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Добірка наукової літератури з теми "FFA4"

Автор: Grafiati

Опубліковано: 15 березня 2025

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Статті в журналах з теми "FFA4"

Freitas, Raquel D. S., Thaís C. Muradás, Ana Paula A. Dagnino, Fernanda L. Rost, Kesiane M. Costa, Gianina T. Venturin, Samuel Greggio, Jaderson C. da Costa, and Maria M. Campos. "Targeting FFA1 and FFA4 receptors in cancer-induced cachexia." American Journal of Physiology-Endocrinology and Metabolism 319, no. 5 (November 1, 2020): E877—E892. http://dx.doi.org/10.1152/ajpendo.00509.2019.

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Free fatty acid (FFA) receptors FFA1 and FFA4 are omega-3 molecular targets in metabolic diseases; however, their function in cancer cachexia remains unraveled. We assessed the role of FFA1 and FFA4 receptors in the mouse model of cachexia induced by Lewis lung carcinoma (LLC) cell implantation. Naturally occurring ligands such as α-linolenic acid (ALA) and docosahexaenoic acid (DHA), the synthetic FFA1/FFA4 agonists GW9508 and TUG891, or the selective FFA1 GW1100 or FFA4 AH7614 antagonists were tested. FFA1 and FFA4 expression and other cachexia-related parameters were evaluated. GW9508 and TUG891 decreased tumor weight in LLC-bearing mice. Regarding cachexia-related end points, ALA, DHA, and the preferential FFA1 agonist GW9508 rescued body weight loss. Skeletal muscle mass was reestablished by ALA treatment, but this was not reflected in the fiber cross-sectional areas (CSA) measurement. Otherwise, TUG891, GW1100, or AH7614 reduced the muscle fiber CSA. Treatments with ALA, GW9508, GW1100, or AH7614 restored white adipose tissue (WAT) depletion. As for inflammatory outcomes, ALA improved anemia, whereas GW9508 reduced splenomegaly. Concerning behavioral impairments, ALA and GW9508 rescued locomotor activity, whereas ALA improved motor coordination. Additionally, DHA improved grip strength. Notably, GW9508 restored abnormal brain glucose metabolism in different brain regions. The GW9508 treatment increased leptin levels, without altering uncoupling protein-1 downregulation in visceral fat. LLC-cachectic mice displayed FFA1 upregulation in subcutaneous fat, but not in visceral fat or gastrocnemius muscle, whereas FFA4 was unaltered. Overall, the present study shed new light on FFA1 and FFA4 receptors’ role in metabolic disorders, indicating FFA1 receptor agonism as a promising strategy in mitigating cancer cachexia.

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Ahn, Seong Hee, Sook-Young Park, Ji-Eun Baek, Su-Youn Lee, Wook-Young Baek, Sun-Young Lee, Young-Sun Lee, et al. "Free Fatty Acid Receptor 4 (GPR120) Stimulates Bone Formation and Suppresses Bone Resorption in the Presence of Elevated n-3 Fatty Acid Levels." Endocrinology 157, no. 7 (May 4, 2016): 2621–35. http://dx.doi.org/10.1210/en.2015-1855.

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Free fatty acid receptor 4 (FFA4) has been reported to be a receptor for n-3 fatty acids (FAs). Although n-3 FAs are beneficial for bone health, a role of FFA4 in bone metabolism has been rarely investigated. We noted that FFA4 was more abundantly expressed in both mature osteoclasts and osteoblasts than their respective precursors and that it was activated by docosahexaenoic acid. FFA4 knockout (Ffar4−/−) and wild-type mice exhibited similar bone masses when fed a normal diet. Because fat-1 transgenic (fat-1Tg+) mice endogenously converting n-6 to n-3 FAs contain high n-3 FA levels, we crossed Ffar4−/− and fat-1Tg+ mice over two generations to generate four genotypes of mice littermates: Ffar4+/+;fat-1Tg−, Ffar4+/+;fat-1Tg+, Ffar4−/−;fat-1Tg−, and Ffar4−/−;fat-1Tg+. Female and male littermates were included in ovariectomy- and high-fat diet-induced bone loss models, respectively. Female fat-1Tg+ mice decreased bone loss after ovariectomy both by promoting osteoblastic bone formation and inhibiting osteoclastic bone resorption than their wild-type littermates, only when they had the Ffar4+/+ background, but not the Ffar4−/− background. In a high-fat diet-fed model, male fat-1Tg+ mice had higher bone mass resulting from stimulated bone formation and reduced bone resorption than their wild-type littermates, only when they had the Ffar4+/+ background, but not the Ffar4−/− background. In vitro studies supported the role of FFA4 as n-3 FA receptor in bone metabolism. In conclusion, FFA4 is a dual-acting factor that increases osteoblastic bone formation and decreases osteoclastic bone resorption, suggesting that it may be an ideal target for modulating metabolic bone diseases.

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Prihandoko, Rudi, Davinder Kaur, Coen H. Wiegman, Elisa Alvarez-Curto, Chantal Donovan, Latifa Chachi, Trond Ulven, et al. "Pathophysiological regulation of lung function by the free fatty acid receptor FFA4." Science Translational Medicine 12, no. 557 (August 19, 2020): eaaw9009. http://dx.doi.org/10.1126/scitranslmed.aaw9009.

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Increased prevalence of inflammatory airway diseases including asthma and chronic obstructive pulmonary disease (COPD) together with inadequate disease control by current frontline treatments means that there is a need to define therapeutic targets for these conditions. Here, we investigate a member of the G protein–coupled receptor family, FFA4, that responds to free circulating fatty acids including dietary omega-3 fatty acids found in fish oils. We show that FFA4, although usually associated with metabolic responses linked with food intake, is expressed in the lung where it is coupled to Gq/11 signaling. Activation of FFA4 by drug-like agonists produced relaxation of murine airway smooth muscle mediated at least in part by the release of the prostaglandin E2 (PGE2) that subsequently acts on EP2 prostanoid receptors. In normal mice, activation of FFA4 resulted in a decrease in lung resistance. In acute and chronic ozone models of pollution-mediated inflammation and house dust mite and cigarette smoke–induced inflammatory disease, FFA4 agonists acted to reduce airway resistance, a response that was absent in mice lacking expression of FFA4. The expression profile of FFA4 in human lung was similar to that observed in mice, and the response to FFA4/FFA1 agonists similarly mediated human airway smooth muscle relaxation ex vivo. Our study provides evidence that pharmacological targeting of lung FFA4, and possibly combined activation of FFA4 and FFA1, has in vivo efficacy and might have therapeutic value in the treatment of bronchoconstriction associated with inflammatory airway diseases such as asthma and COPD.

