{"title":"Comment on “Decidual Cells Induce Release of Free and Exosome-Bound Interferon Epsilon From Vaginal Epithelial Cells”","authors":"Shyam Sundar Sah, Abhishek Kumbhalwar","doi":"10.1111/aji.70177","DOIUrl":"10.1111/aji.70177","url":null,"abstract":"","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Şebnem Karagün, Hamza Yıldız, Yusuf Dal, Ahmet Zeki Nessar, Sefanur Gamze Karaca, Mürşide Çevikoğlu Kıllı, Ayhan Coşkun
Objective
To evaluate the effect of magnesium sulfate (MgSO4) therapy on dynamic changes in maternal inflammation-based hematologic indices and their predictive value for neonatal outcomes in high-risk pregnancies.
Methods
We conducted a retrospective cohort study involving 236 singleton pregnancies treated with MgSO4 for either fetal neuroprotection or seizure prophylaxis. Pre- and 24-h post-treatment complete blood count (CBC)—derived inflammatory markers (including neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], systemic inflammation response index [SIRI], and mean platelet volume [MPV]) were compared. Percentage change (Δ) values were calculated. Associations between these Δ-values and adverse perinatal outcomes were analyzed using correlation tests and ROC curves.
Results
Following MgSO4 administration, significant alterations were observed in maternal inflammatory markers: NLR (+12.2%), WBC (+11.7%), SIRI (+25.6%) increased, whereas PLR (−9.7%), LMR (−6.1%), and platelet count (−9.6%) decreased (all p < 0.05). ΔNLR, ΔMPV, and ΔWBC correlated negatively with gestational age and birth weight, and positively with NICU admission. ROC analysis identified ΔNLR ≥ −15.132 as a predictor of NICU admission (AUC = 0.609, p = 0.016).
Conclusion
Magnesium sulfate induces measurable changes in maternal inflammatory profiles. These dynamic hematologic shifts—especially in NLR and MPV—may carry limited predictive value for adverse neonatal outcomes. Monitoring ∆-inflammatory indices could support exploratory efforts in risk stratification, but further validation is required before clinical application.
{"title":"Magnesium Sulfate–Mediated Inflammatory Modulation in High-Risk Pregnancies: Dynamic Shifts in CBC-Derived Markers Predict Neonatal Outcomes","authors":"Şebnem Karagün, Hamza Yıldız, Yusuf Dal, Ahmet Zeki Nessar, Sefanur Gamze Karaca, Mürşide Çevikoğlu Kıllı, Ayhan Coşkun","doi":"10.1111/aji.70172","DOIUrl":"10.1111/aji.70172","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To evaluate the effect of magnesium sulfate (MgSO<sub>4</sub>) therapy on dynamic changes in maternal inflammation-based hematologic indices and their predictive value for neonatal outcomes in high-risk pregnancies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a retrospective cohort study involving 236 singleton pregnancies treated with MgSO<sub>4</sub> for either fetal neuroprotection or seizure prophylaxis. Pre- and 24-h post-treatment complete blood count (CBC)—derived inflammatory markers (including neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], systemic inflammation response index [SIRI], and mean platelet volume [MPV]) were compared. Percentage change (Δ) values were calculated. Associations between these Δ-values and adverse perinatal outcomes were analyzed using correlation tests and ROC curves.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Following MgSO<sub>4</sub> administration, significant alterations were observed in maternal inflammatory markers: NLR (+12.2%), WBC (+11.7%), SIRI (+25.6%) increased, whereas PLR (−9.7%), LMR (−6.1%), and platelet count (−9.6%) decreased (all <i>p </i>< 0.05). ΔNLR, ΔMPV, and ΔWBC correlated negatively with gestational age and birth weight, and positively with NICU admission. ROC analysis identified ΔNLR ≥ −15.132 as a predictor of NICU admission (AUC = 0.609, <i>p</i> = 0.016).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Magnesium sulfate induces measurable changes in maternal inflammatory profiles. These dynamic hematologic shifts—especially in NLR and MPV—may carry limited predictive value for adverse neonatal outcomes. Monitoring ∆-inflammatory indices could support exploratory efforts in risk stratification, but further validation is required before clinical application.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273373","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Recurrent pregnancy loss (RPL) a reproductive concern affects 1%–5% of couples worldwide and 50% of the cases are idiopathic. Pregnancy, a dynamic state of inflammation is influenced by diverse physiological factors. A multifunctional angiotensin converting enzyme (ACE) has direct effect on inflammation, oxidative stress, and fibrinolytic balance through Angiotensin-II. By blocking the NF-κB1 transcription factor complex, ACE inhibitors stimulate regulatory T-cells (Tregs). Based on this, we postulated that ACE functional polymorphism(s) may influence the Tregs in RPL.
