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Zeitschriftenartikel zum Thema „FFA4“

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Veröffentlicht am 15. März 2025

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1

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 und Maria M. Campos. „Targeting FFA1 and FFA4 receptors in cancer-induced cachexia“. American Journal of Physiology-Endocrinology and Metabolism 319, Nr. 5 (01.11.2020): 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, Nr. 7 (04.05.2016): 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, Nr. 557 (19.08.2020): 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 und 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, Nr. 17 (14.07.2020): 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, Nr. 11 (28.04.2015): 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 und Graeme Milligan. „How Arrestins and GRKs Regulate the Function of Long Chain Fatty Acid Receptors“. International Journal of Molecular Sciences 23, Nr. 20 (13.10.2022): 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, Nr. 26 (2019): 15073–83. http://dx.doi.org/10.1039/c9ra02142f.

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Son, So-Eun, Jung-Min Koh und Dong-Soon Im. „Free Fatty Acid Receptor 4 (FFA4) Activation Ameliorates Imiquimod-Induced Psoriasis in Mice“. International Journal of Molecular Sciences 23, Nr. 9 (19.04.2022): 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 und 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, Nr. 11 (28.05.2024): 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 und 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, Nr. 10 (17.05.2024): 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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Son, So-Eun, Jung-Min Koh und Dong-Soon Im. „Activation of Free Fatty Acid Receptor 4 (FFA4) Ameliorates Ovalbumin-Induced Allergic Asthma by Suppressing Activation of Dendritic and Mast Cells in Mice“. International Journal of Molecular Sciences 23, Nr. 9 (09.05.2022): 5270. http://dx.doi.org/10.3390/ijms23095270.

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Epidemiological and clinical studies have suggested that intake of n-3 polyunsaturated fatty acids (PUFA) reduces the incidence of allergic airway diseases and improves pulmonary function in patients with allergic asthma. However, the pharmacological targets of PUFA have not been elucidated upon. We investigated whether free fatty acid receptor 4 (FFA4, also known as GPR120) is a molecular target for beneficial PUFA in asthma therapy. In an ovalbumin (OVA)-induced allergic asthma model, compound A (a selective agonist of FFA4) was administrated before OVA sensitization or OVA challenge in FFA4 wild-type (WT) and knock-out (KO) mice. Compound A treatment of RBL-2H3 cells suppressed mast cell degranulation in vitro in a concentration-dependent manner. Administration of compound A suppressed in vivo allergic characteristics in bronchoalveolar lavage fluid (BALF) and lungs, such as inflammatory cytokine levels and eosinophil accumulation in BALF, inflammation and mucin secretion in the lungs. Compound A-induced suppression was not only observed in mice treated with compound A before OVA challenge, but in mice treated before OVA sensitization as well, implying that compound A acts on mast cells as well as dendritic cells. Furthermore, this suppression by compound A was only observed in FFA4-WT mice and was absent in FFA4-KO mice, implying that compound A action is mediated through FFA4. Activation of FFA4 may be a therapeutic target of PUFA in allergic asthma by suppressing the activation of dendritic cells and mast cells, suggesting that highly potent specific agonists of FFA4 could be a novel therapy for allergic asthma.

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M. Motair, Hafed. „Modified Firefly Algorithm using Iterated Descent Method to Solve Machine Scheduling Problems“. Al-Nahrain Journal of Science 26, Nr. 4 (01.12.2023): 88–94. http://dx.doi.org/10.22401/anjs.26.4.13.

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One of the most efficient metaheuristic algorithms that is used to solve hard optimization problems is the firefly algorithm (FFA). In this paper we use this algorithm to solve a single machine scheduling problem, we aim to minimize the sum of the two cost functions: the maximum tardiness and the maximum earliness. This problem (P) is NP-hard so we solve this problem using FFA as a metaheuristic algorithm. To explore the search space and get a good solution to a problem (Q), we hybridize FFA by Iterated Descent Method (IDM) in three ways and the results are FFA1, FFA2, and FFA3. In the computational test, we evaluate these algorithms (FFA, FFA1, FFA2, FFA3) compared with the genetic algorithm (GA) through a simulation process with job sizes from 10 jobs to 100 jobs. The results indicate that these modifications improve the performance of the original FFA and one of them (FFA3) gives better performance than others.

