Adenosine-ADORA2A Promotes Ang-Induced Angiogenesis in Intrauterine Growth Restriction Placenta via the Stat3/Akt Pathway.

BACKGROUND: Abnormal placental angiogenesis is an important cause of fetal intrauterine growth restriction (IUGR), but its underlying mechanisms and therapies remain unclear. Adenosine and its mediated signaling has been reported to be associated with the development of angiogenesis. However, whether the adenosine-related signaling plays a role in modulating angiogenesis in placenta and the IUGR pregnancy outcomes remains unclear. METHODS: The angiogenesis and adenosine signaling expressions in normal and IUGR placentas were detected in different species. And the role of adenosine in regulating IUGR pregnancy outcomes was evaluated using diet-induced IUGR mouse model. Molecular mechanisms underlying adenosine-induced angiogenesis were investigated by in vitro angiogenesis assays and in vivo Matrigel plug assays. RESULTS: Here, we demonstrated poor angiogenesis and low adenosine concentration and downregulated expression of its receptor A2a (ADORA2A [adenosine A2a receptor]) in IUGR placenta. Additionally, the beneficial effects of adenosine in improving IUGR pregnancy outcomes were revealed in a diet-induced IUGR mouse model. Moreover, adenosine was found to effectively improve adenosine signaling and angiogenesis in IUGR mice placenta. Mechanistically, by using angiogenesis assays in vitro and in vivo, adenosine was shown to activate ADORA2A to promote the phosphorylation of Stat3 (signal transducer and activator of transcription 3) and Akt (protein kinase B), resulting in increased Ang (angiogenin)-dependent angiogenesis. CONCLUSIONS: Collectively, this study uncovers an unexpected mechanism of promoting placental angiogenesis by adenosine-ADORA2A signaling and advances the translation of this signaling as a prognostic indicator and therapeutic target in IUGR treatment.

Exploring the association between consultation themes and suicidal ideation: a gender-stratified analysis of Hangzhou Mental Health Hotline (2014-2023).

BACKGROUND: Suicide is a critical global public health issue that demands a better understanding of its complex causes and effective interventions. This study examines data from the Hangzhou Mental Health Hotline (2014-2023) to explore the relationship between consultation themes and suicidal ideation, with an emphasis on gender differences and how these associations changed during different phases of the COVID-19 pandemic. METHODS: This retrospective analysis covers 128,245 calls to the hotline over a decade. Chi-square tests identified differences in suicidal ideation across consultation themes and demographics. Multivariate logistic regression models were used to examine the relationship between specific themes and suicidal ideation, adjusting for confounders. The analysis was stratified by gender and pandemic phases to assess the interaction between gender and pandemic-related changes. RESULTS: The incidence of suicidal ideation was highest during the mid-pandemic phase (11.95%), compared to the pre-pandemic (7.68%) and post-pandemic phases (10.66%). Additionally, the rate was slightly higher among female callers (9.8%) than male callers (9.4%). Physical illness (OR = 4.70, 95% CI: 3.71-5.91) had the strongest association with suicidal ideation, followed by mental health issues (OR = 3.35, 95% CI: 3.03-3.70). Compared to male callers, female callers were more significantly affected by physical illness (OR = 6.86 vs. OR = 3.71, p < 0.001) and mental health issues (OR = 6.81 vs. OR = 2.11, p < 0.001). In the context of romantic relationship problems, female callers had a higher likelihood of suicidal ideation (OR = 4.13 vs. OR = 1.88, p < 0.001). Similarly, marital and family issues were more strongly associated with suicidal ideation in female callers (OR = 4.58 vs. OR = 1.21, p < 0.001). During the global COVID-19 pandemic, the association between suicidal ideation and consultation themes among male callers showed a sharp upward trend, which eased after the pandemic. In contrast, the association among female callers gradually accumulated and continued to worsen in the later stages of the pandemic. CONCLUSION: This study highlights the necessity of implementing gender-sensitive mental health interventions tailored to different gender groups during and after global crises such as the COVID-19 pandemic, to safeguard public mental health effectively.