Aim
To assess the association of rs4646994 (I/D) polymorphism with circulating Tregs in south Indian pregnant women with (RPL) and without (nRPL) the history of RPL.
Methods of Study
Genomic DNA and peripheral blood mononuclear cells (PBMC's) from nRPL(60) and RPL(77) pregnant women were isolated and subjected to PCR for rs4646994 genotyping and flow cytometry for enumeration of Tregs, respectively.
Results
We observed significantly diminished circulating Tregs (p < 0.0001) in RPL over the nRPL and lack of association of rs4646994 polymorphism with RPL. However, consistently lower Tregs irrespective of the genotypes within RPL group (p > 0.05) and significant elevation in percentage of Tregs in nRPL pregnant women with II (p = 0.003) and ID (0.007) genotypes when compared to their respective counterparts in RPL group was noted.
Conclusion
This is first study to explore the association between ACE genotypes and distribution of Tregs in RPL. Understanding the relation may help resolve to certain extent the heterogeneity existing in idiopathic RPL for the better management. The limitation of the study is small sample size and lack of information on serum ACE levels.
{"title":"Peripheral CD4+CD25+FOXP3+Tregs Cell Distribution in Women With and Without a History of Recurrent Pregnancy Loss in Relation to ACE rs4646994 (I/D) Polymorphism","authors":"Nargis Fatima, Rashmi Bhuwalka, Sufaya Jameel, Aatika Ejaz, Rajeshwari Bonu, Praveen Jahan","doi":"10.1111/aji.70174","DOIUrl":"10.1111/aji.70174","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>Recurrent pregnancy loss (RPL) a reproductive concern affects 1%–5% of couples worldwide and 50% of the cases are idiopathic. Pregnancy, a dynamic state of inflammation is influenced by diverse physiological factors. A multifunctional angiotensin converting enzyme (ACE) has direct effect on inflammation, oxidative stress, and fibrinolytic balance through Angiotensin-II. By blocking the NF-κB1 transcription factor complex, ACE inhibitors stimulate regulatory T-cells (Tregs). Based on this, we postulated that ACE functional polymorphism(s) may influence the Tregs in RPL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>To assess the association of rs4646994 (I/D) polymorphism with circulating Tregs in south Indian pregnant women with (RPL) and without (nRPL) the history of RPL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods of Study</h3>\u0000 \u0000 <p>Genomic DNA and peripheral blood mononuclear cells (PBMC's) from nRPL(60) and RPL(77) pregnant women were isolated and subjected to PCR for rs4646994 genotyping and flow cytometry for enumeration of Tregs, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed significantly diminished circulating Tregs (<i>p</i> < 0.0001) in RPL over the nRPL and lack of association of rs4646994 polymorphism with RPL. However, consistently lower Tregs irrespective of the genotypes within RPL group (<i>p</i> > 0.05) and significant elevation in percentage of Tregs in nRPL pregnant women with II (<i>p</i> = 0.003) and ID (0.007) genotypes when compared to their respective counterparts in RPL group was noted.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This is first study to explore the association between ACE genotypes and distribution of Tregs in RPL. Understanding the relation may help resolve to certain extent the heterogeneity existing in idiopathic RPL for the better management. The limitation of the study is small sample size and lack of information on serum ACE levels.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lu Chen, Xiaoyan Chen, Qianhan Xu, Joshua Jing Xi Li, Wen-Jui Yang, Hanbin Wu, Chi Chiu Wang, Xiaodan Fan, Jie Ji, Jacqueline Pui Wah Chung, Mingqing Li, Tin Chiu Li, Tao Zhang
Research Question
For women with reproductive failure, prednisone is widely used but remains controversial as a therapy for improving clinical outcomes. This study aimed to investigate the impact of prednisone on various endometrial immune cells.
