15-Keto-PGE2 acts as a biased/partial agonist to terminate PGE2-evoked signaling.

Prostaglandin E2 (PGE2) is well-known as an endogenous proinflammatory prostanoid synthesized from arachidonic acid by the activation of cyclooxygenase-2. E type prostanoid (EP) receptors are cognates for PGE2 that have four main subtypes: EP1 to EP4. Of these, the EP2 and EP4 prostanoid receptors have been shown to couple to Gαs-protein and can activate adenylyl cyclase to form cAMP. Studies suggest that EP4 receptors are involved in colorectal homeostasis and cancer development, but further work is needed to identify the roles of EP2 receptors in these functions. After sufficient inflammation has been evoked by PGE2, it is metabolized to 15-keto-PGE2 Thus, 15-keto-PGE2 has long been considered an inactive metabolite of PGE2 However, it may have an additional role as a biased and/or partial agonist capable of taking over the actions of PGE2 to gradually terminate reactions. Here, using cell-based experiments and in silico simulations, we show that PGE2-activated EP4 receptor-mediated signaling may evoke the primary initiating reaction of the cells, which would take over the 15-keto-PGE2-activated EP2 receptor-mediated signaling after PGE2 is metabolized to 15-keto-PGE2 The present results shed light on new aspects of 15-keto-PGE2, which may have important roles in passing on activities to EP2 receptors from PGE2-stimulated EP4 receptors as a "switched agonist." This novel mechanism may be significant for gradually terminating PGE2-evoked inflammation and/or maintaining homeostasis of colorectal tissues/cells functions.

Twelve-week physical and leisure activity programme improved cognitive function in community-dwelling elderly subjects: a randomized controlled trial.

BACKGROUND: Japan is one of the most rapidly ageing societies in the world. A number of municipalities have started services for the prevention of cognitive decline for community-dwelling elderly individuals, but the effectiveness of these services is currently insufficient. Our study explored the efficacy of a comprehensive intervention programme consisting of physical and leisure activities to prevent cognitive decline in community-dwelling elderly subjects. METHOD: We administered a 12-week intervention programme consisting of physical and leisure activities aimed at enhancing participants' motivation to participate and support one another by providing a pleasant atmosphere, empathetic communication, praise, and errorless support. This programme for the prevention of cognitive decline was conducted as a service by the city of Maebashi. All participants underwent the Five-Cog test, which evaluated the cognitive domains of attention, memory, visuospatial function, language, and reasoning. Executive function was evaluated by the Wechsler Digit Symbol Substitution Test and Yamaguchi Kanji-Symbol Substitution Test. Subjective health status, level of social support, functional capacity, subjective quality of life, and depressive symptoms were assessed with a questionnaire. Grip strength test, timed up-and-go test, 5-m maximum walking times test, and functional reach test were performed to evaluate physical function. Fifty-two participants were randomly allocated to intervention (n = 26) and control (n = 26) groups. Twenty-six participants, aged between 65-87 years, received intervention once a week at a community centre. The programme was conducted by health-care professionals, with the help of senior citizen volunteers. RESULTS: The intervention group (n = 19) showed significant improvement on the analogy task of the Five-Cog test (F(1,38) = 4.242, P = 0.046) and improved quality of life (F(1,38) = 4.773, P = 0.035) as compared to the control group (n = 24). CONCLUSION: A community-based 12-week intervention programme that aimed to enhance motivation to participate in activities resulted in improvements in some aspects of cognitive function and quality of life. Senior citizens who volunteered in the present intervention enabled the smooth implementation of the programme and alleviated the burden on professional staff.

Association of Yersinia Infection With Kawasaki Disease: A Prospective Multicenter Cohort Study.

BACKGROUND: Yersinia infection is known to present with Kawasaki disease (KD)-like symptoms although differentiating the 2 has been a challenge. The present study aimed to describe the clinical characteristics and prevalence of Yersinia infection presenting with KD-like symptoms. METHODS: The present, prospective, multicenter study enrolled patients who received a diagnosis of KD between January 2021 and January 2022 at 2 hospitals in Tokyo. Stool samples were collected within 3 days of the start of KD treatment, and cultures were performed for Yersinia . Clinical history and symptoms suggestive of Yersinia infection were also evaluated. RESULTS: During the study period, 141 KD patients were screened and 117 patients with evaluable stool samples were registered. Only 1 patient was positive for Yersinia pseudotuberculosis , which was detected from both stool and blood cultures. The patient was refractory to KD treatment but improved after initiation of appropriate antibiotic therapy. CONCLUSIONS: Routine screening for Yersinia is not appropriate for patients with KD and should be limited to certain patients in high-risk areas and those who are refractory to the standard KD treatment.

