B(a)P induces ovarian granulosa cell apoptosis via TRAF2-NFκB-Caspase1 axis during early pregnancy.

Benzo(a)pyrene [B(a)P] is an environmental endocrine disruptor with reproductive toxicity. The corpus luteum (CL) of the ovary plays an important role in embryo implantation and pregnancy maintenance. Our previous studies have shown that B(a)P exposure affects embryo implantation and endometrial decidualization in mouse, but its effects and mechanisms on CL function remain unclear. In this study, we explore the mechanism of ovarian toxicity of B(a)P using a pregnant mouse model and an in vitro model of human ovarian granulosa cells (GCs) KGN. Pregnant mice were gavaged with corn oil or 0.2 mg/kg.bw B(a)P from pregnant day 1 (D1) to D7, while KGN cells were treated with DMSO, 1.0IU/mL hCG, or 1.0IU/mL hCG plus benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), a B(a)P metabolite. Our findings revealed that B(a)P exposure damaged embryo implantation and reduced estrogen and progesterone levels in early pregnant mice. Additionally, in vitro, BPDE impaired luteinization in KGN cells. We observed that B(a)P/BPDE promoted oxidative stress (OS) and inflammation, leading to apoptosis rather than pyroptosis in ovaries and luteinized KGN cells. This apoptotic response was mediated by the activation of inflammatory Caspase1 through the cleavage of BID. Furthermore, B(a)P/BPDE inhibited TRAF2 expression and suppressed NFκB signaling pathway activation. The administration of VX-765 to inhibit the Caspase1 activation, over-expression of TRAF2 using TRAF2-pcDNA3.1 (+) plasmid, and BetA-induced activation of NFκB signaling pathway successfully alleviated BPDE-induced apoptosis and cellular dysfunction in luteinized KGN cells. These findings were further confirmed in the KGN cell treated with H2O2 and NAC. In conclusion, this study elucidated that B(a)P/BPDE induces apoptosis rather than pyroptosis in GCs via TRAF2-NFκB-Caspase1 during early pregnancy, and highlighting OS as the primary contributor to B(a)P/BPDE-induced ovarian toxicity. Our results unveil a novel role of TRAF2-NFκB-Caspase1 in B(a)P-induced apoptosis and broaden the understanding of mechanisms underlying unexplained luteal phase deficiency.

Physical Activity Intervention for Leisure-Time Activity Levels Among Older Adults: A Cluster Randomized Trial.

Importance: Current randomized trial evidence of the effects of physical activity interventions in older adults is mainly from developed countries, with little reliable evidence from low- and middle-income countries, such as China, where race, culture, and lifestyles differ substantially from those in Western populations. Objective: To evaluate the effects of a multilevel intervention for increasing leisure-time activity levels in Chinese older adults. Design, Setting, and Participants: This cluster randomized trial was conducted from May 2021 to May 2023, including an 8-week intervention period and a follow-up period of 24 months. Eight villages in China were randomly assigned to the intervention (4 villages) or the control (4 villages) group. Potentially eligible participants were 60 years or older. A total of 511 older adults from the selected 8 villages were enrolled. Interventions: The intervention group received an 8-week socioecological model-based intervention, comprising individual, interpersonal, and community-level components, whereas the control group did not. Main Outcome and Measure: The primary outcome was the change in leisure-time activity at 8 weeks, measured by the Physical Activity Scale for the Elderly (PASE). Possible PASE scores for leisure-time activity range from 0 to 502, with higher scores indicating higher activity levels. Results: A total of 511 older adults from 8 villages were recruited and randomly allocated to the intervention (240 participants, 4 villages) or control (271 participants, 4 villages) groups. The mean (SD) age was 70.95 (5.72) years, and 284 (55.6%) were female participants. Seven serious adverse events (unrelated deaths) were reported. Participants in the intervention group increased leisure-time activity more than those in the control group, with a mean difference in PASE scores of 13.74 points (95% CI, 8.58-18.91 points) between the groups at 8 weeks (P < .001). Significant differences in leisure-time activity were also found over 24 months (mean difference in scores at 4 weeks, 11.66 points; 95% CI, 6.41-16.90 points; P < .001; at 6 months, 12.35 points; 95% CI, 7.19-17.50 points; P < .001; at 12 months, 11.55 points; 95% CI, 6.32-16.78 points; P < .001; and at 24 months, 14.51 points; 95% CI, 9.28-19.75 points; P < .001). Conclusions and Relevance: In this cluster randomized trial, the multilevel intervention was effective in promoting leisure-time activity over 24 months of follow-up in older adults from China. This finding suggests that implementation of such interventions could be an important step in addressing physical inactivity in older adults in low- and middle-income countries. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100045653.