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Velasco, Cristina, Marta Conde-Sieira, Sara Comesaña, Mauro Chivite, Adrián Díaz-Rúa, Jesús M. Míguez, and José L. Soengas. "The long-chain fatty acid receptors FFA1 and FFA4 are involved in food intake regulation in fish brain." Journal of Experimental Biology 223, no. 17 (July 14, 2020): jeb227330. http://dx.doi.org/10.1242/jeb.227330.

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ABSTRACTWe hypothesized that the free fatty acid receptors FFA1 and FFA4 might be involved in the anorectic response observed in fish after rising levels of long-chain fatty acids (LCFAs) such as oleate. In one experiment we demonstrated that intracerebroventricular (i.c.v.) treatment of rainbow trout with FFA1 and FFA4 agonists elicited an anorectic response 2, 6 and 24 h after treatment. In a second experiment, the same i.c.v. treatment resulted after 2 h in an enhancement in the mRNA abundance of anorexigenic neuropeptides pomca1 and cartpt and a decrease in the values of orexigenic peptides npy and agrp1. These changes occurred in parallel with those observed in the mRNA abundance and/or protein levels of the transcription factors Creb, Bsx and FoxO1, protein levels and phosphorylation status of Ampkα and Akt, and mRNA abundance of plcb1 and itrp3. Finally, we assessed in a third experiment the response of all these parameters after 2 h of i.c.v. treatment with oleate (the endogenous ligand of both free fatty acid receptors) alone or in the presence of FFA1 and FFA4 antagonists. Most effects of oleate disappeared in the presence of FFA1 and FFA4 antagonists. The evidence obtained supports the involvement of FFA1 and FFA4 in fatty acid sensing in fish brain, and thus involvement in food intake regulation through mechanisms not exactly comparable (differential response of neuropeptides and cellular signalling) to those known in mammals.

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Christiansen, Elisabeth, Kenneth R. Watterson, Claire J. Stocker, Elena Sokol, Laura Jenkins, Katharina Simon, Manuel Grundmann, et al. "Activity of dietary fatty acids on FFA1 and FFA4 and characterisation of pinolenic acid as a dual FFA1/FFA4 agonist with potential effect against metabolic diseases." British Journal of Nutrition 113, no. 11 (April 28, 2015): 1677–88. http://dx.doi.org/10.1017/s000711451500118x.

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Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration–response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.

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Alharbi, Abdulrahman G., Andrew B. Tobin, and Graeme Milligan. "How Arrestins and GRKs Regulate the Function of Long Chain Fatty Acid Receptors." International Journal of Molecular Sciences 23, no. 20 (October 13, 2022): 12237. http://dx.doi.org/10.3390/ijms232012237.

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FFA1 and FFA4, two G protein-coupled receptors that are activated by long chain fatty acids, play crucial roles in mediating many biological functions in the body. As a result, these fatty acid receptors have gained considerable attention due to their potential to be targeted for the treatment of type-2 diabetes. However, the relative contribution of canonical G protein-mediated signalling versus the effects of agonist-induced phosphorylation and interactions with β-arrestins have yet to be fully defined. Recently, several reports have highlighted the ability of β-arrestins and GRKs to interact with and modulate different functions of both FFA1 and FFA4, suggesting that it is indeed important to consider these interactions when studying the roles of FFA1 and FFA4 in both normal physiology and in different disease settings. Here, we discuss what is currently known and show the importance of understanding fully how β-arrestins and GRKs regulate the function of long chain fatty acid receptors.

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Xu, Fangfang, Han Zhou, Xiumei Liu, Xiuli Zhang, Zhiwei Wang, Tao Hou, Jixia Wang, et al. "Label-free cell phenotypic study of FFA4 and FFA1 and discovery of novel agonists of FFA4 from natural products." RSC Advances 9, no. 26 (2019): 15073–83. http://dx.doi.org/10.1039/c9ra02142f.

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Son, So-Eun, Jung-Min Koh, and Dong-Soon Im. "Free Fatty Acid Receptor 4 (FFA4) Activation Ameliorates Imiquimod-Induced Psoriasis in Mice." International Journal of Molecular Sciences 23, no. 9 (April 19, 2022): 4482. http://dx.doi.org/10.3390/ijms23094482.

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Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been used as an adjunct therapy for psoriasis due to its anti-inflammatory properties. Free fatty acid receptor 4 (FFA4 or GPR120) is a receptor-sensing n-3 PUFA. In the present study, we examined whether FFA4 acted as a therapeutic target for n-3 PUFA in psoriasis therapy. Experimentally, psoriasis-like skin lesions were induced by treatment with imiquimod for 6 consecutive days. A selective FFA4 agonist, Compound A (30 mg/kg), was used in FFA4 WT and FFA4 KO mice. Imiquimod-induced psoriasis-like skin lesions, which present as erythematous papules and plaques with silver scaling, as well as markedly elevated IL-17/IL-23 cytokine levels in skin tissues, were significantly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Enlarged lymph nodes and spleens, as well as imiquimod-induced, elevated IL-17/IL-23 cytokine levels, were also strongly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Imiquimod-induced increases in the CD4+IL-17A+ T cell population in lymph nodes and spleens were suppressed by Compound A treatment in FFA4 WT mice; however, this was not seen in FFA4 KO mice. Furthermore, compound A suppressed the differentiation of CD4+ naïve T cells from splenocytes into TH17 cells in an FFA4-dependent manner. In conclusion, we demonstrated that the activation of FFA4 ameliorates imiquimod-induced psoriasis, and the suppression of the differentiation of TH17 cells may partly contribute to its efficacy. Therefore, we suggest that FFA4 could be a therapeutic target for psoriasis therapy.