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Xu, Fangfang, Jun Wang, Pan Wang, Tao Hou, Han Zhou, Yaopeng Zhao, Jixia Wang, Yanfang Liu und Xinmiao Liang. „Ursodesoxycholic acid is an FFA4 agonist and reduces hepatic steatosis via FFA4 signaling“. European Journal of Pharmacology 917 (Februar 2022): 174760. http://dx.doi.org/10.1016/j.ejphar.2022.174760.

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Freitas, Raquel D. S., und Maria M. Campos. „Understanding the appetite modulation pathways: The role of the FFA1 and FFA4 receptors“. Biochemical Pharmacology 186 (April 2021): 114503. http://dx.doi.org/10.1016/j.bcp.2021.114503.

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Lee, Kyoung-Pil, Soo-Jin Park, Saeromi Kang, Jung-Min Koh, Koichi Sato, Hae-Young Chung, Fumikazu Okajima und Dong-Soon Im. „ω-3 Polyunsaturated fatty acids accelerate airway repair by activating FFA4 in club cells“. American Journal of Physiology-Lung Cellular and Molecular Physiology 312, Nr. 6 (01.06.2017): L835—L844. http://dx.doi.org/10.1152/ajplung.00350.2016.

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A G protein-coupled receptor (GPCR) named free fatty acid receptor 4 (FFA4, also known as GPR120) was found to act as a GPCR for ω-3 polyunsaturated fatty acids. Its expression has been reported in lung epithelial club cells. We investigated whether supplementation of the ω-3 fatty acids benefits lung health. Omacor (7.75 mg/kg), clinically prescribed preparation of ω-3 fatty acids, and FFA4-knockout mice were utilized in a naphthalene-induced mouse model of acute airway injury (1 injection of 30 mg/kg ip). Naphthalene injection induced complete destruction of bronchiolar epithelial cells within a day. Appearance of bronchiolar epithelial cells was observed after 21 days in control mice. It was found, however, that supplementation of Omacor accelerated the recovery. The appearance of bronchiolar epithelial cells was observed between 7 and 14 days after naphthalene injury in Omacor-treated mice. In isolated club cells, ω-3 fatty acids were found to stimulate cell proliferation and migration but to inhibit cell differentiation. With the use of pharmacological tools and FFA4-knockout mice, FFA4 was found to be responsible for ω-3 fatty acids-induced proliferation in vitro in club cells. Furthermore, accelerated recovery from naphthalene-induced airway injury in Omacor-treated mice was not observed in FFA4-knockout mice in vivo. Present findings indicate that ω-3 fatty acids-induced proliferation of bronchiole epithelial cells through FFA4 is responsible for Omacor-induced accelerated recovery from airway injury. Therefore, intermittent administration of Omacor needs to be tested for acute airway injury because ω-3 fatty acids stimulate proliferation but inhibit differentiation of club cells.

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Milligan, Graeme, Elisa Alvarez-Curto, Brian D. Hudson, Rudi Prihandoko und Andrew B. Tobin. „FFA4/GPR120: Pharmacology and Therapeutic Opportunities“. Trends in Pharmacological Sciences 38, Nr. 9 (September 2017): 809–21. http://dx.doi.org/10.1016/j.tips.2017.06.006.

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Duarte Guimarães, Ana Rita, Adriana Modesto und Alexandre Rezende Vieira. „Formation of alkali-soluble fluoride on the surface of human dental enamel after treatment with fluoridated gels: influence of the pH variation and of the treatmenttime“. Journal of Clinical Pediatric Dentistry 24, Nr. 4 (01.07.2000): 303–7. http://dx.doi.org/10.17796/jcpd.24.4.1l437256773n453u.

