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Insulin resistance is common with aging and is associated with the inflammatory response in both humans and rodents. A number of peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists have been tested for their abilities to attenuate insulin resistance and type 2 diabetes. However, there is no study on the effects of PPARα/γ dual agonists on inflammation and insulin resistance during aging. In the present study, we investigated the ability of 2-[4-(5-chlorobenzothiazothiazol-2-yl)phenoxy]-2-methyl-propionic acid (MHY908), a newly synthesized novel PPARα/γ dual agonist, to suppress the inflammatory response and attenuate insulin resistance in aged rats. Twenty-month-old rats were divided into four groups: ad libitum fed, ad libitum fed supplemented with MHY908 (1 mg and 3 mg/kg/day for 4 weeks), and 40% calorie restricted. Six-month-old ad libitum fed rats were used as an age control. The aged rats supplemented with MHY908 showed reduced serum glucose, triglyceride, and insulin levels, as well as reduced liver triglyceride levels. MHY908 brought about a reduction in endoplasmic reticulum stress and activation of the c-Jun N-terminal kinase in the livers of aged rats, which consequently improved insulin signaling. In the kidneys of aged rats, the efficacy of MHY908 as a potent anti-inflammatory agent was shown by its suppression of NF-κB activation through inhibition of the Akt/IκB kinase signaling pathway. Therefore, the major finding of this study is that MHY908 acts as a therapeutic agent against age-related inflammation associated with insulin resistance by activating PPARα and PPARγ, thus attenuating endoplasmic reticulum stress., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In order to ensure prolonged pharmacokinetic profile along with local tolerability at the injection site, tricaprylin‐based drug crystalline suspension (TS) was designed and its local distribution, pharmacokinetics, and inflammatory response, were evaluated with conventional aqueous suspension (AS). As model drug particles, entecavir 3‐palmitate (EV‐P), an ester lipidic prodrug for entecavir (EV), was employed. The EV‐P‐loaded TS was prepared by ultra‐sonication method. Prepared TS and conventional AS exhibited comparable morphology (rod or rectangular), median diameter (2.7 and 2.6 μm), crystallinity (melting point of 160–165°C), and in vitro dissolution profile. However, in vivo performances of drug microparticles were markedly different, depending on delivery vehicle. At AS‐injected site, drug aggregates of up to 500 μm were formed upon intramuscular injection, and were surrounded with inflammatory cells and fibroblastic bands. In contrast, no distinct particle aggregation and adjacent granulation was observed at TS‐injected site, with >4 weeks remaining of the oily vehicle in micro‐computed tomographic observation. Surprisingly, TS exhibited markedly alleviated local inflammation compared to AS, endowing markedly lessened necrosis, fibrosis thickness, inflammatory area, and macrophage infiltration. The higher initial systemic exposure was observed with TS compared to AS, but TS provided prolonged delivery of EV for 3 weeks. Therefore, we suggest that the novel TS system can be a promising tool in designing parenteral long‐acting delivery, with improved local tolerability. [ABSTRACT FROM AUTHOR]

Insulin resistance is common with aging and is associated with the inflammatory response in both humans and rodents. A number of peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists have been tested for their abilities to attenuate insulin resistance and type 2 diabetes. However, there is no study on the effects of PPARα/γ dual agonists on inflammation and insulin resistance during aging. In the present study, we investigated the ability of 2-[4-(5-chlorobenzothiazothiazol-2-yl)phenoxy]-2-methyl-propionic acid (MHY908), a newly synthesized novel PPARα/γ dual agonist, to suppress the inflammatory response and attenuate insulin resistance in aged rats. Twenty-month-old rats were divided into four groups: ad libitum fed, ad libitum fed supplemented with MHY908 (1 mg and 3 mg/kg/day for 4 weeks), and 40% calorie restricted. Six-month-old ad libitum fed rats were used as an age control. The aged rats supplemented with MHY908 showed reduced serum glucose, triglyceride, and insulin levels, as well as reduced liver triglyceride levels. MHY908 brought about a reduction in endoplasmic reticulum stress and activation of the c-Jun N-terminal kinase in the livers of aged rats, which consequently improved insulin signaling. In the kidneys of aged rats, the efficacy of MHY908 as a potent anti-inflammatory agent was shown by its suppression of NF-κB activation through inhibition of the Akt/IκB kinase signaling pathway. Therefore, the major finding of this study is that MHY908 acts as a therapeutic agent against age-related inflammation associated with insulin resistance by activating PPARα and PPARγ, thus attenuating endoplasmic reticulum stress. [ABSTRACT FROM AUTHOR]

Ultraviolet B (UVB; 290~320nm) irradiation-induced lipid peroxidation induces inflammatory responses that lead to skin wrinkle formation and epidermal thickening. Peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists have the potential to be used as anti-wrinkle agents because they inhibit inflammatory response and lipid peroxidation. In this study, we evaluated the function of 2-bromo-4-(5-chloro-benzo[d]thiazol-2-yl) phenol (MHY 966), a novel synthetic PPAR α/γ dual agonist, and investigated its anti-inflammatory and anti-lipid peroxidation effects. The action of MHY 966 as a PPAR α/γ dual agonist was also determined in vitro by reporter gene assay. Additionally, 8-week-old melanin-possessing hairless mice 2 (HRM2) were exposed to 150 mJ/cm2 UVB every other day for 17 days and MHY 966 was simultaneously pre-treated every day for 17 days to investigate the molecular mechanisms involved. MHY 966 was found to stimulate the transcriptional activities of both PPAR α and γ. In HRM2 mice, we found that the skins of mice exposed to UVB showed significantly increased pro-inflammatory mediator levels (NF-κB, iNOS, and COX-2) and increased lipid peroxidation, whereas MHY 966 co-treatment down-regulated these effects of UVB by activating PPAR α and γ. Thus, the present study shows that MHY 966 exhibits beneficial effects on inflammatory responses and lipid peroxidation by simultaneously activating PPAR α and γ. The major finding of this study is that MHY 966 demonstrates potential as an agent against wrinkle formation associated with chronic UVB exposure. [ABSTRACT FROM AUTHOR]