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Lee, Jung-Eun, Ju-Hyun Lee, Jung-Min Koh, and Dong-Soon Im. "Free Fatty Acid 4 Receptor Activation Attenuates Collagen-Induced Arthritis by Rebalancing Th1/Th17 and Treg Cells." International Journal of Molecular Sciences 25, no. 11 (May 28, 2024): 5866. http://dx.doi.org/10.3390/ijms25115866.

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Dietary supplementation with n-3 polyunsaturated fatty acids (PUFA) has been found to be beneficial in rodent rheumatoid arthritis models and human trials. However, the molecular targets of n-3 PUFAs and their beneficial effects on rheumatoid arthritis are under-researched. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor for n-3 PUFA. We aim to investigate whether FFA4 activation reduces collagen-induced rheumatoid arthritis (CIA) by using an FFA4 agonist, compound A (CpdA), in combination with DBA-1J Ffa4 gene wild-type (WT) and Ffa4 gene knock-out (KO) mice. CIA induced an increase in the arthritis score, foot edema, synovial hyperplasia, pannus formation, proteoglycan loss, cartilage damage, and bone erosion, whereas the administration of CpdA significantly suppressed those increases in Ffa4 WT mice but not Ffa4 gene KO mice. CIA increased mRNA expression levels of pro-inflammatory Th1/Th17 cytokines, whereas CpdA significantly suppressed those increases in Ffa4 WT mice but not Ffa4 gene KO mice. CIA induced an imbalance between Th1/Th17 and Treg cells, whereas CpdA rebalanced them in spleens from Ffa4 WT mice but not Ffa4 gene KO mice. In SW982 synovial cells, CpdA reduced the LPS-induced increase in pro-inflammatory cytokine levels. In summary, the present results suggest that the activation of FFA4 in immune and synovial cells could suppress the characteristics of rheumatoid arthritis and be an adjuvant therapy.

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Kang, Saeromi, Jung-Min Koh, and Dong-Soon Im. "N-3 Polyunsaturated Fatty Acids Protect against Alcoholic Liver Steatosis by Activating FFA4 in Kupffer Cells." International Journal of Molecular Sciences 25, no. 10 (May 17, 2024): 5476. http://dx.doi.org/10.3390/ijms25105476.

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Supplementation with fish oil rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) effectively reduces acute and chronic alcohol-induced hepatic steatosis. We aimed to find molecular mechanisms underlying the effects of n-3 PUFAs in alcohol-induced hepatic steatosis. Because free fatty acid receptor 4 (FFA4, also known as GPR120) has been found as a receptor for n-3 PUFAs in an ethanol-induced liver steatosis model, we investigated whether n-3 PUFAs protect against liver steatosis via FFA4 using AH7614, an FFA4 antagonist, and Ffa4 knockout (KO) mice. N-3 PUFAs and compound A (CpdA), a selective FFA4 agonist, reduced the ethanol-induced increase in lipid accumulation in hepatocytes, triglyceride content, and serum ALT levels, which were not observed in Ffa4 KO mice. N-3 PUFAs and CpdA also reduced the ethanol-induced increase in lipogenic sterol regulatory element-binding protein-1c expression in an FFA4-dependent manner. In Kupffer cells, treatment with n-3 PUFA and CpdA reversed the ethanol-induced increase in tumor necrosis factor-α, cyclooxygenase-2, and NLR family pyrin domain-containing 3 expression levels in an FFA4-dependent manner. In summary, n-3 PUFAs protect against ethanol-induced hepatic steatosis via the anti-inflammatory actions of FFA4 on Kupffer cells. Our findings suggest FFA4 as a therapeutic target for alcoholic hepatic steatosis.

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Більше джерел

Дисертації з теми "FFA4"

Raihan, Sheikh Zahir. "Desensitisation of the human long chain fatty acid receptors FFA1 and FFA4." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8144/.

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G protein-coupled receptors (GPCRs) constitute the largest, most ubiquitous and most versatile family of membrane proteins encoded by the human genome. Due to diverse ligands and multiple physiological activities, this set of receptors has frequently been explored as potential drug targets. Deorphanisation of GPCRs successfully identified FFA1 and FFA4 (previously named GPR40 and GPR120) as long chain free fatty acid receptors. With diverse expression patterns and close association to pathophysiology of metabolic diseases, both receptors are being studied to understand both receptor pharmacology and their potential for drug development. Due to the overlap in the activation of FFA1 and FFA4 by endogenous fatty acid ligands, selective synthetic ligands have been developed for these receptors. Using a number of biochemical and biophysical assays, I have characterised TUG-770, TUG-905 and GW-1100 as FFA1 ligands and TUG-891, TUG-1197 and TUG-1275 as FFA4 ligands. TUG-905 was found to be most potent and selective FFA1 agonist and GW-1100 showed insurmountable antagonism at FFA1. At FFA4, TUG-1197 was found to be a highly potent and selective agonist. TUG-1275 showed insurmountable antagonism at FFA4 in β-arrestin2 recruitment, receptor internalisation and inositol monophosphate accumulation studies and showed complete selectivity for hFFA4. Agonist exposure rapidly phosphorylated FFA4 in an agonist-concentration-dependent fashion which was totally blocked by TUG-1275. The protein kinase C activator PMA was also noted to phosphorylate FFAA in a concentration-dependent manner. Thus both homologous and heterologous phosphorylation is involved in FFA4 regulation. The FFA4-agonist TUG-891 produced robust internalisation of FFA4 as detected by each of confocal microscopy, and both cell surface ELISA and biotinylation. PMA was able to internalise FFA4 although it was unable to recruit β-arrestin2 to FFA4 suggesting that this internalisation might not be β-arrestin2-dependent. Constitutive internalisation was seen for FFA1, where the selective FFA1 antagonist GW-1100 had no effect. Repeated agonist-exposure desensitised both FFA1 and FF4 as revealed in single-cell calcium imaging studies. Although there was a small reduction of FFA4-internalisation and a slight elevation of total calcium levels from a single-chronic exposure of agonist, elimination of β-arrestin1/2 from HEK293 cells by genome editing did not significantly change the desensitisation of FFA4 to repeated exposure of agonist and did not prevent agonist-promoted internalisation. These studies indicate that β-arrestins are not the sole factors in desensitisation of human FFA4. Gαq/11 elimination by genome editing completely blocked intracellular calcium mobilisation and accumulation of inositol monophosphates mediated by both FFA1 and FFA4 indicating that Gαq/11 coupling to agonist-activated receptors is essential for this functional signalling outcome via both receptors. FFA4 expressed in Gαq/11-null cells was found to be phosphorylated by agonist, indicating that phosphorylation-mediated desensitisation of this receptor is not dependent on Gαq/11 proteins. FRET and BRET experiments revealed for the first time homo and hetero-oligomerisation of both FFA1 and FFA4. Although ligand regulation of oligomerisation was not investigated these preliminary observations of oligomerisation may help in the future to answer many questions of regulation and desensitisation of these receptors. The selective FFA1 and FFA4 ligands characterised here in this project might be used as tool compounds to further explore the physiology and pharmacology of these therapeutically important receptors.