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The aim of this study was to quantify, in vitro, the formation of CaF2 after the application of three fluoridated gels: one neutral, one acidulated and another highly acidulated, on a bovine enamel dental surface treated with a Dijkman's demineralizing solution (1990). 145 sections were utilized, obtained from 145 sound teeth and divided into seven groups: C (enamel without treatment); FN1 (enamel demineralized and treated with neutral gel for 1 minute); FN4 (enamel demineralized and treated with neutral gel for 4 minutes);FFA1 (enamel demineralized and treated with acidulated gel for 1 minute);FFA4 (enamel demineralized and treated with acidulated gel for 4 minutes); FAA1 (enamel demineralized and treated with highly acidulated gel for 1 minute) and FAA4 (enamel demineralized and treated with highly acidulated gel for 4 minutes). The formation of CaF2 was analyzed by SEM and chemically by Caslavska's method (1975). The average and standard deviations from the groups studied were respectively: C-0.63; 0.38; FN1-23.06; 16.52; FFA1-54.11; 49.00; FAA1-43.87; 32.66; FN4-34.92; 23.00; FFA4-67.91; 42.36; FAA4-56.03; 38.96. (Mann-Whitney non-parametric test). The time of application did not interfere in the CaF2 formation from the acidulated and highly-acidulated gels. A minor concentration of fluoride and amount of pH from highly-acidulated gel did not affect the higher formation from the CaF2 in relation to the acidulated gel in both cases when the application was evaluated.

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Milligan, G., E. Alvarez-Curto, K. R. Watterson, T. Ulven und B. D. Hudson. „Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4“. British Journal of Pharmacology 172, Nr. 13 (27.02.2015): 3254–65. http://dx.doi.org/10.1111/bph.12879.

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Sørensen, Karina V., Mads H. Kaspersen, Jeppe H. Ekberg, Annette Bauer-Brandl, Trond Ulven und Kurt Højlund. „Effects of Delayed-Release Olive Oil and Hydrolyzed Pine Nut Oil on Glucose Tolerance, Incretin Secretion and Appetite in Humans“. Nutrients 13, Nr. 10 (27.09.2021): 3407. http://dx.doi.org/10.3390/nu13103407.

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Background: To investigate the potential synergistic effects of olive oil releasing 2-oleoylglycerol and hydrolyzed pine nut oil containing 20% pinolenic acid on GLP-1 secretion, glucose tolerance, insulin secretion and appetite in healthy individuals, when delivered to the small intestine as potential agonists of GPR119, FFA1 and FFA4. Methods: Nine overweight/obese individuals completed three 6-h oral glucose tolerance tests (OGTTs) in a crossover design. At −30 min, participants consumed either: no oil, 6 g of hydrolyzed pine nut oil (PNO-FFA), or a combination of 3 g hydrolyzed pine nut oil and 3 g olive oil (PNO-OO) in delayed-release capsules. Repeated measures of glucose, insulin, C-peptide, GLP-1, GIP, ghrelin, subjective appetite and gastrointestinal tolerability were done. Results: PNO-FFA augmented GLP-1 secretion from 0–360 min compared to no oil and PNO-OO (p < 0.01). GIP secretion was increased from 240–360 min after both PNO-FFA and PNO-OO versus no oil (p < 0.01). Both oil treatments suppressed subjective appetite by reducing hunger and prospective food consumption and increasing satiety (p < 0.05). Conclusions: In support of previous findings, 6 g of delayed-release hydrolyzed pine nut oil enhanced postprandial GLP-1 secretion and reduced appetite. However, no synergistic effect of combining hydrolyzed pine nut oil and olive oil on GLP-1 secretion was observed. These results need further evaluation in long-term studies including effects on bodyweight and insulin sensitivity.

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Sparks, Steven M., Christopher Aquino, Pierette Banker, Jon L. Collins, David Cowan, Caroline Diaz, Steven T. Dock et al. „Exploration of phenylpropanoic acids as agonists of the free fatty acid receptor 4 (FFA4): Identification of an orally efficacious FFA4 agonist“. Bioorganic & Medicinal Chemistry Letters 27, Nr. 5 (März 2017): 1278–83. http://dx.doi.org/10.1016/j.bmcl.2017.01.034.

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Kaspersen, Mads Holmgaard, Laura Jenkins, Julia Dunlop, Graeme Milligan und Trond Ulven. „Succinct synthesis of saturated hydroxy fatty acids andin vitroevaluation of all hydroxylauric acids on FFA1, FFA4 and GPR84“. MedChemComm 8, Nr. 6 (2017): 1360–65. http://dx.doi.org/10.1039/c7md00130d.