Design
A total of 24 women with repeated implantation failure and recurrent miscarriage underwent their first endometrial biopsy precisely 7 days after luteinizing hormone surge (LH surge +7). Prednisone was administered from the first day of the subsequent menstrual cycle, followed by the second endometrial sampling on day LH surge +7 again. The density and cell–cell clustering of CD3−CD56+CD16− NK cells, CD3−CD56+CD16+ NK cells, CD68+CD16− macrophages, CD68+CD16+ macrophages, CD3+CD56− T cells, and CD3+CD56+ NK-T cells were analyzed by multiplex staining and compared before and after prednisone treatment.
Results
Following prednisone treatment, a significant decrease in the percentage of CD3−CD56+CD16− NK cells (p < 0.001), CD68+CD16− macrophages (p = 0.007), and their clustering degree (p = 0.038) was observed. No significant changes were noted in CD3−CD56+CD16+ NK cells, CD68+CD16+ macrophages, CD3+CD56− T cells, CD3+CD56+ NK-T cells, and their cell–cell clustering.
Conclusion
Prednisone does not generally reduce all endometrial immune cells; instead, it selectively suppresses specific immune cell subtypes in women with reproductive failure.
{"title":"Distinct Suppression of Prednisone on Endometrial Immune Cells in Women With Reproductive Failure","authors":"Lu Chen, Xiaoyan Chen, Qianhan Xu, Joshua Jing Xi Li, Wen-Jui Yang, Hanbin Wu, Chi Chiu Wang, Xiaodan Fan, Jie Ji, Jacqueline Pui Wah Chung, Mingqing Li, Tin Chiu Li, Tao Zhang","doi":"10.1111/aji.70151","DOIUrl":"10.1111/aji.70151","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Research Question</h3>\u0000 \u0000 <p>For women with reproductive failure, prednisone is widely used but remains controversial as a therapy for improving clinical outcomes. This study aimed to investigate the impact of prednisone on various endometrial immune cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Design</h3>\u0000 \u0000 <p>A total of 24 women with repeated implantation failure and recurrent miscarriage underwent their first endometrial biopsy precisely 7 days after luteinizing hormone surge (LH surge +7). Prednisone was administered from the first day of the subsequent menstrual cycle, followed by the second endometrial sampling on day LH surge +7 again. The density and cell–cell clustering of CD3−CD56+CD16− NK cells, CD3−CD56+CD16+ NK cells, CD68+CD16− macrophages, CD68+CD16+ macrophages, CD3+CD56− T cells, and CD3+CD56+ NK-T cells were analyzed by multiplex staining and compared before and after prednisone treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Following prednisone treatment, a significant decrease in the percentage of CD3−CD56+CD16− NK cells (<i>p <</i> 0.001), CD68+CD16− macrophages (<i>p</i> = 0.007), and their clustering degree (<i>p</i> = 0.038) was observed. No significant changes were noted in CD3−CD56+CD16+ NK cells, CD68+CD16+ macrophages, CD3+CD56− T cells, CD3+CD56+ NK-T cells, and their cell–cell clustering.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Prednisone does not generally reduce all endometrial immune cells; instead, it selectively suppresses specific immune cell subtypes in women with reproductive failure.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12503086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145237543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Polycystic ovary syndrome (PCOS) and steatotic liver disease associated with metabolic dysfunction are closely related. The aspartate aminotransferase platelet ratio index (APRI), one of the non-invasive indices, has a high prognostic value in metabolic and cardiovascular abnormalities. The primary outcome of this study was to compare APRI levels in PCOS patients with different metabolic subgroups.
Method of Study
The study included women aged 20–45 years with a diagnosis of PCOS. Baseline blood samples were collected after spontaneous menstrual bleeding between days 2 and 5 of the menstrual cycle, following an overnight fast. Patients were classified as obese or non-obese, with or without hypertriglyceridemia, and with normal or abnormal fasting glucose.