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Patient, Guillaume. "Étude in silico de la structure et des interactions protéine-ligand de FFA4 à des fins de Drug Design." Electronic Thesis or Diss., Université de Lille (2022-....), 2024. http://www.theses.fr/2024ULILS073.

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Les récepteurs couplés aux protéines G (GPCR) sont des cibles médicamenteuses importantes, représentant 35 % du total des cibles médicamenteuses approuvées. Ces récepteurs sont des protéines transmembranaires impliquées dans la signalisation cellulaire de stimuli externes (hormones, neurotransmetteurs, ions...) et induisent l'activation de la protéine G associée via l'échange GDP/GTP. Au cours des 20 dernières années, des RCPG désorphanisés ont été mis en évidence comme étant actifs dans le métabolisme des lipides : des études ont montré que la modulation de l'activité du GPR 120 (FFA4), principalement exprimé dans la langue et l'intestin, a un impact sur la prise (alimentation) et l'absorption des lipides chez la souris, représentant ainsi une nouvelle approche pour promouvoir des traitements dans la prévention de l'obésité et des maladies cardiovasculaires. En complément des études classiques de chimie pharmaceutique, en collaboration avec l'équipe du Pr. Naim Khan de l'Université de Bourgogne, des méthodes in silico ont été appliquées à l'étude des caractéristiques structurelles de la protéine. Le manque d'informations structurelles sur le FFA4 et les essais limités de médicaments contribuent à l'application de méthodes in silico pour déterminer les caractéristiques structurelles et les interactions dynamiques de la protéine. La modélisation par homologie de différents états de FFA4 (inactif, intermédiaire et actif) a été réalisée et la protéine G associée a été modélisée pour l'état actif du récepteur. Des études dynamiques du récepteur en membrane ont permis d'affiner le domaine d'hélices transmembranaires (TM). L'identification du site actif et des interactions avec les ligands ont permis des études préliminaires de docking du TUG-891, un agoniste sélectif puissant du FFA4, et a mis en évidence des interactions ioniques avec les résidus chargés positivement dans la poche de liaison. Des structures cryo-EM expérimentales ont été publiées au cours de nos études in silico. Alors que les structures expérimentales ont confirmé les propriétés structurelles de FFA4 observées dans notre modèle par homologie, des informations complémentaires sur la liaison des ligands peuvent être dérivées de notre modèle pour l'activation de FFA4.Des études de docking de 4 ligands agonistes (TUG-891, acide oléique, acide linoléique et acide linolénique) ont été réalisées et les résultats ont été affinés en utilisant la dynamique moléculaire avec le champ de force AMBER 14IPQ pour prendre en compte les interactions ioniques entre les résidus chargés positivement dans la poche de liaison et le groupe d'acide carboxylique des ligands. Les expériences de dynamique moléculaire pour les différents systèmes protéine-ligand permettent d'identifier le mode de liaison le plus stable et nous ont permis de déterminer les contraintes pharmacophoriques pour un criblage virtuel à haut débit. Les composés les plus prometteurs ont été sélectionnés pour des tests biologiques
G protein-coupled receptors (GPCRs) are important drug targets, accounting for 35% of all approved drug targets. These receptors are transmembrane proteins involved in cell signaling of external stimuli (hormones, neurotransmitters, ions...) and induce activation of the associated G protein via GDP/GTP exchange. Over the last 20 years, deorphanized GPCRs have been shown to be active in lipid metabolism: studies have shown that modulating the activity of GPR 120 (FFA4), mainly expressed in the tongue and intestine, has an impact on lipid intake (feeding) and absorption in mice, representing a new approach to promoting treatments for the prevention of obesity and cardiovascular disease. In addition to classical pharmaceutical chemistry studies, in collaboration with Prof. Naim Khan's team at the University of Burgundy, in silico methods were applied to study the structural characteristics of the protein.The lack of structural information on FFA4 and limited drug testing contribute to the application of in silico methods to determine the structural features and dynamic interactions of the protein. Homology modeling of different FFA4 states (inactive, intermediate and active) was carried out, and the associated G protein was modeled for the receptor's active state. Dynamic studies of the receptor in the membrane were used to refine the transmembrane (TM) helix domain. Identification of the active site and ligand interactions enabled preliminary docking studies of TUG-891, a potent selective FFA4 agonist, and revealed ionic interactions with positively charged residues in the binding pocket. Experimental cryo-EM structures were published during our in silico studies. While the experimental structures confirmed the structural properties of FFA4 observed in our homology model, further information on ligand binding can be derived from our model for FFA4 activation. Docking studies of 4 agonist ligands (TUG-891, oleic acid, linoleic acid and linolenic acid) were carried out and the results refined using molecular dynamics with the AMBER 14IPQ force field to take account of ionic interactions between the positively charged residues in the binding pocket and the carboxylic acid group of the ligands. Molecular dynamics experiments for the different protein-ligand systems identified the most stable binding mode, and enabled us to determine pharmacophore constraints for high-throughput virtual screening. The most promising compounds have been selected for biological testing

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Riaz, Sajjad Ali. "Evaluation of signalling and phosphorylation responses of the human histamine H₄ receptor (H₄R) and the human free fatty acid receptor 4 (FFA4)." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37696.