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Takahashi, Kaede, Kaori Fukushima, Yuka Onishi, Kanako Minami, Shiho Otagaki, Kaichi Ishimoto, Nobuyuki Fukushima, Kanya Honoki und Toshifumi Tsujiuchi. „Involvement of FFA1 and FFA4 in the regulation of cellular functions during tumor progression in colon cancer cells“. Experimental Cell Research 369, Nr. 1 (August 2018): 54–60. http://dx.doi.org/10.1016/j.yexcr.2018.05.005.

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Priyadarshini, Medha, Guadalupe Navarro und Brian T. Layden. „Gut Microbiota: FFAR Reaching Effects on Islets“. Endocrinology 159, Nr. 6 (04.05.2018): 2495–505. http://dx.doi.org/10.1210/en.2018-00296.

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Abstract The G protein–coupled receptors, free fatty acid (FFA) receptors 2 and 3 (FFA2 and FFA3), belonging to the free fatty acid receptor (FFAR) class, sense a distinct class of nutrients, short chain fatty acids (SCFAs). These receptors participate in both immune and metabolic regulation. The latter includes a role in regulating secretion of metabolic hormones. It was only recently that their role in pancreatic β cells was recognized; these receptors are known now to affect not only insulin secretion but also β-cell survival and proliferation. These observations make them excellent potential therapeutic targets in type 2 diabetes. Moreover, expression on both immune and β cells makes these receptors possible targets in type 1 diabetes. Furthermore, SCFAs are generated by gut microbial fermentative activity; therefore, signaling by FFA2 and FFA3 represents an exciting novel link between the gut microbiota and the β cells. This review enumerates the role of these receptors in β cells revealed so far and discusses possible roles in clinical translation.

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Formicola, Rosa, Paolo Pevarello, Christina Kuhn, Chiara Liberati, Francesco Piscitelli und Mariangela Sodano. „FFA4/GPR120 agonists: a survey of the recent patent literature“. Pharmaceutical Patent Analyst 4, Nr. 6 (November 2015): 443–51. http://dx.doi.org/10.4155/ppa.15.33.

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Minami, Kanako, Nanami Ueda, Kaichi Ishimoto und Toshifumi Tsujiuchi. „Regulation of cell survival through free fatty acid receptor 1 (FFA1) and FFA4 induced by endothelial cells in osteosarcoma cells“. Journal of Receptors and Signal Transduction 40, Nr. 2 (06.02.2020): 181–86. http://dx.doi.org/10.1080/10799893.2020.1725047.

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Valenzuela, Pamela, Stefanie Teuber, Carolina Manosalva, Pablo Alarcón, Carlos D. Figueroa, Marcelo Ratto, Rafael A. Burgos und Maria A. Hidalgo. „Functional expression of the free fatty acids receptor-1 and -4 (FFA1/GPR40 and FFA4/GPR120) in bovine endometrial cells“. Veterinary Research Communications 43, Nr. 3 (11.06.2019): 179–86. http://dx.doi.org/10.1007/s11259-019-09758-8.

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Villegas-Comonfort, S., Y. Takei, G. Tsujimoto, A. Hirasawa und J. A. García-Sáinz. „Effects of arachidonic acid on FFA4 receptor: Signaling, phosphorylation and internalization“. Prostaglandins, Leukotrienes and Essential Fatty Acids 117 (Februar 2017): 1–10. http://dx.doi.org/10.1016/j.plefa.2017.01.013.

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Im, Dong-Soon. „Functions of omega-3 fatty acids and FFA4 (GPR120) in macrophages“. European Journal of Pharmacology 785 (August 2016): 36–43. http://dx.doi.org/10.1016/j.ejphar.2015.03.094.

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Li, Ang, Duxiao Yang, Mengyuan Zhu, Keng-chang Tsai, Kun-hong Xiao, Xiao Yu, Jinpeng Sun und Lupei Du. „Discovery of novel FFA4 (GPR120) receptor agonists with β-arrestin2-biased characteristics“. Future Medicinal Chemistry 7, Nr. 18 (Dezember 2015): 2429–37. http://dx.doi.org/10.4155/fmc.15.160.

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Liu, Jiaxiang, Chengsen Tian, Tianyu Jiang, Yuqi Gao, Yubin Zhou, Minyong Li und Lupei Du. „Discovery of the First Environment-Sensitive Fluorescent Probe for GPR120 (FFA4) Imaging“. ACS Medicinal Chemistry Letters 8, Nr. 4 (29.03.2017): 428–32. http://dx.doi.org/10.1021/acsmedchemlett.7b00023.

