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Targeted Degradation Technology Based on the Autophagy-Lysosomal Pathway: A Promising Strategy for Treating Preeclampsia
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-03-06 DOI: 10.1111/aji.70066
Lin Xiao, Zilin Mei, Jin Chen, Kai Zhao, Huiping Zhang, Surendra Sharma, Aihua Liao, Chunyan Liu

In recent years, targeted protein degradation (TPD) strategies leveraging the autophagy-lysosomal pathway (ALP) have transcended the limitations of conventional drug molecules, emerging as a highly promising approach for selectively eliminating disease-related proteins via the cell's intrinsic degradation machinery. These TPD methods, such as autophagosome-tethering compounds (ATTEC), autophagy-targeting chimera (AUTAC), AUTOphagy-TArgeting chimera (AUTOTAC), and chaperone-mediated autophagy (CMA) targeting chimera, exhibit efficacy in degrading misfolded protein aggregates associated with neurodegenerative disorders. Moreover, the excessive accumulation of misfolded proteins or protein complexes in the placenta has been identified as a significant contributor to preeclampsia (PE). Given the lack of effective treatments for PE, the application of autophagy-mediated TPD technology presents a novel therapeutic avenue. This review draws parallels between misfolded protein aggregates in neurodegenerative diseases and placenta-derived PE, integrating a substantial number of full-text studies. By harnessing TPD technologies grounded in the ALP, these autophagic degraders offer a pioneering approach for targeted therapy in PE by dismantling potential targets. Presently, there is limited exploration of ALP technology for identifying target proteins in the placenta. Nonetheless, we have proposed several potential target proteins, laying the groundwork for future therapeutic endeavors.

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引用次数: 0
Causal Relationship Between Abortion and Endometriosis: A Bidirectional Two-Sample Mendelian Randomization Study
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-03-03 DOI: 10.1111/aji.70064
Yan Huang, Deyu Zhang, Yingfang Zhou, Chao Peng

Problem

The relationship between abortion and endometriosis (EMS) has been inconsistent in previous observational studies and remains controversial. We intended to examine the causal relationship between abortion and EMS.

Methods of Study

We conducted a Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics, drawing data from the FinnGen database and the UK Biobank. The primary analysis utilized the random-effects inverse variance weighted (IVW) approach, complemented by weighted median, weighted mode, and MR–Egger methods. Comprehensive sensitivity analyses were conducted, encompassing the Cochran's Q statistic for assessing heterogeneity and MR-PRESSO to detect pleiotropy. Additionally, Leave-One-Out (LOO) analysis was conducted to confirm the stability of our results.

Results

The IVW method revealed no statistically significant causal association between various types of abortion and EMS. Specifically, the odds ratios (ORs) were as follows: medical abortion (OR 0.96, 95% CI: 0.78–1.18, p = 0.72), spontaneous abortion (OR 0.99, 95% CI: 0.81–1.21, p = 0.92), and other types of abortions (OR 1.01, 95% CI: 0.99–1.03, p = 0.36), indicating no significant effects on the risk of EMS. Similarly, analysis in the reverse direction showed no significant causal effects of EMS on the likelihood of experiencing any type of abortion, with ORs for medical abortion (0.97, 95% CI: 0.91–1.03, p = 0.33), spontaneous abortion (0.98, 95% CI: 0.92–1.04, p = 0.50), and other abortions (1.30, 95% CI: 0.76–2.23, p = 0.34). Sensitivity analyses supported these findings, demonstrating no evidence of horizontal pleiotropy or significant heterogeneity.

Conclusion

Our MR results do not support a causal relationship between abortion and EMS.