Exploring the role of psychological assistance hotlines in improving mental health problems among Chinese adult women: A perspective based on social expectations and gender roles.

This paper looks at how social expectations and gender roles affect the mental health of Chinese women. Traditional Chinese culture, influenced by Confucianism and patriarchy, still has a negative impact on women's mental well-being, despite efforts for gender equality. Women's mental health is vital for both individuals and society, and this study aims to understand these issues better to help shape policies and interventions.

Effects of dietary supplementation of different levels of gamma-aminobutyric acid on reproductive performance, glucose intolerance, and placental development of gilts.

This study aimed to investigate the effects of dietary gamma-aminobutyric acid (GABA) supplementation on reproductive performance, glucose intolerance, and placental development of gilts during mid-late gestation. Based on the principle of backfat thickness consistency, 124 gilts at 65 d of gestation were assigned to three dietary groups: CON (basic diet, n = 41), LGABA (basic diet supplemented with 0.03% GABA, n = 42), and HGABA (basic diet supplemented with 0.06% GABA, n = 41). The litter performance, glucose tolerance, placental angiogenesis, and nutrients transporters were assessed. The LGABA group improved piglet vitality and placental efficiency and decreased area under the curve of glucose tolerance test compared to the CON group (P < 0.05). Meanwhile, the LGABA group enhanced placental vessel density, platelet endothelial cell adhesion molecule-1 levels and gene expression of fibroblast growth factor 18 (P < 0.05). Furthermore, LGABA showed an uptrend in glucose transporter type 1 mRNA level (P = 0.09). Taken together, this study revealed that the dietary supplementation of 0.03% GABA can improve piglet vitality, glucose intolerance, and placental development of gilts.

Glucose homeostasis and placental development are two key factors influencing reproductive performance of sows. Some studies have reported that gamma-aminobutyric acid (GABA) can improve glucose intolerance and cerebral angiogenesis in mice. Therefore, we hypothesized that GABA can improve reproductive performance, glucose intolerance, and placental development of gilts during mid-late gestation. In this study, gilts were randomly assigned into three groups: CON (basal diet), LGABA (basal diet supplemented with 0.03% GABA), and HGABA (basal diet supplemented with 0.06% GABA). Results showed that the LGABA group significantly improved the piglet viability, glucose intolerance, and placental development compared with the CON group. Therefore, GABA has a good prospect as a feed additive for gilts.

Cysteamine and N-Acetyl-cysteine Alleviate Placental Oxidative Stress and Barrier Function Damage Induced by Deoxynivalenol.

Sows are highly sensitive to deoxynivalenol (DON) and susceptible to reproductive toxicity caused by oxidative stress, but the potential mechanisms and effective interventions remain unclear. Here, we investigated the role of two antioxidants (cysteamine and N-acetyl-cysteine) in regulating the reproductive performance, redox status, and placental barrier function of sows and their potential mechanisms under DON exposure. Maternal dietary supply of antioxidants from day 85 of gestation to parturition reduced the incidence of stillbirths and low-birth-weight piglets under DON exposure. Moreover, the alleviation of DON-induced reproductive toxicity by dietary antioxidants was associated with the alleviation of placental oxidative stress, the enhancement of the placental barrier, and the vascular function of sows. Furthermore, in vivo and in vitro vascularized placental barrier modeling further demonstrated that antioxidants could reverse both DON transport across the placenta and DON-induced increase of placental barrier permeability. The molecular mechanism of antioxidant resistance to DON toxicity may be related to the signal transducer and activator of the transcription-3-occludin/zonula occludens-1 signaling pathway. Collectively, these results demonstrate the potential of antioxidants to protect the mother from DON-induced reproductive toxicity by alleviating placental oxidative stress and enhancing the placental barrier.

Dietary adenosine supplementation improves placental angiogenesis in IUGR piglets by up-regulating adenosine A2a receptor.