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Reininger, Laura, Marcus Flisher, Caroline Tremblay, Mélanie Ethier, Julien Ghislain, Mark O. Huising und Vincent Poitout. „FFA4 Regulates Insulin Secretion Via Inhibition of Somatostatin Secretion From Delta Cells“. Canadian Journal of Diabetes 46, Nr. 7 (November 2022): S31—S32. http://dx.doi.org/10.1016/j.jcjd.2022.09.093.

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Kytikova, O. Yu, T. P. Novgorodtseva, Yu K. Denisenko, M. V. Antonyuk und T. A. Gvozdenko. „Medium and long chain free fatty acid receptors in the pathophysiology of respiratory diseases“. Bulletin Physiology and Pathology of Respiration, Nr. 80 (16.07.2021): 115–28. http://dx.doi.org/10.36604/1998-5029-2021-80-115-128.

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Chronic inflammatory diseases of the respiratory tract, including asthma and chronic obstructive pulmonary disease, are a global problem of our time due to the widespread prevalence and difficulty of controlling the course. The mechanism of chronic inflammation in the bronchopulmonary system is closely related to metabolic disorders of lipids and their derivatives. Lipids and their mediators play both a pro-inflammatory and anti-inflammatory role in chronic inflammatory bronchopulmonary pathology. In particular, free fatty acids (FFAs) perform important signaling and regu latory functions in the body, coordinating metabolic and immune relationships. The mechanism that potentially binds FFAs and inflammatory reactions involves the activation of their receptors (FFAR – free fatty acid receptor), which are expressed on the cells of the respiratory tract, as well as on nerve and immune cells. Currently, FFARs are considered attractive targets in the treatment of chronic bronchopulmonary pathology, since modulation of their activity through the use of alimentary polyunsaturated fatty acids (PUFA) can affect the activity and resolution of neuroimmune inflammation in the bronchopulmonary system. However, controversial issues regarding their effectiveness and dose standardization of PUFA continue to limit their widespread use. This review summarizes the literature data on the role of medium- and longchain FFAs in the body’s immunoregulation in normal conditions and in chronic bronchopulmonary pathology. Data on medium and long chain FFA receptors – FFAR1 and FFAR4, FFAR-mediated signaling pathways in the regulation of metabolism and immune responses are systematized. The perspective and complex issues of the use of fatty acids in the treatment of chronic bronchopulmonary pathology are discussed.

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Lymperopoulos, Anastasios, Malka S. Suster und Jordana I. Borges. „Short-Chain Fatty Acid Receptors and Cardiovascular Function“. International Journal of Molecular Sciences 23, Nr. 6 (18.03.2022): 3303. http://dx.doi.org/10.3390/ijms23063303.

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Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders.

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Son, So-Eun, Nam-Jung Kim und Dong-Soon Im. „Development of Free Fatty Acid Receptor 4 (FFA4/GPR120) Agonists in Health Science“. Biomolecules & Therapeutics 29, Nr. 1 (01.01.2021): 22–30. http://dx.doi.org/10.4062/biomolther.2020.213.

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Liu, Hong-Da, Wen-bo Wang, Zhi-gang Xu, Chang-hong Liu, Dong-fang He, Lv-Pei Du, Min-Yong Li, Xiao Yu und Jin-peng Sun. „FFA4 receptor (GPR120): A hot target for the development of anti-diabetic therapies“. European Journal of Pharmacology 763 (September 2015): 160–68. http://dx.doi.org/10.1016/j.ejphar.2015.06.028.

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Al Mahri, Saeed, Shuja Shafi Malik, Maria Al Ibrahim, Esraa Haji, Ghida Dairi und Sameer Mohammad. „Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook“. Cells 11, Nr. 4 (21.02.2022): 750. http://dx.doi.org/10.3390/cells11040750.