Effect of physical activity intervention on cognitive function in China: A cluster randomized trial.

INTRODUCTION: Current randomized trial evidence on the effect of physical activity (PA) intervention on cognitive function is scarce and mainly found in well-educated populations, limiting its generalizability. Furthermore, the modification effect of education levels remains understudied. We conducted a cluster randomized trial to evaluate the effects of PA intervention on cognitive function in a general older population, and whether education modifies such effects. METHODS: Eight villages were randomized to the intervention (four villages, n = 240) or the control (four villages, n = 271). The intervention group received an 8-week multilevel PA intervention based on a socio-ecological model, while the control did not. The intervention has been condensed to three levels with activities occurring at the individual (telephone counseling, printed material, and training sessions), interpersonal (peer group), and community levels (group sharing and coaching). The primary outcome was changes in global cognition (overall cognitive function) measured by the Telephone Interview for Cognitive Status (TICS-10) at 12-month follow-up. Repeated measurements were modeled using the linear mixed model, which assumed that the missing values were missing at random. RESULTS: The mean age was 70.94 years (standard deviation 5.71) and 55.6% were women. Compared to the control, the orientation improved from baseline at 12-month follow-up (0.24 points [95% confidence interval (CI), 0.03 to 0.46 points; P = 0.03]). Stratified analysis showed that the global cognition and orientation improved at 12-month follow-up among illiterate participants in the intervention (for global cognition, mean difference, 0.57 points [95% CI, 0.03 to 1.10], P = 0.04; for orientation, mean difference, 0.31 points [95% CI, 0.04 to 0.58], P = 0.03). DISCUSSION: These results confirm the improvements in orientation in older adults, as well as in global cognition and orientation in the illiterate at 12-month follow-up.

Association of Physical Activity With Cognitive Function Among Older Adults in Rural Sichuan, China.

The purpose of this study was to explore the relationship between total physical activity and different dimensions of cognitive function (orientation, attention, and memory) among older adults in rural Sichuan, China. This cross-sectional study involved 715 older adults (average age of 72 years). Total PA was measured by the Physical Activity Scale for the Elderly, and cognitive function was assessed by the Telephone Interview for Cognitive Status (TICS) questionnaire. The multivariate linear regression analysis indicated that total PA and household PA were significantly associated with the overall Telephone Interview for Cognitive Status score (ß = 0.143, p < .001; ß = 0.115, p = .002, respectively), the orientation dimension (ß = 0.142, p < .001; ß = 0.131, p = .001, respectively), and the memory dimension (ß = 0.179, p < .001; ß = 0.134, p = .001, respectively). The study showed a positive association between total PA, household PA, and cognitive function in older adults, especially in the orientation dimension and the memory dimension of cognitive function.

Development and validation of the Nurse's Workplace Mental Health Questionnaire.