Results
A total of 106 patients were included in the study. Triglyceride, low-density lipoprotein cholesterol levels and APRI scores of lean and overweight patients were significantly lower than those of obese patients. APRI was significantly lower in normotriglyceridemic PCOS patients. The APRI score was positively correlated with triglycerides and negatively correlated with sex-hormone binding globulin.
Conclusions
Current evidence-based international guidelines emphasise that PCOS is not an isolated condition but a systemic endocrine disorder that requires multidisciplinary management. Metabolic abnormalities and indicators of cardiovascular disease risk can be assessed non-invasively in women with PCOS, one of the world's most important health problems. At the same time, patients at risk can be followed more closely and carefully. Given that metabolic risks vary by phenotype and region, personalised assessment and management are essential.
{"title":"Elevated Aspartate Aminotransferase to Platelet Ratio Index Associated With Dyslipidaemia and Obesity in Patients With Polycystic Ovary Syndrome","authors":"Muradiye Yildirim, Neval Cayonu Kahraman, Mesut Simsek, Onur Numan, Belgin Savran Ucok, Dilara Duygulu Bulan, Yaprak Engin-Ustun","doi":"10.1111/aji.70171","DOIUrl":"10.1111/aji.70171","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>Polycystic ovary syndrome (PCOS) and steatotic liver disease associated with metabolic dysfunction are closely related. The aspartate aminotransferase platelet ratio index (APRI), one of the non-invasive indices, has a high prognostic value in metabolic and cardiovascular abnormalities. The primary outcome of this study was to compare APRI levels in PCOS patients with different metabolic subgroups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method of Study</h3>\u0000 \u0000 <p>The study included women aged 20–45 years with a diagnosis of PCOS. Baseline blood samples were collected after spontaneous menstrual bleeding between days 2 and 5 of the menstrual cycle, following an overnight fast. Patients were classified as obese or non-obese, with or without hypertriglyceridemia, and with normal or abnormal fasting glucose.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 106 patients were included in the study. Triglyceride, low-density lipoprotein cholesterol levels and APRI scores of lean and overweight patients were significantly lower than those of obese patients. APRI was significantly lower in normotriglyceridemic PCOS patients. The APRI score was positively correlated with triglycerides and negatively correlated with sex-hormone binding globulin.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Current evidence-based international guidelines emphasise that PCOS is not an isolated condition but a systemic endocrine disorder that requires multidisciplinary management. Metabolic abnormalities and indicators of cardiovascular disease risk can be assessed non-invasively in women with PCOS, one of the world's most important health problems. At the same time, patients at risk can be followed more closely and carefully. Given that metabolic risks vary by phenotype and region, personalised assessment and management are essential.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Zhao, Y. Yang, Y. Yang, Z. Chi, and Y. Sun, “Circ-ADAM9 Knockdown Reduces Insulin Resistance and Placental Injury in Diabetic Mice via MAPK Pathway Inactivation,” American Journal of Reproductive Immunology 92, no. 5 (2024): e70017, https://doi.org/10.1111/aji.70017.
In published version, the institution address “The People's Hospital of Nanjing Medical University,” is incorrect. It should be “The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University”.
{"title":"Correction to \"Circ-ADAM9 Knockdown Reduces Insulin Resistance and Placental Injury in Diabetic Mice via MAPK Pathway Inactivation\"","authors":"","doi":"10.1111/aji.70169","DOIUrl":"https://doi.org/10.1111/aji.70169","url":null,"abstract":"<p>A. Zhao, Y. Yang, Y. Yang, Z. Chi, and Y. Sun, “Circ-ADAM9 Knockdown Reduces Insulin Resistance and Placental Injury in Diabetic Mice via MAPK Pathway Inactivation,” <i>American Journal of Reproductive Immunology</i> 92, no. 5 (2024): e70017, https://doi.org/10.1111/aji.70017.</p><p>In published version, the institution address “The People's Hospital of Nanjing Medical University,” is incorrect. It should be “The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University”.</p><p>We apologize for this error.</p>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/aji.70169","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lidan Lu, Ximei Cai, Yang Zhang, Weibo Zhao, Haiyan Ni, Liping Zhang, Peijuan Wang
Objective
This study sought to investigate the therapeutic effects and mechanisms of cryptotanshinone (CT) on unexplained recurrent spontaneous abortion (URSA).
