Serious Game for Change in Behavioral Intention Toward Lifestyle-Related Diseases: Experimental Study With Structural Equation Modeling Using the Theory of Planned Behavior.

BACKGROUND: Health activities should be tailored to individual lifestyles and values. To raise awareness of health behaviors, various practices related to health education, such as interactive activities among individuals with different backgrounds, have been developed. Moreover, serious games have been used as a tool for facilitating communication. However, there have been few investigations that are based on the framework of the theory of planned behavior on the mechanisms of health-related behavioral intention change from playing serious games. OBJECTIVE: We aimed to investigate the mechanisms of behavioral intention change among various age groups after an intervention using a serious game to increase awareness of lifestyle-related diseases. METHODS: Adults, undergraduates, and high school students played a serious game, called Negotiation Battle, and answered a questionnaire-Gaming Event Assessment Form for Lifestyle-related Diseases-before, immediately after, and 2-4 weeks after the game. The questionnaire was composed of 16 items based on the theory of planned behavior. We used structural equation modeling to compare responses from the 3 groups. RESULTS: For all 3 age groups (adults: mean 43.4 years, range 23-67 years; undergraduates: mean 20.9 years, range 19-34 years; high school students: mean 17.9 years, 17-18 years), perceived behavior control was the key factor of behavioral intention change. Immediately after the game, causal relationships between perceived behavioral control and behavioral intention were enhanced or maintained for all groups-adults (before: path coefficient 1.030, P<.001; after: path coefficient 2.045, P=.01), undergraduates (before: path coefficient 0.568, P=.004; after: path coefficient 0.737, P=.001), and high school students (before: path coefficient 14.543, P=.97; after: path coefficient 0.791, P<.001). Analysis of free descriptions after intervention suggested that experiencing dilemma is related to learning and behavioral intention. CONCLUSIONS: The study revealed that the serious game changed the behavioral intention of adolescents and adults regarding lifestyle-related diseases, and changes in perceived behavioral control mediated the alteration mechanism.

F4/80+ Macrophages Contribute to Clearance of Senescent Cells in the Mouse Postpartum Uterus.

Cellular senescence, defined as an irreversible cell cycle arrest, exacerbates the tissue microenvironment. Our previous study demonstrated that mouse uterine senescent cells were physiologically increased according to gestational days and that their abnormal accumulation was linked to the onset of preterm delivery. We hypothesized that there is a mechanism for removal of senescent cells after parturition to maintain uterine function. In the current study, we noted abundant uterine senescent cells and their gradual disappearance in wild-type postpartum mice. F4/80+ macrophages were present specifically around the area rich in senescent cells. Depletion of macrophages in the postpartum mice using anti-F4/80 antibody enlarged the area of senescent cells in the uterus. We also found excessive uterine senescent cells and decreased second pregnancy success rate in a preterm birth model using uterine p53-deleted mice. Furthermore, a decrease in F4/80+ cells and an increase in CD11b+ cells with a senescence-associated inflammatory microenvironment were observed in the p53-deleted uterus, suggesting that uterine p53 deficiency affects distribution of the macrophage subpopulation, interferes with senescence clearance, and promotes senescence-induced inflammation. These findings indicate that the macrophage is a key player in the clearance of uterine senescent cells to maintain postpartum uterine function.

STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation.

Although a close connection between uterine regeneration and successful pregnancy in both humans and mice has been consistently observed, its molecular basis remains unclear. We here established a mouse model of decellularized uterine matrix (DUM) transplantation. Resected mouse uteri were processed with SDS to make DUMs without any intact cells. DUMs were transplanted into the mouse uteri with artificially induced defects, and all the uterine layers were recovered at the DUM transplantation sites within a month. In the regenerated uteri, normal hormone responsiveness in early pregnancy was observed, suggesting the regeneration of functional uteri. Uterine epithelial cells rapidly migrated and formed a normal uterine epithelial layer within a week, indicating a robust epithelial-regenerating capacity. Stromal and myometrial regeneration occurred following epithelial regeneration. In ovariectomized mice, uterine regeneration of the DUM transplantation was similarly observed, suggesting that ovarian hormones are not essential for this regeneration process. Importantly, the regenerating epithelium around the DUM demonstrated heightened STAT3 phosphorylation and cell proliferation, which was suppressed in uteri of Stat3 conditional knockout mice. These data suggest a key role of STAT3 in the initial step of the uterine regeneration process. The DUM transplantation model is a powerful tool for uterine regeneration research.

