πŸ’ The Platelet Activating Factor (PAF) Signaling Cascade in Systemic Inflammatory Responses

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Inflammation and hypersensitivity reactions are reactions of vascularized tissue Acute circulatory collapse caused by platelet-activating factor (PAF-aceter) in.


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Platelet-activating factor (PAF) is a lipid mediator that is well-known for its ability to cause platelet aggregation, inflammation, and allergic response at very low.


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The PAF Signaling Cascade in Sepsis. Sepsis is a syndrome of pathologic systemic inflammation and dysregulated hemostasis that involves.


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Adv. Inflammation Res., 4 (), pp. The cellular origin of human PAF: Monocytes, polymorphonuclear neutrophils and basophils. Immunology, 42​.


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Adv. Inflammation Res., 4 (), pp. The cellular origin of human PAF: Monocytes, polymorphonuclear neutrophils and basophils. Immunology, 42​.


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PAF initiates an inflammatory response in allergic reactions. This has been demonstrated in the skin of humans and in the paws and skin of lab rabbits and rodents.


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Adv. Inflammation Res., 4 (), pp. The cellular origin of human PAF: Monocytes, polymorphonuclear neutrophils and basophils. Immunology, 42​.


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Background. Platelet activating factor (PAF) is an endogenous, active phospholipid released from inflammatory cells, platelets, and endothelial.


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Since PAF is participating in inflammation, these compounds are potential anti-​inflammatory drugs. After that, following a systematic approach [], we have.


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Inflammation and hypersensitivity reactions are reactions of vascularized tissue Acute circulatory collapse caused by platelet-activating factor (PAF-aceter) in.