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Анотація:

The knowledge that G protein-coupled receptors (GPCRs) are regulated by phosphorylation in a process that results in the recruitment of arrestins, leading to receptor desensitisation is now well known. The histamine H₄ receptor (H₄R) and the free fatty acid receptor 4 (FFA4) are family A GPCRs that both have the ability to become phosphorylated in their third intracellular loops and C-terminal tails by kinases found in the cytosolic milieu of the cells and tissues they are expressed in. Investigations into the phosphorylation status of the histamine H4 receptor have revealed a receptor that is highly phosphorylated even in the basal state. The endogenous, full agonist for the human H₄R, histamine, induced a robust increase in receptor phosphorylation. However, the β-arrestin-biased agonist JNJ7777120 did not. Extending this study using mass spectrometry revealed the individual sites of phosphorylation. Histamine and JNJ7777120 also caused H₄R internalisation. Our data suggests a similar level of endocytosis induced by histamine and JNJ7777120 at 5 or 30 min stimulation. Thus, we show that JNJ7777120, while previously demonstrating its differing effects on H₄R signalling, also shows differences in the phosphorylation of the H₄R when compared to histamine. Using the wild type FFA4 receptor and its phosphorylation-deficient mutants, we show the importance of phosphorylation in the recruitment of arrestin to the receptor as well as delineating G protein-dependent and independent downstream signalling pathways. Knowledge of the different signalling cascades and their mechanism of activation would be useful in the design of biased ligands for therapeutic benefits in order to develop safer and more efficacious drugs. The use of a FFA4 receptor which is phosphorylation-deficient and, therefore, couples to arrestin-3 in a reduced manner may be useful in proof-of-concept studies where the downstream signalling in a physiological setting is mediated by arrestin as opposed to G proteins. Further evidence of the importance of phosphorylation is provided by my work with the phosphomimetic FFA4 mutant receptor, which I show does not faithfully mimic phosphorylated serine and/or threonine residues resulting, in a reduced ability to couple to arrestin-3.

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Lamodière, Elisabeth. "Nouveaux concepts dans la pharmacologie des récepteurs aux acides gras à chaîne courte FFA2 et FFA3." Phd thesis, Université de Bourgogne, 2011. http://tel.archives-ouvertes.fr/tel-00668234.

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Les maladies métaboliques, comme le diabète, la dyslipidémie ou l'obésité, constituent un problème majeur de santé publique dans les pays développés. Ces maladies très répandues restent encore difficiles à traiter malgré une recherche active. Les stratégies thérapeutiques contre ces maladies incluent le développement de nouvelles molécules ciblant les récepteurs aux acides gras, étant donné leur rôle essentiel dans l'homéostasie du métabolisme. C'est dans ce contexte que s'inscrit ce travail portant sur deux récepteurs couplés aux protéines G, les récepteurs aux acides gras à courte chaîne 2 et 3 ou free fatty acid receptors 2 (FFA2) et 3 (FFA3). Nous avons tout d'abord cherché à déterminer le profil d'expression des deux récepteurs. Ensuite, nous avons établi des lignées cellulaires stable exprimant FFA2 ou FFA3 afin d'étudier la pharmacologie d'agonistes synthétiques et endogènes de ces récepteurs. Après avoir identifié les voies de signalisation engendrées par l'activation des récepteurs, nous avons démontré que les agonistes synthétiques étaient des activateurs allostériques, c'est-à-dire qu'ils se liaient aux récepteurs sur un site distinct de celui des ligands endogènes. Pour identifier les résidus d'acides aminés nécessaires à la reconnaissance des ligands, nous avons généré une gamme de mutants ponctuels de ces récepteurs par mutagénèse dirigée. En analysant l'effet des mutations dans des tests fonctionnels, nous avons pu déterminer avec précision où se liaient les ligands et ainsi pu dessiner par informatique des modèles structuraux des récepteurs qui pourront être utilisés pour le drug design de futures molécules agonistes de ces récepteurs.

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Moussaud, Elisabeth. "Nouveaux concepts dans la pharmacologie des récepteurs aux acides gras à chaîne courte FFA2 et FFA3." Thesis, Dijon, 2011. http://www.theses.fr/2011DIJOS014/document.