Objectives: This study aimed to develop and validate the Nurse's Workplace Mental Health Questionnaire (NWMHQ). Methods: The questionnaire was developed based on the two continua model of mental illness and health proposed by Keyes. The initial questionnaire was generated through literature review, two rounds of Delphi expert consultation, followed by a pilot survey. Finally, the reliability and validity of the questionnaire were validated through an online survey of 2,815 registered nurses selected from the public hospitals in 11 provinces from June to July 2020. Results: The item-content validity index (I-CVI) of the questionnaire ranged from 0.750 to 1.000 and the average scale-level content validity index (S-CVI/Ave) was 0.906. Cronbach's α coefficient was 0.948 and test-retest reliability was 0.850. The self-rating depression scale score was negatively related to the NWMHQ score (r = -0.664, P < 0.01). The exploratory factor analysis (EFA) yielded six factors (emotional status, psychological security, positive relationship, resilience, self-efficacy, and subjective well-being), consisting of 32 items. The cumulative variance contribution rate was 65.58%. Confirmatory factor analysis (CFA) showed an acceptable fit. Conclusion: The NWMHQ developed in this study showed good reliability and validity. This questionnaire may help assess the mental health status of nurses and help nursing managers to develop appropriate targeted psychological interventions.

A Multilevel Physical Activity Intervention Among Chinese Rural Older Adults (Stay Active While Aging): A Study Protocol for a Clustered Randomized Controlled Trial.

Background: Although a large number of studies have confirmed the benefits of physical activity (PA) in preventing age-related diseases and disabilities, a growing number of older people spent more time in sedentary behavior as opposed to PA. To reverse the alarming trend, numerous studies have corroborated the effectiveness of PA interventions in improving PA among older adults. However, such research is scarce in rural China, where a majority of older adults do not meet the PA recommendation. The Stay Active While Aging (SAWA) aimed to conduct an intervention to improve the PA level among older adults in rural China. Methods: The SAWA is designed as a single-blind, clustered randomized controlled trial carried out in rural Sichuan, China with an 8-week intervention and a 24-month follow-up. The intervention group will receive a multilevel intervention (individual, interpersonal, and community levels), while the control group will not. The primary outcome is the PA level. Secondary outcome measures include sedentary behavior level, self-efficacy, self-regulation, cognitive function, night-time sleep quality, and anthropometry. The difference-in-differences (DID) will be performed to investigate the between-group differences, adjusted for baseline data and covariates. Discussion: The SAWA trial will provide a multilevel intervention based on the socio-ecologic model among older adults in rural China. We target the PA level and health status changes while also focus on the maintenance of such intervention during 24 months. If the SAWA produces positive results, it will be possible to recommend similar strategies to be implemented in other Chinese older adults and beyond. Trial registration: ChiCTR2100045653 (https://www.chictr.org.cn/index.aspx).

Association between socio-ecological factors and leisure time physical activity (LTPA) among older adults in Sichuan, China: a structural equation modeling analysis.

BACKGROUND: Few studies examined socio-ecological factors and leisure time physical activities (LTPA) and rarely focused on self-regulation and social capital, which might play a significant role in impacting people's physical activity behavior. This study aimed to examine the direct and indirect effects of individual level (perceived benefits, perceived barriers, and self-efficacy), interpersonal level (self-regulation), social level (social capital), and environmental level factors (perceived physical environment) on LTPA among older adults. METHODS: A cross-sectional study was conducted in 737 older adults from Sichuan, China. Structural equation modeling (SEM) analysis was used to examine the associations of individual, interpersonal, social, and environmental level factors with LTPA. RESULTS: The mean age of all participants was 71.22 (range, 60-97), and 56.1% of them were women. The SEM results showed that individual level variables (ß = 0.32, ρ < 0.001), self-regulation (ß = 0.18, ρ < 0.001) and social capital (ß = 0.14, ρ < 0.001) could all directly affect LTPA while there was no significant association of perceived physical environment with LTPA. Self-regulation served as a bridge linking social capital and LTPA. Individual level variables contributed the largest total effect (0.32) on LTPA. Self-regulation and social capital had the same total effect (0.18) on LTPA. CONCLUSIONS: Factors on three levels were all significantly associated with LTPA. Interventions that incorporate individual, interpersonal, social factors may be considered to promote LTPA in older adults. Self-regulation should receive more attention in future interventions.