{"title":"Causal Relationship Between Abortion and Endometriosis: A Bidirectional Two-Sample Mendelian Randomization Study","authors":"Yan Huang,&nbsp;Deyu Zhang,&nbsp;Yingfang Zhou,&nbsp;Chao Peng","doi":"10.1111/aji.70064","DOIUrl":"https://doi.org/10.1111/aji.70064","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>The relationship between abortion and endometriosis (EMS) has been inconsistent in previous observational studies and remains controversial. We intended to examine the causal relationship between abortion and EMS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods of Study</h3>\u0000 \u0000 <p>We conducted a Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary statistics, drawing data from the FinnGen database and the UK Biobank. The primary analysis utilized the random-effects inverse variance weighted (IVW) approach, complemented by weighted median, weighted mode, and MR–Egger methods. Comprehensive sensitivity analyses were conducted, encompassing the Cochran's <i>Q</i> statistic for assessing heterogeneity and MR-PRESSO to detect pleiotropy. Additionally, Leave-One-Out (LOO) analysis was conducted to confirm the stability of our results.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The IVW method revealed no statistically significant causal association between various types of abortion and EMS. Specifically, the odds ratios (ORs) were as follows: medical abortion (OR 0.96, 95% CI: 0.78–1.18, <i>p</i> = 0.72), spontaneous abortion (OR 0.99, 95% CI: 0.81–1.21, <i>p</i> = 0.92), and other types of abortions (OR 1.01, 95% CI: 0.99–1.03, <i>p</i> = 0.36), indicating no significant effects on the risk of EMS. Similarly, analysis in the reverse direction showed no significant causal effects of EMS on the likelihood of experiencing any type of abortion, with ORs for medical abortion (0.97, 95% CI: 0.91–1.03, <i>p</i> = 0.33), spontaneous abortion (0.98, 95% CI: 0.92–1.04, <i>p</i> = 0.50), and other abortions (1.30, 95% CI: 0.76–2.23, <i>p</i> = 0.34). Sensitivity analyses supported these findings, demonstrating no evidence of horizontal pleiotropy or significant heterogeneity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our MR results do not support a causal relationship between abortion and EMS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"93 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530373","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}
引用次数: 0
The Role of Mast Cells in the Development and Advancement of Endometriosis
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-03-03 DOI: 10.1111/aji.70019
Masoud Hassanzadeh Makoui, Shiva Fekri, Reza Hassanzadeh Makoui, Negar Ansari, Abdolreza Esmaeilzadeh

Endometriosis is a medical condition identified by the presence of endometrium-like tissue outside the uterus. This condition is known to result in symptoms such as frequent pelvic pain, infertility, and irregularities in the menstrual cycle. The development of endometriosis is complex and, involving abnormal body responses, hormonal imbalances, and genetic predispositions. Although endometriosis is common and affects quality of life, its mechanisms of development and progression are not fully understood. Mast cells (MCs), a type of immune cell, are renowned for their involvement in allergic and inflammatory responses. These cells are essential in the modulation of the immune system and the inflammatory process through the secretion of different mediators like histamine, cytokines, and proteases. In recent years, MCs have been shown to play a role in the pathogenesis of many diseases, including endometriosis. This article explores the relationship between MCs and endometriosis, including disease development, pain perception, angiogenesis, and other important processes. It elucidates how MCs, via their mediators, actively participate in the pathogenesis of endometriosis and the associated inflammatory environment. Moreover, the research emphasizes the potential of targeting MCs as a therapeutic approach for treating endometriosis. Insight into the interplay between endometriosis and MCs holds promise for developing innovative therapeutic strategies to manage this condition effectively.

{"title":"The Role of Mast Cells in the Development and Advancement of Endometriosis","authors":"Masoud Hassanzadeh Makoui,&nbsp;Shiva Fekri,&nbsp;Reza Hassanzadeh Makoui,&nbsp;Negar Ansari,&nbsp;Abdolreza Esmaeilzadeh","doi":"10.1111/aji.70019","DOIUrl":"https://doi.org/10.1111/aji.70019","url":null,"abstract":"<div>\u0000 \u0000 <p>Endometriosis is a medical condition identified by the presence of endometrium-like tissue outside the uterus. This condition is known to result in symptoms such as frequent pelvic pain, infertility, and irregularities in the menstrual cycle. The development of endometriosis is complex and, involving abnormal body responses, hormonal imbalances, and genetic predispositions. Although endometriosis is common and affects quality of life, its mechanisms of development and progression are not fully understood. Mast cells (MCs), a type of immune cell, are renowned for their involvement in allergic and inflammatory responses. These cells are essential in the modulation of the immune system and the inflammatory process through the secretion of different mediators like histamine, cytokines, and proteases. In recent years, MCs have been shown to play a role in the pathogenesis of many diseases, including endometriosis. This article explores the relationship between MCs and endometriosis, including disease development, pain perception, angiogenesis, and other important processes. It elucidates how MCs, via their mediators, actively participate in the pathogenesis of endometriosis and the associated inflammatory environment. Moreover, the research emphasizes the potential of targeting MCs as a therapeutic approach for treating endometriosis. Insight into the interplay between endometriosis and MCs holds promise for developing innovative therapeutic strategies to manage this condition effectively.</p>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"93 3","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143530315","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}
引用次数: 0
Finding Potential Drug Targets for Pre-Eclampsia Using Mendelian Randomisation and Colocalisation Analysis
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-03-03 DOI: 10.1111/aji.70063
Yuexin Xu, Yingzi Pan, Chengqian Wu, Tingting Zhao, Jiayan Miao, Xiaohong Ji

Introduction

Pre-eclampsia (PE) is a common complication of pregnancy and there is an urgent need for new drug targets. We performed whole proteome-wide Mendelian randomisation (MR) and colocalisation analyses to identify potential therapeutic targets for PE.