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Les maladies métaboliques, comme le diabète, la dyslipidémie ou l’obésité, constituent un problème majeur de santé publique dans les pays développés. Ces maladies très répandues restent encore difficiles à traiter malgré une recherche active. Les stratégies thérapeutiques contre ces maladies incluent le développement de nouvelles molécules ciblant les récepteurs aux acides gras, étant donné leur rôle essentiel dans l’homéostasie du métabolisme. C’est dans ce contexte que s’inscrit ce travail portant sur deux récepteurs couplés aux protéines G, les récepteurs aux acides gras à courte chaîne 2 et 3 ou free fatty acid receptors 2 (FFA2) et 3 (FFA3). Nous avons tout d'abord cherché à déterminer le profil d'expression des deux récepteurs. Ensuite, nous avons établi des lignées cellulaires stable exprimant FFA2 ou FFA3 afin d’étudier la pharmacologie d’agonistes synthétiques et endogènes de ces récepteurs. Après avoir identifié les voies de signalisation engendrées par l’activation des récepteurs, nous avons démontré que les agonistes synthétiques étaient des activateurs allostériques, c’est-à-dire qu’ils se liaient aux récepteurs sur un site distinct de celui des ligands endogènes. Pour identifier les résidus d’acides aminés nécessaires à la reconnaissance des ligands, nous avons généré une gamme de mutants ponctuels de ces récepteurs par mutagénèse dirigée. En analysant l’effet des mutations dans des tests fonctionnels, nous avons pu déterminer avec précision où se liaient les ligands et ainsi pu dessiner par informatique des modèles structuraux des récepteurs qui pourront être utilisés pour le drug design de futures molécules agonistes de ces récepteurs
Metabolic diseases, such as diabetes, dyslipidemia or obesity, are more and more weighing on public health expenses in developed countries. Despite active research, these widespread diseases remain difficult to handle. Promising new therapeutic strategies against metabolic diseases include the development of drugs targeting the free fatty acid receptors, as key players in metabolism homeostasis. In this context, the current PhD thesis focuses on the study of two G protein-coupled receptors, namely the short-chain free fatty acid receptors 2 (FFA2) and 3 (FFA3). First, we investigated the expression of the two receptors of interest in a variety of cell types. Then, in order to study the pharmacology and the binding mode of endogenous and synthetic agonists on FFA2 and FFA3, we established stable cell lines expressing each receptor. Once we identified the signaling pathways engendered in response to receptor activation, we showed that synthetic agonists were allosteric activators of the receptors, in the sense that they bind to the receptors at a distinct site from short-chain fatty acids, i.e. the endogenous agonists. To identify the aminoacid residues that were involved in ligand binding, we generated a variety of point mutated receptors by site-directed mutagenesis. By analyzing the effects of the mutations in functional tests, we determined precisely the aminoacid residues that were essential for ligand binding. From these results, we designed in silico structural models which may aid future drug design efforts for the discovery of new FFA2 and FFA3 agonists

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Josefsson, Ragnar, and Joel Storm. "Materialförsörjning hos FFAB." Thesis, Linköpings universitet, Kommunikations- och transportsystem, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-151067.

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Denna rapport är en fallstudie som har gjorts på det båttillverkande företaget FFAB. FFAB har svårigheter att styra materialflödet, från varumottag till montering, på ett standardiserat och förutsägbart vis. Som en följd av detta har montörerna svårt att hitta alla komponenter de behöver vilket spiller tid från själva monteringsarbetet. Syftet med fallstudien har således varit att klargöra materialförsörjningen till en av FFABs produktionslinor och ge förbättringsförslag för att reducera andelen icke-värdeskapande aktiviteter kopplat till produktionsprocessen. Fallstudien fann fem grundorsaker till icke-värdeskapande aktiviteter; oreda, materialpresentationen, monteringsstrukturen, informationssystemet och kittningen. Åtgärderna till de rådande problemen och därmed vår slutsats blev att införa 5S för att få bukt på den oreda som finns vid samtliga lagerpunkter, att standardisera kittningen och systematiken på materialfasaderna och att i större utsträckning involvera montörerna i planeringsarbetet.

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LAGRANGE, Jean-Baptiste Henri Raymond. "Study of zero-chromaticity in FFAG accelerators." 京都大学 (Kyoto University), 2012. http://hdl.handle.net/2433/157577.

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Vanderbos, Sara. "Factors that influence secondary students to join the Collegiate FFA." DigitalCommons@USU, 2013. https://digitalcommons.usu.edu/etd/1489.

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Student involvement on college campuses is important for the professional growth, leadership development and learning of today's college student. This research sought to determine the factors that influence former high school FFA members' reasons for joining and participating in the Collegiate FFA. The study showed that students who are involved in the National FFA at the secondary level are more likely to join Collegiate FFA while attending a university that offers the Collegiate FFA option. These students were actively engaged on campus and were interested in helping others. Collegiate FFA programs, the National FFA, and universities across the country should begin their recruitment efforts with current high school FFA members.

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Yamakawa, Emi. "Study of serpentine acceleration in zero-chromatic FFAG accelerators." 京都大学 (Kyoto University), 2013. http://hdl.handle.net/2433/174929.

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PLANCHE, Thomas. "Study of zero-chromatic FFAG synchrotron for muon acceleration." 京都大学 (Kyoto University), 2010. http://hdl.handle.net/2433/131890.

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Книги з теми "FFA4"

Paul, Korky. Trysor Twm Ffat. Llandysul: Gomer, 1994.

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International, Workshop on FFAG Accelerators (13th 2007 Osaka Japan). The International Workshop on FFAG Accelerators. Ōsaka-fu, Sennan-gun, Kumatori-chō: Research Reactor Institute, Kyoto University, 2008.

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M, Lefèvre A., ed. Jac a'r goeden ffa. Llanrwst: Gwasg Carreg Gwalch, 2001.

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J, Petersilie Erin, and Future Farmers of America, eds. The FFA cookbook: Favorite recipes from FFA members and alumni across America. Minneapolis, Minn: MBI Pub. Company, 2009.

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Ayala, Julio Guillermo Meza. Derecho de pensiones en la PNP y FFAA. Perú: s.n., 2004.

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Razeto, Sebastián Briones. ¿Construyendo confianza?: Fronteras, FFAA y política en América Latina. Santiago de Chile: FLACSO-CHILE, 2008.

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Rodrigo, Álvarez V., ed. ¿Construyendo confianza?: Fronteras, FFAA y política en América Latina. Santiago de Chile: FLACSO-CHILE, 2008.

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Xanna, Siraabuzuu. Royal lammummaa fi amala gaarii: Kutaa 7- 8 ffaa. [Ethiopia]: Computeraan Bareessuf, 1997.

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Hughes, A. V. FFA member country contributions: A revised formula : report. Port Vila, Vanuatu: United Nations, Economic and Social Commission for Asia and the Pacific, Pacific Operations Centre, 1996.

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Petty, Dustin. Michigan FFA: A legacy of Great Lakes leadership. Evansville, IN: M.T. Pub. Co., 2008.

