The prostaglandin (PG) EP 4 receptor subtype is expressed by peripheral sensory neurons. Although a potential role of EP 4 receptor in pain has been suggested, a limited number of selective ligands have made it difficult to explore the physiological functions of EP 4 or its potential as a new analgesic target. Here, we describe the in vitro and in vivo pharmacology of a novel EP 4 receptor antagonist, N- [({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors are mainstays of the pharmacopoeia for the treatment of signs and symptoms of osteoarthritis and inflammatory pain of various etiologies. Their mechanism of action is to decrease prostaglandin (PG) synthesis by inhibiting COX activities. Two isoforms of COX, COX-1 and COX-2, have been identified. COX-1 is constitutively expressed throughout the body, and it is thought to play an essential role in normal gastrointestinal and renal function, whereas COX-2 is induced in the presence of inflammation. NSAIDs inhibit both isoforms and inhibition of COX-1 is thought to cause the adverse gastrointestinal effects such as gastric erosion, ulceration, and hemorrhage, whereas inhibition of COX-2 is associated with the therapeutic effects of NSAIDs. Thus, inhibition of PG synthesis by NSAIDs has demonstrated clear efficacy in the reduction of K.N. and A.M. contributed equally to this work. Article, publication date, and citation information can be found at
Brown rice is known to improve glucose intolerance and prevent the onset of diabetes. However, the underlying mechanisms remain obscure. In the current study, we investigated the effect of brown rice and its major component, γ-oryzanol (Orz), on feeding behavior and fuel homeostasis in mice. When mice were allowed free access to a brown rice–containing chow diet (CD) and a high-fat diet (HFD), they significantly preferred CD to HFD. To reduce hypothalamic endoplasmic reticulum (ER) stress on an HFD, mice were administered with 4-phenylbutyric acid, a chemical chaperone, which caused them to prefer the CD. Notably, oral administration of Orz, a mixture of major bioactive components in brown rice, also improved glucose intolerance and attenuated hypothalamic ER stress in mice fed the HFD. In murine primary neuronal cells, Orz attenuated the tunicamycin-induced ER stress. In luciferase reporter assays in human embryonic kidney 293 cells, Orz suppressed the activation of ER stress–responsive cis-acting elements and unfolded protein response element, suggesting that Orz acts as a chemical chaperone in viable cells. Collectively, the current study is the first demonstration that brown rice and Orz improve glucose metabolism, reduce hypothalamic ER stress, and, consequently, attenuate the preference for dietary fat in mice fed an HFD.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.