Material and Methods

A two-sample MR study was conducted using summary-level statistics of 734 plasma proteins retrieved from large genome-proteome-wide association studies. The summary statistics of PE or eclampsia were obtained from the FinnGen consortium. Wald ratio and Inverse variance weighted (IVW) were used to assess the causal association between proteins and PE. Colocalisation analyses were conducted to examine whether the identified proteins and PE shared incidental variants.

Results

Genetically predicted circulating levels of 42 proteins were associated with PE risk after Benjamini-Hochberg correction. Nineteen of the gene-predicted proteins showed evidence of increased PE risk (CRELD1, CPA4, AHSG, NFASC, QDPR, NTM, PZP, FAM171B, RTN4R, FLRT2, ADH4, ADM, SPINK5, LGALS4, CKM, SPON2, UROS, CXCL10 and APOBEC3G); 23 proteins reduced the risk of PE (CLIC5, NEO1, SWAP70, KLK8, VWA2, FSTL1, CXCL11, APOB, NPPB, CNTN4, IL12B, ACHE, TCN1, GFRA2, GNMT, HPGDS, DPT, MANBA, SPARCL1, ACE, FUT8, BST1 and ACP1). Bayesian colocalisation indicated that six proteins (VWA2, ACHE, CXCL10, PZP, AHSG and UROS) and PE, which were identified as high evidence of colocalisation with PE.

Conclusions

This study provides evidence of the causal association between genetically predicted 42 proteins associated with PE risk, which might be promising drug targets for PE.

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引用次数: 0
Causal Association Between Female Infertility and Circulating Immune Cells: A Bidirectional Mendelian Randomization Study
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-25 DOI: 10.1111/aji.70061
Xuan Zhou, Yu-Xuan Fang, Li-Ya Ma, Da-Wei Zhang, Man-Man Yao

Background

Female infertility (FI) is a global health issue. The etiology remains incompletely understood, but immunologic factors play important roles. This study aims to elucidate the causal association between FI and immune cells (ICs) via Mendelian randomization (MR) analysis.

Methods

The MR analyses employ genetic variants as instrumental variables to evaluate exposure's causal impact on outcomes. In this study, the two-sample MR method was performed to investigate the causal correlation of FI with 731 immunophenotypes of human peripheral blood lymphocytes. Complementary MR methods performed included the weighted median estimator (WME) and inverse variance weighted (IVW). In addition, sensitivity analyses were performed to assess and minimize heterogeneity and horizontal pleiotropy, and reverse MR analysis was used to assess reverse causality.

Results

The results revealed that four immune phenotypes were substantially linked with the risk of developing FI: CD33dim HLA DR+CD11b+%CD33dim HLA DR + (IVW: p = 0.0396, OR: 0.98 and WME: p = 0.0208, OR: 0.97), CD39+CD4+AC (IVW: p = 0.0031, OR: 1.03 and WME: p = 0.0264, OR: 1.03), CD27 on IgD-CD38bright (IVW: p = 0.0401, OR: 0.93 and WME: p = 0.0194, OR: 0.90), CD28 on resting Treg (IVW: p = 0.0019, OR: 0.91 and WME: p = 0.0128, OR: 0.92). The main findings were validated by the sensitivity analyses, indicating data reliability.

Conclusions

In summary, this investigation carried out MR analysis to provide evidence suggesting a causal association between ICs and FI, thereby furnishing new literature on the disease as well as a basis for the establishment of immunomodulatory therapeutic avenues.

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引用次数: 0
Aging Is Associated With Decreased Lactobacillus and Increased Cervicovaginal Inflammation in Canadian Women
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-19 DOI: 10.1111/aji.70058
Ha T. Dang, Laura Noel-Romas, Samantha Knodel, Kenzie Birse, Alana Lamont, Kateryna Kratzer, Peter McQueen, Michelle Perner, Hossaena Ayele, Alicia R. Berard, John J. Schellenberg, Stuart McCorrister, Garrett Westmacott, Bonnie Sandberg, Adelicia Yu, Margaret Burnett, Vanessa Poliquin, Adam D. Burgener, Christina Farr Zuend

Problem

Aging is characterized by a general dysregulation of systemic immune responses that increases susceptibility to infections and malignancies. Immune cells in the female genital tract (FGT) are regulated by sex hormones, but little is known about the impact of aging and menopause on immunology in the FGT.