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Частини книг з теми "FFA4"

Gribble, Fiona M., Eleftheria Diakogiannaki, and Frank Reimann. "Gut Hormone Regulation and Secretion via FFA1 and FFA4." In Free Fatty Acid Receptors, 181–203. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/164_2016_46.

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Hansen, Steffen V. F., and Trond Ulven. "Pharmacological Tool Compounds for the Free Fatty Acid Receptor 4 (FFA4/GPR120)." In Free Fatty Acid Receptors, 33–56. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/164_2016_60.

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Tang, Cong, and Stefan Offermanns. "FFA2 and FFA3 in Metabolic Regulation." In Free Fatty Acid Receptors, 205–20. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/164_2016_50.

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Méot, François. "FFAG, Scaling." In Particle Acceleration and Detection, 385–444. Cham: Springer International Publishing, 2024. http://dx.doi.org/10.1007/978-3-031-59979-8_10.

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AbstractThis chapter is an introduction to Fixed-Field Alternating Gradient (FFAG) cyclic accelerators. It begins with a brief reminder of the historical and technological context, and continues with the theoretical material needed for the simulation exercises. It relies on charged particle optics and acceleration concepts introduced in the previous cyclotron and synchrotron chapters. Furthermore it addresses design aspects of scaling FFAGs, beam dynamics in radial- and spiral-sector rings, synchrotron acceleration and various other acceleration techniques. Simulations introduce dedicated keywords providing an analytical modeling of the field: FFAG (radial sector dipole) and FFAG-SPI (spiral sector). They otherwise use optical elements met in the previous chapters: DIPOLE[S], TOSCA, CAVITE, data input/output keywords such as FAISCEAU, FAISTORE, the SYSTEM keyword, etc. Beam dynamics simulations include particle trajectories through multiple-dipole FFAG cells, closed-orbit finding, from multi-turn raytracing or using FIT, deriving ancillary outcomes from rays, such as transport matrices using MATRIX, periodic optical functions and their transport using TWISS, finding dynamical aperture.

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Méot, François. "FFAG, Linear." In Particle Acceleration and Detection, 445–75. Cham: Springer International Publishing, 2024. http://dx.doi.org/10.1007/978-3-031-59979-8_11.

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AbstractThis chapter is an introduction to linear Fixed-Field Alternating Gradient (FFAG) cyclic accelerators. It begins with a brief reminder of the historical and technological context, and continues with the theoretical material needed for the simulation exercises. It relies on charged particle optics and acceleration concepts introduced in the previous synchrotron and scaling FFAG chapters and further addresses design aspects of linear FFAGs, diverse specificities of linear FFAG optics, beam dynamics in rings, serpentine acceleration. Simulations do not require specific keywords, they use optical elements met in the previous chapters, including MULTIPOL DIPOLE[S], CAVITE, data input/output keywords such as FAISCEAU, FAISTORE, the SYSTEM keyword, etc. Beam dynamics simulations include – computation of optical parameters, – particle trajectories through a cell or a ring, – closed-orbit finding, from multi-turn raytracing or by coordinate matching, – deriving ancillary outcomes from rays, such as $$\bullet $$ ∙ transport matrices using MATRIX, $$\bullet $$ ∙ periodic optical functions and their transport using TWISS, – finding dynamical aperture, – serpentine fast acceleration, and more.

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Bast, Thomas, and Günter Krämer. "Fenfluramin (FFA)." In Medikamenten-Pocket Epilepsie, 149–52. Berlin, Heidelberg: Springer Berlin Heidelberg, 2024. http://dx.doi.org/10.1007/978-3-662-67716-2_21.

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Méot, François. "Synchrocyclotron." In Particle Acceleration and Detection, 225–36. Cham: Springer International Publishing, 2024. http://dx.doi.org/10.1007/978-3-031-59979-8_7.

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AbstractThis chapter introduces the concept of phase focusing by synchronous acceleration, and the synchrocyclotron which confirmed the principle. Synchrocyclotron style of acceleration in a fixed field alternating gradient accelerator (FFAG) is also addressed. The theoretical material needed for the simulation exercises is essentially that of the Weak Focusing Synchrotron, Chap. 8, regarding phase stability, and that of the Classical Cyclotron, Chap. 3, or FFAG optics, Chap. 10, regarding transverse stability. The chapter begins with a brief reminder of the historical context, and continues with the theoretical material which the synchrocyclotron optics and acceleration techniques lean on. The simulation of a synchrocyclotron is achieved using just three keywords: DIPOLE for the magnet, and CAVITE and SCALING for acceleration. FFAG dipoles have their specific keywords, FFAG and FFAG-SPI (Chap. 10). Particle monitoring uses FAISCEAU, FAISTORE, and some others. Optics matching and optimization, and the design of RF programs as well, use FIT[2]. INCLUDE is resorted to, although there is no obligation, in order mostly to simplify the input data files. SYSTEM calls to gnuplot scripts allow ending simulations with various graphs; gnuplot reads data from output files such as zgoubi.fai (produced by FAISTORE), zgoubi.plt (resulting from IL $$=$$ = 2) and from files zgoubi.*.out resulting from a PRINT command.

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Labille, Jérôme, Natalia Pelinovskaya, Céline Botta, Jean-Yves Bottero, Armand Masion, Dilip S. Joag, Richard G. Forbes, et al. "Free Flow Aoustophoresis (FFA)." In Encyclopedia of Nanotechnology, 884. Dordrecht: Springer Netherlands, 2012. http://dx.doi.org/10.1007/978-90-481-9751-4_100261.

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Mohapatra, Pradyumna, Sunita Panda, and Siba Prasada Panigrahi. "Equalizer Modeling Using FFA Trained Neural Networks." In Advances in Intelligent Systems and Computing, 569–77. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-5687-1_51.

