Low-dose aspirin protects unexplained recurrent spontaneous abortion via downregulation of HMGB1 inflammation activation.

Background: High mobility group box protein 1 (HMGB1) is considered as a kind of sterile inflammatory mediators, which is an overexpression in patients with unexplained recurrent spontaneous abortion (URSA). Specific targeting effect of aspirin on HMGB1 has been revealed. Our previous studies have explored the application of HMGB1 as a therapeutic target of aspirin in URSA disease of mice model and human, but the dynamic process of aspirin downregulating HMGB1 concentration has not been demonstrated. Methods: From December 2018 to November 2020, women with URSA (n = 91) and control women (n = 90) with no history of recurrent abortion or adverse pregnancy were included in the Reproductive Medicine Center of the First Affiliated Hospital of Anhui Medical University. ELISA was applied to detect the concentrations of HMGB1 and IFN-γ in the peripheral blood. Thirty-one URSA patients were monitored for low-dose aspirin treatment (2 and 4 weeks), the changes of HMGB1 and IFN-γ concentrations in peripheral blood of URSA patients before and after using aspirin were compared, and pregnancy outcomes after aspirin treatment were followed up. Results: The levels of HMGB1 in peripheral blood were significantly higher in URSA patients compared with controls, decreasing trends of HMGB1 and IFN-γ concentrations in plasma of URSA patients were observed after treatment with low-dose aspirin continuously, and the expression of HMGB1 was positively correlated with IFN-γ. There were no birth abnormalities in the babies of the URSA patients treated with aspirin. Conclusions: High levels of HMGB1 may be one of the pathogenesis of URSA. Low-dose aspirin may provide protective effect on the HMGB1-triggered URSA.

Cohort profile: Anhui Maternal-Child Health Study in China.

PURPOSE: The Anhui Maternal-Child Health Study (AMCHS) aims to examine determinants of reproduction, pregnancy and postpartum maternal and child health outcomes in Chinese women who received assisted reproductive technology (ART). STUDY DESIGN AND PARTICIPANTS: AMCHS is an ongoing cohort study starting from May 2017. AMCHS recruits participants from all couples who sought ART treatment in the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China. The participants are interviewed to document baseline sociodemography, lifestyles, dietary intake and environmental exposure. Their clinical characteristics are obtained from hospital records. Samples of blood, follicular fluid and semen are collected at the clinic. Participants receive a standard long pituitary downregulation or a short protocol with an antagonist for the treatment. They are followed up from preconception to delivery, or discontinuation of ART treatment. Details of their children's health are documented through a questionnaire focusing on developmental status and anthropometry measurement. FINDINGS TO DATE: Until April 2021, AMCHS had recruited 2042 couples in the study. 111 women withdrew from the study and 19 failed to retrieve oocytes. Among the 1475 confirmed pregnancies, 146 had miscarriages or terminated their pregnancies, 9 had stillbirths and 263 were ongoing pregnancies. The implantation failure increased with maternal age; adjusted OR was 1.43 (95% CI 1.16 to 1.77) in the age of 31-35 years, 1.97 (95% CI 1.46 to 2.66) in 35-39 years and 6.52 (95% CI 3.35 to 12.68) in ≥40 years compared with those aged 20-30 years. Among the 1057 couples with successful ART who were followed up for delivering babies, 576 had their children examined at age 30-42 days, 459 at 6 months and 375 at 12 months. FUTURE PLANS: The AMCHS will identify comprehensive risk factors for poor ART outcomes and explore potential interaction effects of multiple factors including sociopsychological aspects of environmental exposure, dietary intake and genetics on maternal and child health.

Upregulated HMGB1 levels in maternal-fetal interface of patients with unexplained recurrent spontaneous abortion from different sources.

OBJECTIVE: To investigate the expression and sources of high mobility group box 1 (HMGB1) protein in the maternal-fetal interface of patients with unexplained recurrent spontaneous abortion (URSA), and further to verify the role of HMGB1 in the etiology of URSA. METHODS: 55 women at early pregnancy with URSA and 55 women undergoing selective termination of normal early pregnancy as control were included. The abortion tissues including villi and decidua were collected. The expression of HMGB1, CD45, CK7, and vimentin in abortion tissues was detected, and the localization and sources of HMGB1 were analyzed. RESULTS: Infiltrating immune cells and expression of HMGB1 were significantly increased in villi and decidua in URSA group compared with those in the control group. In the URSA group, HMGB1 was colocalized with the CD45-labeled immune cells, and it was more obvious in decidua than in villi; in addition, HMGB1 was colocalized with the vimentin-labeled decidual stromal cells, but not with the CK7- labeled villous epithelial cells. CONCLUSION: High expression of HMGB1 in the maternal-fetal interface in URSA patients was actively secreted by the infiltrating immune cells, and decidual stromal cells may passively release HMGB1 during necrosis.

Scalable Synthesis of Porous SiFe@C Composite with Excellent Lithium Storage.