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It is the aim of this microreview to reveal the critical role of the metal center and of the molecular structure different coordination geometries of the relevant metal complexes within this series of new metal-based potent inhibitors of PAF. Apart from Mediterranean products, PAF inhibitors can also be found in many other products as garlic [ 93 β€” 95 ], soy sauce [ 96 ], and tea [ 97 ]. As far as it concerns already used pharmaceutical products, there are many of them that were found to exhibit potent inhibitory effect against PAF actions, which is expected as Platelet Activating Factor is implicated in inflammatory processes and therefore in a plethora of pathological conditions with inflammatory background. The studies around its inhibition against PAF have revealed that it is a nonspecific PAF inhibitor [ 15 ] with a plethora of promising effects as anti-inflammatory, anticancer, immunomodulatory, antiviral, and cardioprotective [ 16 ]. Yangambin is a natural furofuran lignan, isolated from the Brazilian plant Ocotea duckei Vattimo. Considering the expanding role of PAF and other lipid mediators in human pathophysiology, the study of their dietary modulation is of increasing scientific interest. Andrographolide has a labdane diterpenoid structure and it is obtained from the stems and the leaves of a Asian plant called Andrographis paniculata which was traditionally used against viral infections and inflammatory diseases [ 14 ]. In addition, a number of metal ions, playing a vital role for life, are involved in many natural biological processes [ β€” ]. Upon purification the mer -[Rh L Cl 3 MeOH ] isomer Rh-4 crystallizes selectively from a mixture of both isomers in solution, while the fac -isomer was not isolated in a pure form. Referring to vitamins, paracitol Vitamin D is known to improve the inflammatory status of hemodialysis patients, an ability possibly due to its anti-PAF activities [ ] and also tocopherol Vitamin E inhibits PAF-induced aggregation [ , ]. A small library of 30 metal complexes has been thus created; their anti-inflammatory activity has been further evaluated owing to their inhibitory effect against PAF in washed rabbit platelets WRPs. PAF exerts its autocrine and paracrine actions through binding to a well-characterized G-protein coupled receptor GPCR located on the plasma membrane of a wide variety of mammalian cells such as endothelial cells, neutrophils, monocytes, dendritic cells, platelets, and leukocytes [ 7 ]. Moreover, the use of PAF inhibitors, such as metal compounds, which may have additional direct anticancer properties, will amplify the effectiveness of the common anticancer treatments. Last but not least comes the use of rupatadine against allergic rhinitis and several other allergic disorders [ 60 ], the positive outcomes of which resulted in the production of the first circulating drug based on a PAF inhibitor, named Rupafin. However, there are also trials with positive results such as UK, on airway and systemic responses [ 55 ], levocetirizine in chronic idiopathic urticaria [ 56 ], WEB gel against UVB-induced dermatitis [ 57 ], BN on pulmonary function in the early postischemic period [ 58 ], and Y in bronchial hyperresponsiveness in patients with asthma [ 59 ]. This is a vast research area and work on this field has not been referred to previously. Originally, the term PAF was meant to be one phosphoglycerylether lipid, identified as 1-O-alkylacetyl- sn -glycerophosphocholine with 16β€”18 carbons at the ether-bonded fatty chain at the sn-1 position of the glycerol backbone, as shown in Figure 1 [ 2 ]. Evaluation of the anticancer activity of these substances is currently underway so as to check the relationship between PAF and cancer vide infra. Molecular docking theoretical calculations were in accord with the previous reported finding, denoting that the octahedral Rh III complex Rh - 1 and Rh - 2 and Rh-3 with two aromatic ligands cannot fit into the ligand-binding site of the PAFR model. In addition, both cisplatin and WEB administered to animal models decreased dramatically tumor growth [ ]. The most bioactive compound came from olive pomace and has been chemically characterized as a glycerylether-snacetyl glycolipid [ 87 ]. Moreover, metal complexes present a number of special characteristics such as wide structural diversity, the possibility of tuning thermodynamic and kinetic ligand substitution, and different oxidation states [ β€” ]. Cedrol is a sesquiterpene alcohol which is found as an essential oil in many plants as Biota orientalis , Pterocarpus indicusirginia , in various types of conifers as Cupressus and Juniperus , and in Origanum onites [ 28 ]. The lipid molecule, di-hydroxy-chimyl-alcohol, derived from pine pollen, was also found to exert anti-PAF action [ 27 ]. These molecules contain heterocyclic structures which are characterized by sp 2 nitrogen atom that is able to interact with PAFR as a hydrogen bond acceptor. From the reaction of L with one equivalent of , the [Rh L Cl 3 MeOH ] complex has been prepared as a mixture of the mer and fac isomers. As it is a potent anti-inflammatory agent, it may be used for the inhibition or prevention of allergic