MicroRNA-200a locally attenuates progesterone signaling in the cervix, preventing embryo implantation.

Although cervical pregnancy and placenta previa, in which the embryo and placenta embed in or adjacent to the cervix, are life-threatening complications that result in massive bleeding and poor pregnancy outcomes in women, the incidence of these aberrant conditions is uncommon. We hypothesized that a local molecular mechanism is normally in place to prevent embryo implantation in the cervix. The ovarian hormones progesterone (P(4)) and estrogen differentially direct differentiation and proliferation of endometrial cells, which confers the receptive state for implantation: P(4) dominance causes differentiation of the luminal epithelium but increases stromal cell proliferation in preparation of the uterus for implantation. In search for the cause of cervical nonresponsiveness to implantation, we found that the statuses of cell proliferation and differentiation between the uterus and cervix during early pregnancy are remarkably disparate under identical endocrine milieu in both mice and humans. We also found that cervical levels of progesterone receptor (PR) protein are low compared with uterine levels during this period, and the low PR protein levels are attributed to elevated levels of microRNA(miR)-200a in the cervix. These changes were associated with up-regulation of the P(4)-metabolizing enzyme 20α-hydroxysteroid dehydrogenase (200α-HSD) and down-regulation of its transcriptional repressor signal transducer and activator of transcription 5 in the cervix. The results provide evidence that elevated levels of miR-200a lead to down-regulation of P(4)-PR signaling and up-regulation of (200α-HSD) in the cervix, rendering it nonresponsive to implantation. These findings may point toward not only the physiological but also the pathological basis of the cervical milieu in embryo implantation.

Combinatory approaches prevent preterm birth profoundly exacerbated by gene-environment interactions.

There are currently more than 15 million preterm births each year. We propose that gene-environment interaction is a major contributor to preterm birth. To address this experimentally, we generated a mouse model with uterine deletion of Trp53, which exhibits approximately 50% incidence of spontaneous preterm birth due to premature decidual senescence with increased mTORC1 activity and COX2 signaling. Here we provide evidence that this predisposition provoked preterm birth in 100% of females exposed to a mild inflammatory insult with LPS, revealing the high significance of gene-environment interactions in preterm birth. More intriguingly, preterm birth was rescued in LPS-treated Trp53-deficient mice when they were treated with a combination of rapamycin (mTORC1 inhibitor) and progesterone (P4), without adverse effects on maternal or fetal health. These results provide evidence for the cooperative contributions of two sites of action (decidua and ovary) toward preterm birth. Moreover, a similar signature of decidual senescence with increased mTORC1 and COX2 signaling was observed in women undergoing preterm birth. Collectively, our findings show that superimposition of inflammation on genetic predisposition results in high incidence of preterm birth and suggest that combined treatment with low doses of rapamycin and P4 may help reduce the incidence of preterm birth in high-risk women.

Uterine receptivity and embryo-uterine interactions in embryo implantation: lessons from mice.

Implantation is a process of the first feto-maternal encounter in the uterus. A competent blastocyst and a receptive uterus are critical for successful implantation. For an acquisition of uterine receptivity, the following conditions need to be satisfied in the uterine environments: the endometrial preparation with stromal proliferation and epithelial differentiation in the pre-receptive phase and proper interactions between the uterus and blastocyst later in the phase. Focusing on these points and primarily referring to the mouse in vivo evidence, this review article has shown detailed molecular mechanisms for successful implantation.

Estrogen-dependent uterine secretion of osteopontin activates blastocyst adhesion competence.

Embryo implantation is a highly orchestrated process that involves blastocyst-uterine interactions. This process is confined to a defined interval during gestation referred to as the "window of embryo implantation receptivity". In mice this receptive period is controlled by ovarian estrogen and involves a coordination of blastocyst adhesion competence and uterine receptivity. Mechanisms coordinating the acquisition of blastocyst adhesion competence and uterine receptivity are largely unknown. Here, we show that ovarian estrogen indirectly regulates blastocyst adhesion competence. Acquisition of blastocyst adhesion competence was attributed to integrin activation (e.g. formation of adhesion complexes) rather than de novo integrin synthesis. Osteopontin (OPN) was identified as an estrogen-dependent uterine endometrial gland secretory factor responsible for activating blastocyst adhesion competence. Increased adhesion complex assembly in OPN-treated blastocysts was mediated through focal adhesion kinase (FAK)- and phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways. These findings define for the first time specific regulatory components of an estrogen-dependent pathway coordinating blastocyst adhesion competence and uterine receptivity.