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Hongji, Zhou, Fu Wei, Zhang Tianjun, Wang Chuan, Wang Fei, Liu Jingyuan, Zhu Xiaofeng, and Zhang Suping. "Simulation and Analysis of Cryogenic System for FFAG Superconducting Magnets." In Proceedings of the 28th International Cryogenic Engineering Conference and International Cryogenic Materials Conference 2022, 1140–47. Singapore: Springer Nature Singapore, 2023. http://dx.doi.org/10.1007/978-981-99-6128-3_148.

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Тези доповідей конференцій з теми "FFA4"

Chen, Haoda, Lifu Chen, Yawu Liu, Junqi Zhao, and Yuchen Jin. "FFAE-Net for automatic semantic segmentation of point clouds in the power corridor." In 5th International Conference on Computer Vision and Data Mining (ICCVDM 2024), edited by Xin Zhang and Minghao Yin, 30. SPIE, 2024. http://dx.doi.org/10.1117/12.3048086.

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Liao, Powei, Pei-Chun Chien, Hiroki Tsukida, Yoichi Kato, and Jun Ohya. "FFAD: Fixed-Position Few-Shot Anomaly Detection for Wire Harness Utilizing Vision-Language Models." In 14th International Conference on Pattern Recognition Applications and Methods, 647–56. SCITEPRESS - Science and Technology Publications, 2025. https://doi.org/10.5220/0013164400003905.

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Green, Andrea, Neha Chitre, Kalyn Rambacher, Kevin Murnane, and Nader Moniri. "Probing the role of Free-Fatty Acid Receptor-4 (FFA4) as novel target for Parkinson’s Disease: FFA4 agonists increase dopamine synthesis and reduce 6-OHDA-induced cell death." In ASPET 2024 Annual Meeting Abstract. American Society for Pharmacology and Experimental Therapeutics, 2024. http://dx.doi.org/10.1124/jpet.148.924990.

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Bourke, J. E., M. Lam, L. Allan, R. Angeles, C. Donovan, J. Jaffar, G. Westall, and S. Royce. "The FFA4 Agonist TUG891 Maintains Bronchodilator Efficacy Under Conditions of Reduced Salbutamol Effectiveness." In American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a4423.

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Ruda, Mitchell. "The Foucault Test." In Optical Fabrication and Testing. Washington, D.C.: Optica Publishing Group, 1990. http://dx.doi.org/10.1364/oft.1980.ffa4.

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The Foucault test (referred to as the knife edge or wire test) was invented by L. M. Foucault in 1858. In its most basic form only a white light point source and a knife edge are necessary to qualitatively detect small errors on an optical surface. It has been shown that under ideal conditions, errors on the surface as small as λ/600 can be detected. Thus this is one of the most sensitive yet economical tests and should always be considered as an option when one has a limited testing budget.

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Mills, F. E. "Early FFAG development." In CYCLOCTRONS AND THEIR APPLICATIONS 2001: Sixteenth International Conference. AIP, 2001. http://dx.doi.org/10.1063/1.1435232.

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Tennant, Christopher. "Longitudinal Dynamics in ERLs." In FFAG Workshop, Cornell University, September 6, 2017. US DOE, 2017. http://dx.doi.org/10.2172/1986270.

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Tennant, Christopher. "Introduction to and history of ERLs." In FFAG Workshop, Cornell University, September 6, 2017. US DOE, 2017. http://dx.doi.org/10.2172/1986272.

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Pasternak, J., J. Fourrier, E. Froidefond, B. Autin, F. Meot, D. Neuveglise, and T. Planche. "Spiral FFAG for protontherapy." In 2007 IEEE Particle Accelerator Conference (PAC). IEEE, 2007. http://dx.doi.org/10.1109/pac.2007.4440770.

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Méot, F., Osamu Yasuda, Naba Mondal, and Chihiro Ohmori. "The RACCAM FFAG Project." In NEUTRINO FACTORIES, SUPERBEAMS AND BETABEAMS: 9th International Workshop on Neutrino Factories, Superbeams, and Betabeams. AIP, 2008. http://dx.doi.org/10.1063/1.2898985.

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Звіти організацій з теми "FFA4"

Brooks, S. FFAG Cell Candidate February 2017. Office of Scientific and Technical Information (OSTI), February 2017. http://dx.doi.org/10.2172/1412717.

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Berg, J. Scott. FFAG Designs for Muon Collider Acceleration. Office of Scientific and Technical Information (OSTI), January 2014. http://dx.doi.org/10.2172/1119569.

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Berg, J. Scott. The EMMA Non-Scaling FFAG Experiment. Office of Scientific and Technical Information (OSTI), August 2011. http://dx.doi.org/10.2172/1439844.

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Ruggiero A. G. AGS-less RIA with FFAG Accelerators. Office of Scientific and Technical Information (OSTI), May 2006. http://dx.doi.org/10.2172/1061829.

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Ruggiero A. FFAG Accelerator Proton Driver for Neutrino Factory. Office of Scientific and Technical Information (OSTI), October 2005. http://dx.doi.org/10.2172/1061810.

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Ruggiero A. G., J. Alessi, E. Beebe, A. Pikin, T. Roser, and D. Trbojevic. FFAG-based Accelerator for Radio-Isotopes Production. Office of Scientific and Technical Information (OSTI), July 2007. http://dx.doi.org/10.2172/1061870.

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Fleming, Skylynn. National FFA Convention Planning Guide. Ames (Iowa): Iowa State University, May 2022. http://dx.doi.org/10.31274/cc-20240624-1036.

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BERG, J. S. Dynamics in a Spiral FFAG with Tilted Cavities. Office of Scientific and Technical Information (OSTI), December 2007. http://dx.doi.org/10.2172/923368.

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Ruggiero A. G., M. Blaskiewicz, E. Courant, D. Trbojevic, N. Tsoupas, and W. Zhang. 1.5-GeV FFAG Accelerator for the AGS Facility. Office of Scientific and Technical Information (OSTI), February 2004. http://dx.doi.org/10.2172/1061730.

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Berg, J. S. Beam Loading Computation for the IDS-NF FFAG. Office of Scientific and Technical Information (OSTI), October 2011. http://dx.doi.org/10.2172/1034063.

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