syndromes, providing new antiallergic medicine that exhibits fewer side effects [ 18 ]. It is one of the well-known PAF antagonists [ 29 ]. The hypothesis claims that the tumor cells express PAF receptor and therefore there are high PAF levels all around the microenvironment of the tumor. Among all diets, the Mediterranean diet consists of numerous products that exert potent anti-PAF activities in the washed platelet aggregation assay, such as virgin or regular olive oil [ 73 , 74 ], wine and grapes [ 75 β€” 78 ], honey [ 79 ], fish [ 80 β€” 82 ], milk and yoghurt [ 83 ], and traditional Greek meals [ 84 ], the isolation and structural characterization of which demonstrated the presence of complex polar lipids as glycolipids and ganglioside derivatives, phenolics, and phenol glucosides [ 65 ]. PAF is known to be implicated in atherosclerosis [ 65 ] and many statins as well as digoxin, which are used for their cardioprotective properties, are also PAF inhibitors [ 66 , 67 ]. Interestingly, while most of the ether lipids replaced their ether bond with esterified analogues through time, PAF conserved its ether bond in sn-1 position because of its important biological role [ 3 ]. Many PAF inhibitors were tested in clinical trials displaying tolerability and safety but with no effectiveness. Also, various compounds with anti-PAF activities, as Ginkgo biloba extracts [ , ], andrographolide [ , ], tussilagone [ ], WEB [ ], and WEB [ ], have been shown to exert anticancer properties in vitro. In addition, emphasis has also been placed on the identification of preliminary structure-activity relationships for the different classes of metal-based inhibitors. On the other hand, the implication of PAF in carcinogenesis and cancer metastasis has been well documented, whereas the known BN inhibitor has showed antitumor effects [ ]. All the above synthetic antagonists display a great variability in their chemical structure which might have importance in their different pharmacological profile. In fact, transition metal coordination compounds display a number of different coordination numbers and geometries square planar, tetrahedral, and octahedral as opposed to the typical tetrahedral geometry for the organic congeners. The corresponding bidentate ligand has been chosen owing to the remarkable biological properties reported [ , ], while, on the other hand, investigation of the biological activity of inert metal complexes, such as rhodium III compounds, shows gradually increasing interest [ β€” ]. Cytotoxicity tests of the Rh-1 compound against HEK and cancer cell lines MCF-7 breast cancer were performed using cisplatin as a reference. In addition, molecules demonstrating dual antagonistic actions against PAF as well as against another inflammatory mediator have been synthesized and their therapeutic properties have been studied in vitro. The first one revealed three distinct classes of binding sites for PAF. Platelet Activating Factor PAF has been characterized as a new, ubiquitous, potent, and unique class of lipid chemical mediators that share similar biological activities, namely, PAF-like activity molecules [ 1 ]. Preliminary structure-activity relationships have been established, studying diverse parameters such as i the coordination geometry of the metal complex square planar versus octahedral, etc. Other classes of anti-inflammatory compounds do not constitute the aim of this minireview. There are many ways to classify PAF inhibitors such as i their source, isolated from natural sources or chemically synthesized; ii their chemical structure, nitrogen heterocyclic compounds, PAF analogues PAF-like molecules , dihydropyridines, natural medicines, and others; or iii the way they interact with PAF receptor, specific or nonspecific inhibitors. These include covalent modification and the internalization of PAFR, the modulation of PAFR gene expression, and binding potential along with the fine-tuning of the signal transduction pathways by a plethora of intracellular and extracellular modulators [ 6 ]. The idea, behind this, was to examine the possible effect of the carboxylic acid groups on the inhibition of the PAF, since, recently, an apparent dependence of biological activities cytotoxicity and antioxidant efficiency on incorporation of -COOH groups in the bipyridine ring has been reported [ ]. The IC 50 values reflect the inhibition strength of each compound, since a low IC 50 value reveals stronger inhibition of the PAF-induced aggregation for a given metal complex concentration. Studies have revealed that it is a specific PAF inhibitor which antagonizes competitively PAF binding to its receptor [ 22 ]. These kinds of inhibitors are pyrrolothiazole-related antagonists as tulopafant [ 38 ], thiazolidine derivatives as SM [ 39 ], imidazolyl derivatives as modipafant [ 40 ], and lexipafant [ 41 ] and hetrazepine derivatives as WEB and WEB [ 42 ]. Since PAF is participating in inflammation, these compounds are potential anti-inflammatory drugs. However, in pathological conditions, excess amounts of PAF can cause inflammation and lead to inflammatory conditions or diseases, such as allergy, asthma, atherosclerosis, diabetes, renal diseases, cancer, HIV pathogenesis, and periodontitis [ 6 ].

