extracellular concentration of protons (88). MitTx activates ASIC in the form of dimer: its α subunit interacts with the lower palm and palm-finger loop, and β subunit binds on the thumb domain, presenting the whole molecule as a “bottle opener of triangular tip” attaching to the surface of the adjacent subunit. Lipids are the first class of ASIC endogenous agonists to be found (54). In the physiological condition, lipid signaling formed by lysophosphatidylcholine (LPC) and arachidonic acid directly activate ASIC3, which might be caused by decreasing the dependence of ASIC3 on acidosis (89). In addition to those substances, endogenous isoquinoline alkaloids (EIAs) can also activate ASIC3 in an acidic environment so that EIAs recover hASIC3 from desensitization and induce instantaneous current, but a high concentration of EIAs can activate rat ASIC3 both under physiological pH or alkaline condition (95). Other ligands have also been found to modulate maximum activation and desensitization of channels. Deoxycholic acid strengthens the acidic current in hASIC1a (96); the inhibitor of ASIC3, APETx2, increases that of ASIC1b and ASIC2a (97,98). FMRFamide, the FaNaC agonist, modulates the desensitization of ASIC1a and ASIC3 through increasing their sustained currents (93,99); FMRFamide-like neuropeptide FF and RPRFamide also modulate this type of current in ASIC3 channels (32,100).
New insights into human prefrontal cortex aging with a lipidomics approach
Published in Expert Review of Proteomics, 2021
Mariona Jové, Natalia Mota-Martorell, Pascual Torres, Manuel Portero-Otin, Isidre Ferrer, Reinald Pamplona
At the molecular level, FA determine the main structural diversity of lipids of neuronal and glial cells [26] and develop a crucial role in the membrane integrity, the formation of lipid signaling mediators, and the chemical vulnerability to oxidative damage [19]. In hPFC, the fatty acid composition determines an average chain length of 18 carbon atoms, and a relative distribution between unsaturated (UFA) and saturated (SFA) fatty acids of about 60:40 [79]. The most abundant UFA is the monounsaturated (MUFA) 18:1 n-9, and the PUFAs AA, and DHA; and among SFA, 16:0 and 18:0 are the predominant [79]. Remarkably, the concentration of these PUFAs in hPFC is greatest across human brain regions, is supported at the mRNA and protein expression levels, and is ascribed to inherent neuronal activity [79]. Considering that lipid rafts from hPFC are characterized by their high level of SFA and reduced amounts of PUFA [85], the high abundance of highly UFAs must be ascribed to non-raft domains of the cell membrane, pointing to a clear and marked asymmetry in lipid distribution throughout the cell membrane in hPFC.
The COX-2/prostanoid signaling cascades in seizure disorders
Published in Expert Opinion on Therapeutic Targets, 2019
Asheebo Rojas, Di Chen, Thota Ganesh, Nicholas H. Varvel, Raymond Dingledine
Taken together, these observations highlight the complexity of inflammatory lipid signaling in the brain. A picture is emerging whereby neuronal release of PGE2 from constitutively expressed COX-2 during SE activates EP2 on nearby neurons to promote neuroprotection and blood–brain barrier integrity, then a few hours later neuronal COX-2 is induced, causing massive PGE2 release that activates EP2 on nearby microglia to trigger an inflammatory reaction with accompanying neuronal injury and exacerbation of blood-brain barrier breakdown. A major question is whether timely application of an EP2 antagonist will prevent, delay, or modify the development of epilepsy in animals at risk, for example after SE or head injury. Regardless of the outcome of these experiments, delayed administration of an EP2 antagonist would appear to be a viable adjunctive treatment to attenuate the pathology attendant SE.
The design and discovery of phospholipase A2 inhibitors for the treatment of inflammatory diseases
Published in Expert Opinion on Drug Discovery, 2021
Charikleia S. Batsika, Anna-Dimitra D. Gerogiannopoulou, Christiana Mantzourani, Sofia Vasilakaki, George Kokotos
In conclusion, state-of-the-art lipidomic technologies and advanced computational approaches, combined with classical medicinal chemistry procedures, may clarify the importance and the particular role of each PLA2 subgroup in cells and tissues. The effect of each particular small-molecule inhibitor has to be explored on a full set of lipids rather than a unique lipid, thus helping to understand potential opposing role of lipids in order to overcome undesired side effects. Such combined approaches may identify novel lipid signaling molecules, opening new horizons for the development of medicines presenting novel mechanisms of action.