Exposure to benzo(a)pyrene suppresses mitophagy via ANT1-PINK1-Parkin pathway in ovarian corpus luteum during early pregnancy.

Exposure to benzo (a)pyrene (BaP) has been confirmed to interfere with embryo implantation. As the primary organ of progesterone synthesis during early pregnancy, the ovarian corpus luteum (CL) is essential for embryo implantation and pregnancy maintenance. We previously demonstrated that BaP impaired luteal function, but the molecular mechanism remains unclear. In CL cells, mitochondria are the main sites of progesterone synthesis. Mitophagy, a particular type of autophagy, regulates mitochondrial quality by degrading damaged mitochondria and ensuring the homeostasis of cell physiology. Therefore, the present study investigated the effects and the potential molecular mechanisms of BaP on ovarian mitophagy during early pregnancy. We found that BaP and its metabolite, BPDE, inhibited autophagy and PINK1/Parkin-mediated mitophagy in the pregnant ovaries and luteinized granulosa cell, KGN. Notably, adenine nucleotide translocator 1 (ANT1), a crucial mediator of PINK1-dependent mitophagy, was suppressed by BaP and BPDE both in vivo and in vitro. The inhibition of ANT1 leads to the decrease in the PINK1 bound to the outer membrane of mitochondria and consequently reduces recruitment of Parkin to the mitochondria, which is required for the subsequent clearance of mitochondria. Meanwhile, exposure to BPDE also damaged mitochondrial function, causing the reduction in mitochondrial potential and ATP production. Overexpression of ANT1 in KGN cells partially relieved the inhibition of mitophagy caused by BPDE, restored mitochondrial function and expression of hormone synthesis-associated genes. Collectively, our study firstly clarified that BaP and BPDE suppress mitophagy of CL cells via the ANT1-PINK1-Parkin pathway, which provides a new insight to explore the detailed mechanism of the BaP-induced ovarian toxicity.

Melatonin alleviates benzo(a)pyrene-induced ovarian corpus luteum dysfunction by suppressing excessive oxidative stress and apoptosis.

Benzo(a)pyrene (B(a)P) is a widespread persistent organic pollutant (POP) and a well-known endocrine disruptor. Exposure to BaP is known to disrupt the steroid balance and impair embryo implantation, but the mechanism under it remains unclear. The corpus luteum (CL), the primary source of progesterone during early pregnancy, plays a pivotal role in embryo implantation and pregnancy maintenance. The inappropriate luteal function may result in implantation failure and spontaneous abortions. Therefore, this study was conducted to assess the effects and potential mechanisms of B(a)P on the CL function. Our results showed that pregnant mice received B(a)P displayed impaired embryo implantation and dysfunction of ovarian CL. The estrogen and progesterone levels decreased by B(a)P. In vitro, exposure to BPDE, which is the metabolite of B(a)P, affected the luteinization of granular cell KK-1. Additionally, melatonin and its receptors, which are important for ovarian function and anti-oxidative damage, were affected by B(a)P or BPDE. B(a)P or BPDE-treated alone impaired antioxidant capacity of ovarian granulosa cells, caused an increasing of ROS and cell apoptosis, and disrupted the PI3K/AKT/GSK3ß signaling pathway in vivo and in vitro. Co-treatment with melatonin alleviated B(a)P or BPDE-induced CL dysfunction by ameliorating oxidative stress, counteracting phosphorylation of PI3K/AKT/GSK3ß signaling pathway, decreasing the apoptosis of the ovarian cells. Moreover, activation of the melatonin receptor by ramelteon in KK-1 cells exhibits an analogous protective effect as melatonin. In conclusion, our findings not only firstly clarify the potential mechanisms of BaP-induced CL dysfunction, but also extend the understanding about the ovarian protection of melatonin and its receptors against B(a)P exposure.