Cellular density-dependent increases in HIF-1α compete with c-Myc to down-regulate human EP4 receptor promoter activity through Sp-1-binding region.

The up-regulated expression of E-type prostanoid (EP) 4 receptors has been implicated in carcinogenesis; however, the expression of EP4 receptors has also been reported to be weaker in tumor tissues than in normal tissues. Indeed, EP4 receptors have been suggested to play a role in the maintenance of colorectal homeostasis. This study aimed to examine the underlying mechanisms/reasons for why inconsistent findings have been reported regarding EP4 receptor expression levels in homeostasis and carcinogenesis by focusing on cellular densities. Thus, the human colon cancer HCA-7 cells, which retain some functional features of normal epithelia, and luciferase reporter genes containing wild-type or mutated EP4 receptor promoters were used for elucidating the cellular density-dependent mechanisms about the regulation of EP4 receptor expression. In silico analysis was also utilized for confirming the relevance of the findings with respect to colon cancer development. We here demonstrated that the expression of EP4 receptors was up-regulated by c-Myc by binding to Sp-1 under low cellular density conditions, but was down-regulated under high cellular density conditions via the increase in the expression levels of HIF-1α protein, which may pull out c-Myc and Sp-1 from DNA-binding. The tightly regulated EP4 receptor expression mechanism may be a critical system for maintaining homeostasis in normal colorectal epithelial cells. Therefore, once the system is altered, possibly due to the transient overexpression of EP4 receptors, it may result in aberrant cellular proliferation and transformation to cancerous phenotypes. However, at the point, EP4 receptors themselves and their mediated homeostasis would be no longer required.

PGE1 and E3 show lower efficacies than E2 to ß-catenin-mediated activity as biased ligands of EP4 prostanoid receptors.

The 2-series of prostaglandin E (PGE2 ) is regarded as a pro-cancer prostanoid, whereas the 1-series (PGE1 ) and the 3-series (PGE3 ) are considered to act as anti-cancer prostanoids. In the present study, we provide possible reasons why PGE1 and PGE3 , but not PGE2 , exert anti-cancer effects by focusing on each diverged E-type prostanoid (EP)4 receptor-mediated signaling pathway. PGE1 , PGE2 and PGE3 function as full agonists in terms of Gαs - and Gαi -protein-mediated signaling. However, PGE1 and PGE3 function as partial agonists of T-cell factor (TCF)/ß-catenin (ß-cat)-mediated activity, the well-known cancer-related signaling pathway. Furthermore, pretreatment with PGE1 or PGE3 almost completely reduces PGE2 -induced TCF/ß-cat activity. These results provide a plausible reason why PGE1 and PGE3 function as anti-cancer prostanoids as a result of novel biased activity for EP4 receptors.

Prostaglandin E2-stimulated prostanoid EP4 receptors induce prolonged de novo prostaglandin E2 synthesis through biphasic phosphorylation of extracellular signal-regulated kinases mediated by activation of protein kinase A in HCA-7 human colon cancer cells.

Approximately two decades have passed since E-type prostanoid 4 (EP4) receptors were cloned, and the signaling pathways mediated by these receptors have since been implicated in cancer development through the alliance of Gαi-protein/phosphatidylinositol 3-kinase (PI3K)/extracellular signal-regulated kinases (ERKs) activation. Although prostanoid EP4 receptors were initially identified as Gαs-coupled receptors, the specific/distinctive role(s) of prostanoid EP4 receptor-induced cAMP/protein kinase A (PKA) pathways in cancer development have not yet been elucidated in detail. We previously reported using HCA-7 human colon cancer cells that prostaglandin E2 (PGE2)-stimulated prostanoid EP4 receptors induced cyclooxygenase-2 (COX-2) as an initiating event in development of colon cancer. Moreover, this induction of COX-2 was mediated by transactivation of epidermal growth factor (EGF) receptors. However, direct activation of EGF receptors by EGF also induced similar amounts of COX-2 in this cell line. Thus, the emergence of unique role(s) for prostanoid EP4 receptors is expected by clarifying the different signaling mechanisms between PGE2-stimulated prostanoid EP4 receptors and EGF-stimulated EGF receptors to induce COX-2 and produce PGE2. We here demonstrated that prostanoid EP4 receptor activation by PGE2 in HCA-7 cells led to PKA-dependent re-activation of ERKs, which resulted in prolonged de novo synthesis of PGE2. Although EGF-stimulated EGF receptors in cells also induced COX-2 and the de novo synthesis of PGE2, the activation of this pathway was transient and not mediated by PKA. Therefore, the novel mechanism underlying prolonged de novo synthesis of PGE2 has provided an insight into the importance of prostanoid EP4 receptor-mediated Gαs-protein/cAMP/PKA pathway in development of colon cancer.