Methods
The DBA/2 male and CBA/J female mice were caged together to construct a URSA model before treatment with high and medium-low doses of CT. Enzyme-linked immunosorbent assay (ELISA) was used to detect levels of interleukin (IL)-1 beta (β), IL-17, and IL-22 in serum in each category of mice. Hematoxylin–eosin (HE) pathology was employed to detect decidua and uterine tissues, while polymerase chain reaction (PCR) was utilized to ascertain relative expression levels of serum messenger ribonucleic acid (mRNA) of IL-17, IL-22, and IL-1β. The effects of CT on H2O2-induced HTR-8/SVneo cells were investigated using cell counting kit-8 (CCK-8) assays and cell migration assays, while flow cytometry was used for the detection of apoptosis. Network pharmacology was used to analyze the mechanism of CT in the treatment of URSA. The repair effects and underlying mechanisms of the tumor protein 53 (p53) inhibitor and signal and transducer of transcription 3 small interfering RNA (STAT3 siRNA) were evaluated using ELISA assays, CCK-8, cell migration assays, flow cytometry, immunofluorescence, and Western blot techniques.
Results
Different doses of CT exerted protective effects on the uterine tissues of URSA. Also, CT could reduce levels of IL-17, IL-22, and IL-1β and their relative mRNA content in the serum of URSA mice, as well as increase the activity and migration rate of HTR-8/SVneo cells, and reduce the rate of apoptosis. Using p53 and STAT3 as mechanistic targets, we found that the p53 inhibitor, STAT3 siRNA, and CT restored the migratory activity of HTR-8/SVneo cells, reduced their apoptotic rate, and simultaneously downregulated the expression of retinoic acid receptor-related orphan receptor γt (RORγt) and vascular endothelial growth factor (VEGF).
Conclusion
The mechanism by which CT regulated the activity of HTR-8/SVneo cells involved the inhibition of p-p53, with STAT3, RORγt, and VEGF functioning as downstream targets of the p53 pathway.
{"title":"The Role of Cryptotanshinone Regulates HTR-8/SVneo Cells Activity Through the p53/STAT3 Pathway in Unexplained Recurrent Spontaneous Abortion","authors":"Lidan Lu, Ximei Cai, Yang Zhang, Weibo Zhao, Haiyan Ni, Liping Zhang, Peijuan Wang","doi":"10.1111/aji.70163","DOIUrl":"10.1111/aji.70163","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study sought to investigate the therapeutic effects and mechanisms of cryptotanshinone (CT) on unexplained recurrent spontaneous abortion (URSA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The DBA/2 male and CBA/J female mice were caged together to construct a URSA model before treatment with high and medium-low doses of CT. Enzyme-linked immunosorbent assay (ELISA) was used to detect levels of interleukin (IL)-1 beta (β), IL-17, and IL-22 in serum in each category of mice. Hematoxylin–eosin (HE) pathology was employed to detect decidua and uterine tissues, while polymerase chain reaction (PCR) was utilized to ascertain relative expression levels of serum messenger ribonucleic acid (mRNA) of IL-17, IL-22, and IL-1β. The effects of CT on H<sub>2</sub>O<sub>2</sub>-induced HTR-8/SVneo cells were investigated using cell counting kit-8 (CCK-8) assays and cell migration assays, while flow cytometry was used for the detection of apoptosis. Network pharmacology was used to analyze the mechanism of CT in the treatment of URSA. The repair effects and underlying mechanisms of the tumor protein 53 (p53) inhibitor and signal and transducer of transcription 3 small interfering RNA (STAT3 siRNA) were evaluated using ELISA assays, CCK-8, cell migration assays, flow cytometry, immunofluorescence, and Western blot techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Different doses of CT exerted protective effects on the uterine tissues of URSA. Also, CT could reduce levels of IL-17, IL-22, and IL-1β and their relative mRNA content in the serum of URSA mice, as well as increase the activity and migration rate of HTR-8/SVneo cells, and reduce the rate of apoptosis. Using p53 and STAT3 as mechanistic targets, we found that the p53 inhibitor, STAT3 siRNA, and CT restored the migratory activity of HTR-8/SVneo cells, reduced their apoptotic rate, and simultaneously downregulated the expression of retinoic acid receptor-related orphan receptor γt (RORγt) and vascular endothelial growth factor (VEGF).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The mechanism by which CT regulated the activity of HTR-8/SVneo cells involved the inhibition of p-p53, with STAT3, RORγt, and VEGF functioning as downstream targets of the p53 pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fabio Scarpellini, Marco Sbracia, Daniela Marconi, Alice Fracassi, Katya Santi, Eugenio Desole
Problem
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine promoting leukocyte proliferation and trophoblast growth. Recurrent implantation failure (RIF) is the repeated failure to reach pregnancy in IVF cycles. In this randomized controlled trial, the use of low dose of GM-CSF in the treatment of RIF in egg donation cycles was tested.