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Fatty acids (FFAs) are important biological molecules that serve as a major energy source and are key components of biological membranes. In addition, FFAs play important roles in metabolic regulation and contribute to the development and progression of metabolic disorders like diabetes. Recent studies have shown that FFAs can act as important ligands of G-protein-coupled receptors (GPCRs) on the surface of cells and impact key physiological processes. Free fatty acid-activated receptors include FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids like acetate, propionate, and butyrate, whereas FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids like palmitate, oleate, linoleate, and others. FFARs have attracted considerable attention over the last few years and have become attractive pharmacological targets in the treatment of type 2 diabetes and metabolic syndrome. Several lines of evidence point to their importance in the regulation of whole-body metabolic homeostasis including adipose metabolism. Here, we summarize our current understanding of the physiological functions of FFAR isoforms in adipose biology and explore the prospect of FFAR-based therapies to treat patients with obesity and Type 2 diabetes.

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Patti, Angelo Maria, Rosaria Vincenza Giglio, Nikolaos Papanas, Dragos Serban, Anca Pantea Stoian, Kalliopi Pafili, Khalid Al Rasadi et al. „Experimental and Emerging Free Fatty Acid Receptor Agonists for the Treatment of Type 2 Diabetes“. Medicina 58, Nr. 1 (11.01.2022): 109. http://dx.doi.org/10.3390/medicina58010109.

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The current management of Type 2 Diabetes Mellitus (T2DM) includes incretin-based treatments able to enhance insulin secretion and peripheral insulin sensitivity as well as improve body mass, inflammation, plasma lipids, blood pressure, and cardiovascular outcomes. Dietary Free Fatty Acids (FFA) regulate metabolic and anti-inflammatory processes through their action on incretins. Selective synthetic ligands for FFA1-4 receptors have been developed as potential treatments for T2DM. To comprehensively review the available evidence for the potential role of FFA receptor agonists in the treatment of T2DM, we performed an electronic database search assessing the association between FFAs, T2DM, inflammation, and incretins. Evidence indicates that FFA1-4 agonism increases insulin sensitivity, induces body mass loss, reduces inflammation, and has beneficial metabolic effects. There is a strong inter-relationship between FFAs and incretins. FFA receptor agonism represents a potential target for the treatment of T2DM and may provide an avenue for the management of cardiometabolic risk in susceptible individuals. Further research promises to shed more light on this emerging topic.

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Hudson, Brian D., Bharat Shimpukade, Graeme Milligan und Trond Ulven. „The Molecular Basis of Ligand Interaction at Free Fatty Acid Receptor 4 (FFA4/GPR120)“. Journal of Biological Chemistry 289, Nr. 29 (24.05.2014): 20345–58. http://dx.doi.org/10.1074/jbc.m114.561449.

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Watterson, Kenneth R., Steffen V. F. Hansen, Brian D. Hudson, Elisa Alvarez-Curto, Sheikh Zahir Raihan, Carlos M. G. Azevedo, Gabriel Martin et al. „Probe-Dependent Negative Allosteric Modulators of the Long-Chain Free Fatty Acid Receptor FFA4“. Molecular Pharmacology 91, Nr. 6 (06.04.2017): 630–41. http://dx.doi.org/10.1124/mol.116.107821.

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Sparks, Steven M., Grace Chen, Jon L. Collins, Dana Danger, Steven T. Dock, Channa Jayawickreme, Stephen Jenkinson et al. „Identification of diarylsulfonamides as agonists of the free fatty acid receptor 4 (FFA4/GPR120)“. Bioorganic & Medicinal Chemistry Letters 24, Nr. 14 (Juli 2014): 3100–3103. http://dx.doi.org/10.1016/j.bmcl.2014.05.012.

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Lee, S. J. L., und I. Dong-Soon. „Omega-3 Polyunsaturated Fatty Acids Protect Endothelial Adhesion Of Monocytes Through Ffa4 In Monocytes“. Atherosclerosis 287 (August 2019): e237-e238. http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.729.

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Freitas, Raquel, und Maria M. Campos. „Protective Effects of Omega-3 Fatty Acids in Cancer-Related Complications“. Nutrients 11, Nr. 5 (26.04.2019): 945. http://dx.doi.org/10.3390/nu11050945.