Abnormal placental angiogenesis is associated with the occurrence of intrauterine growth restriction (IUGR) in piglets, and effective treatment strategies against this occurrence remain to be explored. Adenosine has been reported to play an important role in angiogenesis, but its role in placental angiogenesis is still unknown. Here, we investigated the effect of dietary adenosine supplementation on IUGR occurrence in piglets by analyzing the role of adenosine in placental angiogenesis for Normal and IUGR piglets. Specifically, 88 sows were allotted to 2 treatments (n = 44) and fed a basal diet supplemented with 0% or 0.1% of adenosine from day 65 of gestation until farrowing, followed by collecting the placental samples of Normal and IUGR piglets, and recording their characteristics. The results showed that adenosine supplementation increased the mean birth weight of piglets (P < 0.05) and placental efficiency (P < 0.05), while decreasing the IUGR piglet rate (P < 0.05). Expectedly, the placenta for IUGR neonates showed a down-regulated vascular density (P < 0.05) and angiogenesis as evidenced by the expression level of vascular cell adhesion molecule-1 (VCAM1) (P < 0.05). Notably, dietary adenosine supplementation promoted angiogenesis (P < 0.05) both in the Normal and IUGR placenta. More importantly, the expression level of adenosine A2a receptor (ADORA2A) was lower (P < 0.05) in the IUGR placenta than in Normal placenta, whereas adenosine treatment could significantly increase ADORA2A expression, and also had an interaction effect between factors IUGR and Ado. Collectively, placentae for IUGR piglets showed impaired angiogenesis and down-regulated expression level of ADORA2A, while dietary adenosine supplementation could activate ADORA2A expression, improve the placental angiogenesis, and ultimately decrease the occurrence of IUGR in piglets.

Dietary fiber supplementation during the last 50 days of gestation improves the farrowing performance of gilts by modulating insulin sensitivity, gut microbiota, and placental function.

Our previous study found dietary konjac flour (KF) supplementation could improve insulin sensitivity and reproductive performance of sows, but its high price limits its application in actual production. This study aimed to investigate the effects of supplementation of a cheaper combined dietary fiber (CDF, using bamboo shoots fiber and alginate fiber to partially replace KF) from the last 50 days of gestation to parturition on farrowing performance, insulin sensitivity, gut microbiota, and placental function of gilts. Specifically, a total of 135 pregnant gilts with a similar farrowing time were blocked by backfat thickness and body weight on day 65 of gestation (G65d) and assigned to 1 of the 3 dietary treatment groups (n = 45 per group): basal diet (CON), basal diet supplemented with 2% KF or 2% CDF (CDF containing 15% KF, 60% bamboo shoots fiber, and 25% alginate fiber), respectively. The litter performance, insulin sensitivity and glucose tolerance parameters, placental vessel density, and short-chain fatty acids (SCFAs) levels in feces were assessed. The gut microbiota population in gilts during gestation was also assessed by 16S rDNA gene sequencing. Compared with CON, both KF and CDF treatments not only increased the piglet birth weight (P < 0.05) and piglet vitality (P < 0.01) but also decreased the proportion of piglets with birth weight ≤ 1.2 kg (P < 0.01) and increased the proportion of piglets with birth weight ≥ 1.5 kg (P < 0.01). In addition, KF or CDF supplementation reduced fasting blood insulin level (P < 0.05), homeostasis model assessment-insulin resistance (P < 0.05), serum hemoglobin A1c (P < 0.05), and the level of advanced glycation end products (P < 0.05) at G110d, and increased the placental vascular density (P < 0.05) at farrowing. Meanwhile, KF or CDF supplementation increased microbial diversity (P < 0.05) and SCFAs levels (P < 0.05) in feces at G110d. Notably, the production cost per live-born piglet was lower in CDF group (¥ 36.1) than KF group (¥ 41.3). Overall, KF or CDF supplementation from G65d to farrowing could improve the farrowing performance of gilts possibly by improving insulin sensitivity, regulating gut microbiota and metabolites, and increasing placental vascular density, with higher economic benefits and a similar effect for CDF vs. KF, suggesting the potential of CDF as a cheaper alternative to KF in actual production.