Methods of Study
A randomized controlled trial was conducted on women with RIF after egg donation cycles. The inclusion criteria were age between 30 and 49 years old: at least three previous transfers failed with good quality blastocysts in egg donation cycles: no uterine defects. The patients were randomly subdivided into two groups: one treated with subcutaneous GM-CSF 0.3microg/kg/day from the day before embryo transfer to the b-hCG day. Since RIF patients may be at risk for miscarriage, this treatment was continued until the eighth week of gestation to avoid possible early miscarriage. The control group was treated with a subcutaneous saline solution infusion in the same way as the study group. Primary outcomes were the clinical pregnancy rate and live-birth rate.
Results
Epidemiological data of the two groups did not show statistically significant differences. The clinical pregnancy rate in the GM-CSF group was 73.5% (39/53), while in control group it was 34.6% (18/52) (p < 0.0001), the live-birth rate was 67.9% (36/53) and 28.8% (15/52), respectively (p < 0.0001).
Conclusion
The clinical use of GM-CSF in women who experienced implantation failure may be a useful treatment in a selected group of patients. The model of women with RIF after egg donation, at the light of our results, may be considered a valid model to study this clinical entity.
{"title":"A Randomised Controlled Trial on the Treatment of Recurrent Implantation Failure Women Who Failed Egg Donation Cycles Using Low-Dose GM-CSF","authors":"Fabio Scarpellini, Marco Sbracia, Daniela Marconi, Alice Fracassi, Katya Santi, Eugenio Desole","doi":"10.1111/aji.70162","DOIUrl":"10.1111/aji.70162","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine promoting leukocyte proliferation and trophoblast growth. Recurrent implantation failure (RIF) is the repeated failure to reach pregnancy in IVF cycles. In this randomized controlled trial, the use of low dose of GM-CSF in the treatment of RIF in egg donation cycles was tested.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods of Study</h3>\u0000 \u0000 <p>A randomized controlled trial was conducted on women with RIF after egg donation cycles. The inclusion criteria were age between 30 and 49 years old: at least three previous transfers failed with good quality blastocysts in egg donation cycles: no uterine defects. The patients were randomly subdivided into two groups: one treated with subcutaneous GM-CSF 0.3microg/kg/day from the day before embryo transfer to the b-hCG day. Since RIF patients may be at risk for miscarriage, this treatment was continued until the eighth week of gestation to avoid possible early miscarriage. The control group was treated with a subcutaneous saline solution infusion in the same way as the study group. Primary outcomes were the clinical pregnancy rate and live-birth rate.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Epidemiological data of the two groups did not show statistically significant differences. The clinical pregnancy rate in the GM-CSF group was 73.5% (39/53), while in control group it was 34.6% (18/52) (<i>p</i> < 0.0001), the live-birth rate was 67.9% (36/53) and 28.8% (15/52), respectively (<i>p</i> < 0.0001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The clinical use of GM-CSF in women who experienced implantation failure may be a useful treatment in a selected group of patients. The model of women with RIF after egg donation, at the light of our results, may be considered a valid model to study this clinical entity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ClinicalTrials.gov identifier: NCT01715974.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 3","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chelsea A. DeBolt, Haocheng Yu, Valerie Riis, Liqhwa Ncube, Amir Horowitz, Michal A. Elovitz
Problem
Significant immunological shifts, systemically and at the maternal–fetal interface, are required for successful pregnancy. As immune perturbations are emerging as pivotal drivers of adverse maternal health, elucidating how normal pregnancy alters maternal systemic immunity is imperative.
