Till the 21 st century, fatty acids were considered as merely building blocks for triglycerides, phospholipids, or cholesteryl esters. However, the discovery of G protein-coupled receptors (GPCRs) for free fatty acids at the beginning of the 21 st century challenged that idea and paved way for a new field of research, merged into the field of receptor pharmacology for intercellular lipid mediators. Among the GPCRs for free fatty acids, free fatty acid receptor 4 (FFA4, also known as GPR120) recognizes long-chain polyunsaturated fatty acids such as DHA and EPA. It is significant in drug discovery because it regulates obesity-induced metaflammation and GLP-1 secretion. Our study reviews information on newly developed FFA4 agonists and their application in pathophysiologic studies and drug discovery. It also offers a potency comparison of the FFA4 agonists in an AP-TGF-α shedding assay.
High dose intake of docosahexaenoic acid showed beneficial effects on atopic dermatitis in patients and was found to increase regulatory T cells in mice, but its molecular target has not been identified. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor sensing polyunsaturated long-chain fatty acids including docosahexaenoic acid. In the present study, we examined whether FFA4 acted as a therapeutic target of docosahexaenoic acid for treating atopic dermatitis. Experimental atopic dermatitis was induced in mice by 2,4-dinitrochlorobenzene (DNCB) sensitization on day 0, followed by repeated DNCB challenges from D7 to D48. The mice were treated with a selective agonist compound A (30 mg· kg −1 · d −1 , ip) from D19 to D48, and sacrificed on D49. We found that DNCB-induced atopic dermatitis-like skin lesions, i.e. hypertrophy and mast cell infiltration in skin tissues, as well as markedly elevated serum IgE levels. Administration of compound A significantly suppressed the atopic responses in ears and lymph nodes, such as hypertrophy and mast cell infiltration in the ears, enlarged sizes of lymph nodes, and elevated serum IgE and levels of cytokines IL-4, IL-13, IL-17, and IFN-γ in ear tissue. The therapeutic effects of compound A were abolished by FFA4 knockout. Similarly, increased CD4 + Foxp3 + regulatory T-cell population in lymph nodes was observed in wide-type mice treated with compound A, but not seen in FFA4-deficient mice. In conclusion, we demonstrate that activation of FFA4 ameliorates atopic dermatitis by increasing CD4 + Foxp3 + regulatory T cells, suggesting FFA4 as a therapeutic target for atopic dermatitis.
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.
The present study describes the development of a wearable device designed to assist those who work in an unstructured posture. In the manufacturing sector, industrial accidents have been steadily on the rise due to poor work environments and excessive workloads imposed on workers. Against this backdrop, the present study aimed to analyze various types of work, especially those performed in unstructured postures by heavy industry workers, who are frequently exposed to high workloads and poor work environments. Based on the analysis results, an attempt was made to develop a shoulder muscle-assistive wearable device capable of assisting a wearer who is working using their shoulder muscles. Various types of unstructured posture work are performed in heavy industries, including activities such as the welding and grinding of ship components and plant structures. They are typically conducted in narrow spaces with limited postures, causing many workers to suffer muscle fatigue. In the present study, as the first step of developing a shoulder muscle-assistive wearable device, different working scenarios were simulated, and the corresponding motion data and required torque values were estimated using motion capture devices. The obtained motion data and required torque values were reflected in the design of the wearable device. The main structural body of the shoulder muscle-assistive wearable device was made of a carbon fiber-reinforced composite to be lightweight. This shoulder muscle-assistive wearable device was designed to fully cover the range of motion for workers working in unstructured postures while generating the torque required for a given job, thereby enhancing the muscular endurance of the workers. The gravity compensation module of the designed shoulder muscle-assistive wearable device generates a support force of 4.47 Nm per shoulder. The shoulder muscle assistive wearable device was developed to provide support for approximately 30% of the shoulder joint’s maximum torque generated in overhead tasks. This shoulder muscle-assistive wearable device is expected to contribute to improving the productivity of field workers, while reducing the occurrence of musculoskeletal injuries arising from the aging of the working-age population.
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