Dietary konjac flour (KF) supplementation could improve insulin sensitivity and reproductive performance of sows, but its high price limits its application in actual production. This study investigated the impact of 2% konjac flour (KF) and 2% combined dietary fiber (CDF, containing 15% KF, 60% bamboo shoots fiber, and 25% alginate fiber) supplementation from the last 50 days of gestation to farrowing on farrowing performance, placental function, insulin sensitivity, and gut microbiota of gilts. Results indicated that KF or CDF supplementation during this time could improve the farrowing performance of gilts possibly by improving insulin sensitivity and gut microbiota, and increasing placental vascular density. Meanwhile, CDF could lower the production cost per live-born piglet and have a similar effect to KF, thus a cheaper alternative to KF in actual production. This study facilitates understanding the beneficial effects of KF and non-conventional dietary fiber sources on the reproductive performance of gilts.

Lachnospiraceae-derived butyrate mediates protection of high fermentable fiber against placental inflammation in gestational diabetes mellitus.

Inflammation-associated insulin resistance is a key trigger of gestational diabetes mellitus (GDM), but the underlying mechanisms and effective interventions remain unclear. Here, we report the association of placental inflammation (tumor necrosis factor-α) and abnormal maternal glucose metabolism in patients with GDM, and a high fermentable dietary fiber (HFDF; konjac) could reduce GDM development through gut flora-short-chain fatty acid-placental inflammation axis in GDM mouse model. Mechanistically, HFDF increases abundances of Lachnospiraceae and butyrate, reduces placental-derived inflammation by enhancing gut barrier and inhibiting the transfer of bacterial-derived lipopolysaccharide, and ultimately resists high-fat diet-induced insulin resistance. Lachnospiraceae and butyrate have similar anti-GDM and anti-placental inflammation effects, and they can ameliorate placental function and pregnancy outcome effects probably by dampening placental immune dysfunction. These findings demonstrate the involvement of important placental inflammation-related mechanisms in the progression of GDM and the great potential of HFDFs to reduce susceptibility to GDM through gut-flora-placenta axis.

Konjac flour-mediated gut microbiota alleviates insulin resistance and improves placental angiogenesis of obese sows.

Our previous study revealed that dietary konjac flour (KF) could remodel gut microbiota and improve reproductive performance of sows, but its underlying mechanisms remain unclear. This experiment aimed to investigate how dietary KF improves reproductive performance of obese sows. Here, 60 sows were assigned into three groups according to their backfat thickness: normal backfat sows fed with control diet (CON-N), high backfat sows fed with control diet (CON-H) and high backfat sows fed with KF inclusion diet (KF-H). The characteristics of sows and piglets were recorded. Next, fecal microbiota transplantation (FMT) was performed on female mice, followed by recording the characteristics of female mice. The results showed that compared with CON-H group, KF-H group showed downtrend in stillbirth rate (P = 0.07), an increase in placental efficiency (P < 0.01) and average piglet weight (P < 0.01); coupled with a decrease in the values of homeostasis model assessment-insulin resistance (P < 0.01); as well as an increase in placental vascular density and protein expression of angiogenesis markers (P < 0.01). As expected, sows fed KF diets had improved abundance and diversity of gut microbiota. More importantly, compared with CON-H(FMT) group, KF-H(FMT) group showed improvement in reproductive performance and insulin sensitivity (P < 0.05), as well as an increase in placental labyrinth zone and protein expression of angiogenesis markers (P < 0.05). Furthermore, we found a content increase (P < 0.05) of SCFAs in both KF-H group sow and KF-H (FMT) group mice. Overall, KF supplementation could alleviate insulin resistance, promote placental angiogenesis, and ultimately improve the reproductive performance of sows via gut microbiota remodeling.

Effects of dietary supplementation of gestating sows with adenosine 5'-monophosphate or adenosine on placental angiogenesis and vitality of their offspring.