Methods
From our prospectively enrolled cohort of Black women, peripheral blood samples were collected pre-pregnancy (V1) and in the second trimester (16–24 weeks, V2). Among those who became pregnant, 23 had available samples from both time points. RNA was extracted and subjected to bulk RNA sequencing, followed by differential gene expression analyses, immune cell-type deconvolution, and pathway enrichment analyses. Participants were stratified by pre-pregnancy obesity (body mass index ≥ 30 kg/m2) to examine its impact on pregnancy-induced immune changes.
Results
Pathway analyses revealed innate immune activation and increased neutrophil-driven inflammation during pregnancy. Significant increase in neutrophils and monocytes occurred during pregnancy, whereas naïve CD8+ T-cell and B-cell subsets were significantly decreased. Pre-pregnancy obesity amplified these changes, further increasing innate populations (gamma delta T cells, neutrophils) and decreasing adaptive populations (CD8 naïve T cells, B memory cells).
Conclusion
From individuals with uncomplicated pregnancies, we demonstrate dramatic immunological changes when transitioning from a non-pregnant to pregnant state. Intricate immune modulation, including changes in inflammatory mechanisms and immune cell dynamics were observed. Pre-pregnancy obesity enhances these inflammatory shifts, providing insights into potential mechanisms driving adverse pregnancy outcomes in obese women. Future studies investigating how these immunological shifts are required for optimal maternal health and/or may promote increased vulnerability to adverse pregnancy outcomes will create new opportunities to improve maternal outcomes.
{"title":"Revealing the Complexity of Immunobiological Shifts From Non-Pregnant to Pregnant State","authors":"Chelsea A. DeBolt, Haocheng Yu, Valerie Riis, Liqhwa Ncube, Amir Horowitz, Michal A. Elovitz","doi":"10.1111/aji.70166","DOIUrl":"10.1111/aji.70166","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>Significant immunological shifts, systemically and at the maternal–fetal interface, are required for successful pregnancy. As immune perturbations are emerging as pivotal drivers of adverse maternal health, elucidating how normal pregnancy alters maternal systemic immunity is imperative.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>From our prospectively enrolled cohort of Black women, peripheral blood samples were collected pre-pregnancy (V1) and in the second trimester (16–24 weeks, V2). Among those who became pregnant, 23 had available samples from both time points. RNA was extracted and subjected to bulk RNA sequencing, followed by differential gene expression analyses, immune cell-type deconvolution, and pathway enrichment analyses. Participants were stratified by pre-pregnancy obesity (body mass index ≥ 30 kg/m<sup>2</sup>) to examine its impact on pregnancy-induced immune changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Pathway analyses revealed innate immune activation and increased neutrophil-driven inflammation during pregnancy. Significant increase in neutrophils and monocytes occurred during pregnancy, whereas naïve CD8+ T-cell and B-cell subsets were significantly decreased. Pre-pregnancy obesity amplified these changes, further increasing innate populations (gamma delta T cells, neutrophils) and decreasing adaptive populations (CD8 naïve T cells, B memory cells).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>From individuals with uncomplicated pregnancies, we demonstrate dramatic immunological changes when transitioning from a non-pregnant to pregnant state. Intricate immune modulation, including changes in inflammatory mechanisms and immune cell dynamics were observed. Pre-pregnancy obesity enhances these inflammatory shifts, providing insights into potential mechanisms driving adverse pregnancy outcomes in obese women. Future studies investigating how these immunological shifts are required for optimal maternal health and/or may promote increased vulnerability to adverse pregnancy outcomes will create new opportunities to improve maternal outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 3","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Takashi Matsuzaki, Hiroaki Hamaguchi, Ken R. Ito, Ryota Nakagawa, Hiroya Nakamura, Hiroaki Ito, Chiyuki Ueshima, Akihiko Yoshizawa, Hironori Haga, Tatsuki R. Kataoka
Problem
Gonadotropin-releasing hormone (GnRH), primarily known for its hypothalamic role in regulating gonadotropin secretion, is also expressed in extra-hypothalamic tissues, including trophoblasts at implantation sites. We investigated the association between trophoblasts and mast cells, demonstrating their role in producing leukemia inhibitory factor (LIF) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesized an additional interaction between trophoblasts and mast cells mediated by GnRH.