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Omega-3 polyunsaturated fatty acids (PUFAs) are considered immunonutrients and are commonly used in the nutritional therapy of cancer patients due to their ample biological effects. Omega-3 PUFAs play essential roles in cell signaling and in the cell structure and fluidity of membranes. They participate in the resolution of inflammation and have anti-inflammatory and antinociceptive effects. Additionally, they can act as agonists of G protein-coupled receptors, namely, GPR40/FFA1 and GPR120/FFA4. Cancer patients undergo complications, such as anorexia-cachexia syndrome, pain, depression, and paraneoplastic syndromes. Interestingly, the 2017 European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines for cancer patients only discuss the use of omega-3 PUFAs for cancer-cachexia treatment, leaving aside other cancer-related complications that could potentially be managed by omega-3 PUFA supplementation. This critical review aimed to discuss the effects and the possible underlying mechanisms of omega-3 PUFA supplementation in cancer-related complications. Data compilation in this critical review indicates that further investigation is still required to assess the factual benefits of omega-3 PUFA supplementation in cancer-associated illnesses. Nevertheless, preclinical evidence reveals that omega-3 PUFAs and their metabolites might modulate pivotal pathways underlying complications secondary to cancer, indicating that this is a promising field of knowledge to be explored.

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Grundmann, Manuel, Eckhard Bender, Jens Schamberger und Frank Eitner. „Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators“. International Journal of Molecular Sciences 22, Nr. 4 (10.02.2021): 1763. http://dx.doi.org/10.3390/ijms22041763.

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The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of marketed GPCR drugs interact exclusively with the orthosteric binding site, allosteric mechanisms in GPCR biology stay medically underexploited, with only several allosteric ligands currently approved. This review summarizes the current knowledge on the biology of FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), FFAR4 (GPR120), and GPR84, including structural aspects of FFAR1, and discusses the molecular pharmacology of FFAR allosteric ligands as well as the opportunities and challenges in research from the perspective of drug discovery.

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Ulven, Trond, und Elisabeth Christiansen. „Dietary Fatty Acids and Their Potential for Controlling Metabolic Diseases Through Activation of FFA4/GPR120“. Annual Review of Nutrition 35, Nr. 1 (17.07.2015): 239–63. http://dx.doi.org/10.1146/annurev-nutr-071714-034410.

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Kang, Saeromi, Jin Huang, Bo-Kyung Lee, Young-Suk Jung, Eunok Im, Jung-Min Koh und Dong-Soon Im. „Omega-3 polyunsaturated fatty acids protect human hepatoma cells from developing steatosis through FFA4 (GPR120)“. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1863, Nr. 2 (Februar 2018): 105–16. http://dx.doi.org/10.1016/j.bbalip.2017.11.002.

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Im, Dong-Soon. „FFA4 (GPR120) as a fatty acid sensor involved in appetite control, insulin sensitivity and inflammation regulation“. Molecular Aspects of Medicine 64 (Dezember 2018): 92–108. http://dx.doi.org/10.1016/j.mam.2017.09.001.

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Senatorov, Ilya S., und Nader H. Moniri. „The role of free-fatty acid receptor-4 (FFA4) in human cancers and cancer cell lines“. Biochemical Pharmacology 150 (April 2018): 170–80. http://dx.doi.org/10.1016/j.bcp.2018.02.011.

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Son, So-Eun, Jung-Min Koh und Dong-Soon Im. „Free fatty acid receptor 4 (FFA4) activation attenuates obese asthma by suppressing adiposity and resolving metaflammation“. Biomedicine & Pharmacotherapy 174 (Mai 2024): 116509. http://dx.doi.org/10.1016/j.biopha.2024.116509.

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Liu, Ze, Mandi M. Hopkins, Zhihong Zhang, Chrystal B. Quisenberry, Louise C. Fix, Brianna M. Galvan und Kathryn E. Meier. „Omega-3 Fatty Acids and Other FFA4 Agonists Inhibit Growth Factor Signaling in Human Prostate Cancer Cells“. Journal of Pharmacology and Experimental Therapeutics 352, Nr. 2 (09.12.2014): 380–94. http://dx.doi.org/10.1124/jpet.114.218974.

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Xu, Fangfang, Yaopeng Zhao, Han Zhou, Chunzhi Li, Xiuli Zhang, Tao Hou, Lala Qu et al. „Synthesis and evaluation of 3-(4-(phenoxymethyl)phenyl)propanoic acid and N-phenylbenzenesulfonamide derivatives as FFA4 agonists“. Bioorganic & Medicinal Chemistry Letters 30, Nr. 24 (Dezember 2020): 127650. http://dx.doi.org/10.1016/j.bmcl.2020.127650.

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