Our previous study found that dietary nucleotide supplementation, including adenosine 5'-monophosphate (AMP), could increase AMP content in sow milk and promote piglet growth, but its effects on placental efficiency and piglet vitality remain unknown. This experiment aimed to investigate the effects of dietary AMP or its metabolite adenosine (ADO) supplementation on sow reproductive performance and placental angiogenesis. A total of 135 sows with a similar farrowing time were blocked by backfat and body weight (BW) at day 65 of gestation and assigned to one of three dietary treatment groups (n = 45 per treatment): basal diet, basal diet supplemented with 0.1% AMP or 0.1% ADO, respectively. Placental analysis and the characteristics of sows and piglets unveiled that compared with control (CON) group, AMP or ADO supplementation could improve sow placental efficiency (P < 0.05) and newborn piglet vitality (P < 0.05), increase piglet birth weight (P < 0.05), and reduce stillbirth rate (P < 0.05). More importantly, AMP or ADO supplementation could increase the contents of AMP, ADO, and their metabolites in placentae (P < 0.05). Meanwhile, AMP or ADO supplementation could also increase placental vascular density (P < 0.05) and the expression of vascular endothelial growth factor A (P < 0.05), as well as promote the migration and tube formation of porcine iliac artery endothelial cells (P < 0.05). Overall, maternal dietary AMP or ADO supplementation could increase their contents in the placenta, thereby improving placental angiogenesis and neonatal piglet vitality.

Placental angiogenesis regulates piglet growth and development. Adenosine 5ʹ-monophosphate (AMP), a breakdown product of adenosine triphosphate, can be further converted to adenosine with various biological activities. However, little is known about whether AMP supplementation favors piglet growth and development as well as placental angiogenesis. This study facilitates the understanding of the promoting effects of AMP supplementation on placental angiogenesis and farrowing performance.

Dietary fibers with low hydration properties exacerbate diarrhea and impair intestinal health and nutrient digestibility in weaned piglets.

BACKGROUND: This study aimed to investigate the hydration properties of different-source fibrous materials by comparing their water-binding capacity (WBC), water swelling capacity (WSC), viscosity, and in vivo effects of selected samples on growth performance, nutrient digestibility, diarrhea, and intestinal health in weaned piglets. METHODS: A total of 13 commercially available fibrous materials were first compared in chemical composition and in vitro hydration property. Subsequently, 40 weaned piglets were randomized to five experimental dietary groups (8 piglets per group): control diet (a basal diet without dietary fiber, CON), basal diet supplemented with 5% microcrystalline cellulose (MCC), 5% wheat bran (WB), 5% Moringa oleifera leaf powder (MOLP), or 5% sugar beet pulp (SBP), followed by analyzing their growth performance and diarrhea rate in a 28-d experiment. After the feeding experiment, anaesthetized piglets were killed, and their intestinal and colon content or plasma samples were analyzed in nutrient digestibility, intestinal morphology, intestinal barrier, short-chain fatty acids (SCFAs), and bacterial population. RESULTS: In vitro studies showed low hydration properties for WB and MCC, while medium hydration properties for MOLP and SBP. In vivo studies indicated that compared with medium hydration property groups, low hydration property groups showed (1) exacerbated diarrhea, impaired intestinal health, and reduced apparent fecal digestibility of dry matter, gross energy, acid detergent fiber, and neutral detergent fiber; (2) decreased SCFAs concentration and relative levels of Lactobacillus and Bifidobacterium, but increased levels of Escherichia coli and Brachyspira hyodysenteriae in colon contents. Additionally, SBP showed optimal performance in reducing diarrhea and increasing SCFAs production. Correlation analysis revealed a positive correlation of fiber hydration properties with in vitro SCFAs production, and diarrhea index and nutrient digestibility were negatively and positively correlated with SCFAs levels in the colon contents of weaned piglets, respectively. CONCLUSIONS: Different-source dietary fibers varied in their hydration properties and impacts on diarrhea, microbial composition and SCFAs production in weaned piglets. WB and MCC could exacerbate diarrhea and impair nutrient digestibility, probably because their low hydration properties were detrimental to gut microbial homeostasis and fermentation. Our findings provide new ideas for rational use of fiber resources in weaned piglets.