Utilizing cost-effective raw materials to prepare high-performance silicon-based anode materials for lithium-ion batteries (LIBs) is both challenging and attractive. Herein, a porous SiFe@C (pSiFe@C) composite derived from low-cost ferrosilicon is prepared via a scalable three-step procedure, including ball milling, partial etching, and carbon layer coating. The pSiFe@C material integrates the advantages of the mesoporous structure, the partially retained FeSi2 conductive phase, and a uniform carbon layer (12-16 nm), which can substantially alleviate the huge volume expansion effect in the repeated lithium-ion insertion/extraction processes, effectively stabilizing the solid-electrolyte interphase (SEI) film and markedly enhancing the overall electronic conductivity of the material. Benefiting from the rational structure, the obtained pSiFe@C hybrid material delivers a reversible capacity of 1162.1 mAh g-1 after 200 cycles at 500 mA g-1 , with a higher initial coulombic efficiency of 82.30 %. In addition, it shows large discharge capacities of 803.1 and 600.0 mAh g-1 after 500 cycles at 2 and 4 A g-1 , respectively, manifesting an excellent electrochemical lithium storage. This work provides a good prospect for the commercial production of silicon-based anode materials for LIBs with a high lithium-storage capacity.

Inhibition of HMGB1 Ameliorates the Maternal-Fetal Interface Destruction in Unexplained Recurrent Spontaneous Abortion by Suppressing Pyroptosis Activation.

Recurrent spontaneous abortion (RSA) is a common complication of pregnancy that affects the physical and mental health of pregnant women, and approximately 50% of the mechanisms are unclear. Our previous studies have found that high mobility group box 1 (HMGB1) molecules are highly expressed at the maternal-fetal interface of unexplained recurrent spontaneous abortion (URSA) patients. The purpose of this study was to further detect the expression of HMGB1 and pyroptosis in decidual tissue of URSA patients, and explore the potential mechanism of the protective role of HMGB1 in URSA patients and mouse model. The decidua tissues of 75 URSA patients and 75 women who actively terminated pregnancy were collected, and URSA mouse models were established and treated with HMGB1 inhibitor-aspirin. The expression of HMGB1, and their receptors (RAGE, TLR2, TLR4), pyroptosis-associated proteins (NLRP-3, caspase-1, GSDMD) and NF-κB was examined at the maternal-fetal interface of human and mouse. Our study found that HMGB1, NLRP-3, Caspase-1, GSDMD, RAGE, TLR2 and TLR4 were highly expressed and NF-κB signaling pathway were activated in the decidua tissue of URSA group. Moreover, immune cell disorder and co-localization of HMGB1 and macrophages were found at the maternal-fetal interface of URSA mice. However, HMGB1, TLR2, TLR4, NF-κB, and pyroptosis-associated proteins can be down-regulated by administering low-dose aspirin. These data may indicate that highly expressed HMGB1 was actively secreted by macrophages and then activated pyroptosis through the TLR2/TLR4-NF-κB pathway to cause aseptic inflammation, leading to the occurrence and development of URSA. Moreover, low-dose aspirin can reduce HMGB1 protein levels of serum and decidual in URSA.

Destruction in maternal-fetal interface of URSA patients via the increase of the HMGB1-RAGE/TLR2/TLR4-NF-κB signaling pathway.

AIMS: HMGB1 has been reported to play a crucial role in the physiological and pathophysiological responses during pregnancy. However, it is still unknown whether excessively expressed HMGB1 at the maternal-fetal interface related to Unexplained Recurrent Spontaneous Abortion (URSA). This study was designed to investigate the local capability of HMGB1 in the pathology of URSA, determined the distributions and characteristics of HMGB1, its receptors (RAGE/TLR2/TLR4) and important signaling molecule NF-κB p65 expression at the maternal-fetal interface，as well as compared the differences of HMGB1 expression between the URSA group, control group and aspirin treatment group. MATERIAL AND METHODS: H&E staining, Western blot analysis, immunofluorescence assay and immunohistochemical staining were applied to determine the effect of HMGB1 and its receptors at the maternal-fetal interface. ELISA was utilized to detect the concentration of HMGB1 in plasma. KEY FINDINGS: Our study demonstrated that the activation of the HMGB1-RAGE/TLR2/TLR4-NF-κB pathway at the maternal-fetal interface may have occurred in the URSA group. HMGB1 concentration in plasma was higher in the URSA group than the control group. Furthermore, the levels of HMGB1 of subjects with URSA could be reduced by administrating low doses of aspirin (ASPL). SIGNIFICANCE: This is the first report indicating the roles of HMGB1 at the maternal-fetal interface of URSA patients and broadening the horizons for clinical treatment of URSA. HMGB1-RAGE/TLR2/TLR4-NF-κB signaling pathway may be activated at the maternal-fetal interface in URSA and account for its pathogenesis. HMGB1 have the potential to be promising biomarkers in prevention and therapy of URSA.