At first, results of organic compounds natural and synthetic ones and paf inflammation and nonspecific as inhibitors of PAF are reported. This manuscript studies whether a new class of potent metal-based anti-inflammatory drugs could induce indirect anticancer properties.

The calculated binding affinity of 3.

Later, other studies certified the intracellular existence of PAFR as well as the presence of PAF binding sites in the nucleus, both at the nuclear envelope and at nuclear matrix [ 9 β€” 11 ]. In vivo, polar extracts from olive oil and olive pomace have reduced the atheromatic lesion in hypercholesterolemic rabbits [ 89 , 90 ] and mellitus patients reduced platelet sensitivity after one month of traditional Mediterranean diet [ 84 ], while wine consumption improved platelet sensitivity independently of alcohol [ 91 ]. Biological results of these compounds are reviewed and added to the dataset base of inorganic metal-based anti-inflammatory drugs. There are several hundreds of phytochemical products that can inhibit PAF biological activities and therefore act as anti-inflammatory agents. It displays beneficial actions against allergy and headache [ 23 , 24 ] along with its cardioprotective role [ 25 ]. Moreover, microconstituents of several seed oils, such as sesame, corn, and sunflower, were found to have either inhibitors or agonists of PAF. As mentioned in the previous part, organic compounds represent well-known antagonists in the area, while application of metal-based compounds as PAF inhibitors has been systematically ignored, although the advantages of metal-based therapeutics over the organic analogues have been well addressed recently [ ]. This work was motivated by the fact that a comprehensive survey on metal-based potent inhibitors of PAF as active anti-inflammatory drugs has not been previously described in the literature. In the present minireview, PAF inhibitors will be divided into a new classification method as organic and inorganic. Moreover, SRA did not decrease the symptoms of acute ulcerative colitis [ 51 ]; BN showed no significant amelioration of rheumatoid arthritis [ 52 ] as well as Ro against psoriasis [ 53 ] and TCV against septic shock [ 54 ]. A recent review by Leung et al. There is a plethora of pathological conditions, where PAF is implicated, and Ginkgo biloba extracts have managed to ameliorate, as cognitive disorders, HIV infection, ischemia, tissue injuries, cancer, and airway diseases as asthma and allergy [ 13 ]. In the second part, the structural characteristics and the biological activity against PAF, of different classes of metal-based inhibitors, are presented. Lexipafant, one of the most potent PAF inhibitors, was tested against cognitive impairment [ 47 ], myocardial infraction [ 48 ], sepsis [ 49 ], and organ failure in severe pancreatitis [ 50 ] with no significant results. In another study, olive pomace, crude olive pomace oil, and waste byproducts from olive pomace oil production were found to contain polar lipids as bioactive compounds that inhibit or antagonize PAF. Perhaps these compounds of the chemical formulas cis -[Rh L 2 Cl 2 ]Cl, that inhibit PAF action, may also be used as a potential anticancer agent. Furthermore, from the acetylation of poplar lipids and phenolic compounds derived acetylated products with anti-PAF action [ 85 , 86 ], especially, olive oil was found to contain high levels of PAF antagonists among other vegetable oils and the structure of its most active fraction was found to be a glycerolglycolipid [ 74 ]. In an effort to get an insight about the possible mechanism of action of these substances related to the PAFR, we performed radioactivity experiments Scatchard analysis involving the specific binding of [ 3 H]-PAF to washed rabbit platelets and its inhibition by complex Rh-1 , that is the most potent of these Rh III derivatives. The specific PAF antagonist, BN , was used as a reference compound and the radioactivity was measured by scintillation counting. Below, we describe the existing different categories of metal-based inhibitors of PAF which have been systematically studied. The success of the in vitro studies of PAF inhibitors in combination with the use of many natural PAF inhibitors as traditional remedies for inflammatory diseases had been very promising for the use of PAF inhibitors in the clinical practice. Emphasis is given on recent results about a new class of the so-called metal-based inhibitors of PAF. Under physiological conditions, the production of PAF is regulated by its enzymes [ 5 ] and the produced PAF participates in physiological processes as reproduction, memory formation, vascular tone, apoptosis, and angiogenesis. Today, a plethora of studies report molecules that inhibit the cellular effects of PAF in vitro and in experimental animal models or human studies in vivo, which are well presented in the review of Nomikos et al. The involvement of PAF in cancer is already known and especially in carcinogenesis, melanoma, or metastasis [ β€” ]. Rupatadine, as well, is both an oral PAFR antagonist and a histamine H 1 -receptor antagonist [ 64 ]. The purpose of this review is not to list all of them, so below are some of the most promising ones for therapeutic use or dietary supplements Figure 2. Most of them have been screened in vitro in cell systems and animal models and the ones with the best properties, in terms of potency, bioavailability, and safety, have been also tested in clinical trials. Additionally, curcumin managed to reduce colonic mucosal and tumor PLA 2 [ 98 , 99 ]. It is a benzofuranoid neolignan whose structure was used as a template for the development of synthetic PAF antagonists as well as for the molecular modeling of PAFR [ 19 ]. The review is divided into two general parts. In this respect, it is the aim of the present minireview to present existing metal-based coordination compounds that exert their inflammatory activity by blocking the expression of PAF. There are hundreds of molecules that are able to inhibit biological actions, mediated by PAF. The signal transduction pathways activated by PAF are cell and species dependent and are regulated by several mechanisms. Two of them were found on the microsomes and the third one was on the synaptic plasma membranes of rat cerebral cortex [ 8 ]. There are few studies that prove the existence of PAFR in endomembranes as well. Tussilagone or L, is a terpene that comes from the buds of the plant Tussilago farfara and acts as a nonspecific PAF inhibitor by blocking the calcium channels [ 20 ]. Lipid extracts from the plant Urtica dioica , the common nettle, were found to contain both PAF and PAF-like activity molecules and glycolipid derivatives which act as PAF inhibitors and hence explain the sense of urticaria and the beneficial effects of nettle as traditional allergy relief and diuretic remedy [ 26 ]. These reasons led us to design the target molecule Rh-1 Figure 4 with octahedral coordination geometry and evaluate in vitro its inhibitory effect against PAF-induced platelet aggregation in washed rabbit platelets WRPs. Last but not least comes curcumin which exerts potent antiplatelet activity through the inhibition of COX and the blockade of calcium signaling. The use of anti-PAF compounds decreases PAF levels ergo inflammation and therefore enhances the anticancer properties of the chemotherapy. However, a significant number of coordination compounds with potential anti-inflammatory action have not been included. Kadsurenone is the first potent PAF antagonist that was discovered and comes from the Chinese herb Piper futokadsurae.