Method of Study
Immunohistochemical analysis was conducted to investigate GnRH receptor (GnRHR) expressing mast cell in endometrial and tubal tissues from both pregnant and non-pregnant conditions (2005–2018). We established a human mast cell line LAD2 with forced expression of GnRHR expression (GnRHR-expressing LAD2) via lentiviral transfection method. The cells were stimulated with or without leuprorelin (1 µM) and transcriptomic analysis and cell migration assays were conducted.
Results
GnRHR is expressed in decidual mast cells during uterine pregnancy and in mast cells adjacent to or embedded in trophoblasts of tubal pregnancy. Notably, GnRHR expression was also observed in endometrial mast cells in non-pregnancy conditions. The levels of transcripts encoding LIF, MMP-9, and a natural killer (NK) cell attractant C-X-C motif chemokine ligand 16 (CXCL16) were significantly upregulated in GnRHR-expressing LAD2 than in control cells. In addition, culture supernatants from GnRHR-expressing LAD2 cells enhanced the migration of the trophoblast cell line HTR-8/SVneo and the NK cell line NK-92 MI.
Conclusions
These findings suggest that GnRHR expression in mast cells promotes their supportive role in pregnancy establishment by increasing the LIF, MMP-9, and CXCL16 productions, recruiting trophoblasts and NK cells.
{"title":"Aberrant Expression of Gonadotropin-Releasing Hormone Receptor in Human Mast Cells Enhances the Recruitments of Trophoblasts and NK Cells","authors":"Takashi Matsuzaki, Hiroaki Hamaguchi, Ken R. Ito, Ryota Nakagawa, Hiroya Nakamura, Hiroaki Ito, Chiyuki Ueshima, Akihiko Yoshizawa, Hironori Haga, Tatsuki R. Kataoka","doi":"10.1111/aji.70168","DOIUrl":"10.1111/aji.70168","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>Gonadotropin-releasing hormone (GnRH), primarily known for its hypothalamic role in regulating gonadotropin secretion, is also expressed in extra-hypothalamic tissues, including trophoblasts at implantation sites. We investigated the association between trophoblasts and mast cells, demonstrating their role in producing leukemia inhibitory factor (LIF) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesized an additional interaction between trophoblasts and mast cells mediated by GnRH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method of Study</h3>\u0000 \u0000 <p>Immunohistochemical analysis was conducted to investigate GnRH receptor (GnRHR) expressing mast cell in endometrial and tubal tissues from both pregnant and non-pregnant conditions (2005–2018). We established a human mast cell line LAD2 with forced expression of GnRHR expression (GnRHR-expressing LAD2) via lentiviral transfection method. The cells were stimulated with or without leuprorelin (1 µM) and transcriptomic analysis and cell migration assays were conducted.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>GnRHR is expressed in decidual mast cells during uterine pregnancy and in mast cells adjacent to or embedded in trophoblasts of tubal pregnancy. Notably, GnRHR expression was also observed in endometrial mast cells in non-pregnancy conditions. The levels of transcripts encoding LIF, MMP-9, and a natural killer (NK) cell attractant C-X-C motif chemokine ligand 16 (CXCL16) were significantly upregulated in GnRHR-expressing LAD2 than in control cells. In addition, culture supernatants from GnRHR-expressing LAD2 cells enhanced the migration of the trophoblast cell line HTR-8/SVneo and the NK cell line NK-92 MI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings suggest that GnRHR expression in mast cells promotes their supportive role in pregnancy establishment by increasing the LIF, MMP-9, and CXCL16 productions, recruiting trophoblasts and NK cells.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 3","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145084582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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