Method of Study

This study conducted an age-focused sub-analysis of cervicovaginal samples collected from 47 women enrolled in the Vaginal Mucosal Systems study in Winnipeg, Canada. Paired cervicovaginal lavage and cervical cytobrush were collected and analyzed by Luminex cytokine array, mass spectrometry based metaproteomics, metabolomics, and high dimensional flow cytometry.

Results

The median age of study participants was 38 (range 19–88), with 12 over the age of 50. Increasing age was significantly correlated with increased cervicovaginal inflammation, including inflammatory cytokine MIP-1β (r = 0.335, p = 0.023), and activated T cells (CD4+HLA-DR+ r = 0406, p = 0.009; CD8+HLA-DR+ r = 0.399, p = 0.010; CD8+CD38+HLA-DR+ r = 0.386, p = 0.013). Proteomic analysis of cervicovaginal mucus identified 925 human proteins, with 108 (11.7%) significantly correlated with age. Pathway analysis indicated biofunctions related to immune response, migration, and myeloid cell phagocytosis increased with age. Interestingly, neutrophil related pathways decreased with age, including G-CSF (r = −0.396, p = 0.006) and reactive oxygen species (z-score = −2.607, p = 2.31E-4). Vaginal Lactobacillus crispatus, a species associated with mucosal health, significantly decreased with age (r = −0.340, p = 0.022), with participants over the age of 50 more likely to have non-Lactobacillus dominant microbiomes compared to those under 40.

Conclusions

Together, our data suggests that there is an increase in cervicovaginal inflammation and a decrease in L. crispatus that occurs with aging.

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引用次数: 0
Immune Treatment Strategies in Unexplained Recurrent Pregnancy Loss
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 DOI: 10.1111/aji.70060
Rui Cai, Qiaoran Yang, Yingjun Liao, Lang Qin, Jinbiao Han, Rui Gao

Recurrent pregnancy loss (RPL) is characterized by the occurrence of two or more consecutive pregnancy losses. Approximately half of these cases lack a clear etiology and are termed unexplained recurrent pregnancy loss (URPL). Maternal–fetal immune dysfunction is thought to be involved in causing URPL. Increased human leukocyte antigen compatibility, susceptibility genes, lack of blocking antibodies, and dysfunction of immune cells can all disrupt the immune tolerance environment of the maternal–fetal interface. To correct the maternal–fetal immune imbalances, some immunotherapies were recently tried to be used for patients with URPL. This review summarizes the characteristics and mechanisms of the immune microenvironment at the maternal–fetal interface of URPL patients, and the present immunotherapies for URPL patients, to serve as a reference for future research.

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引用次数: 0
Understanding the Associations of Urogenital Microbiomes With Fertility and In Vitro Fertilization
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-13 DOI: 10.1111/aji.70035
Alicia R. Berard, Douglas K. Brubaker, Dalí X. Nemecio, Christina Farr Zuend

Infertility, defined as the inability to establish a clinical pregnancy after a year of regular, unprotected sexual intercourse, impacts 8%–12% of couples worldwide. Many of these couples turn to in vitro fertilization (IVF) to build their families. The success rate of IVF procedures is variable, with estimates of up to 40% of embryo transfers being unsuccessful. Herein we review the existing literature on the role of the female and male urogenital microbiomes and genital inflammation on fertility and IVF outcomes. We discuss the microbiome across the female reproductive tract (FRT) and identify associations with female infertility, female genital tract inflammation, and success of IVF procedures. We also discuss the male urogenital microbiome and the associations between microbial taxa, genital inflammation, and male fertility parameters. Finally, we consider microbial transfer within couples and the impact this may have on fertility and the success of IVF procedures.

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引用次数: 0
Comments on “Efficacy of Corticosteroids in Patients With Recurrent Pregnancy Loss: A Systematic Review and Meta-Analysis”
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-13 DOI: 10.1111/aji.70059
Nosaibah Razaqi, Rachana Mehta, Shubham Kumar, Ranjana Sah
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引用次数: 0
Investigation of the Potential Treatment Effect of Botulinum Toxin Type A in Ovarian Torsion: Findings From the Rat Model
IF 2.5 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-08 DOI: 10.1111/aji.70057
Çağlayan Ateş, Berna Dilbaz, Seval Yılmaz Ergani, Pelin Seçken, Caner Köse

Background

The aim of this study was to investigate the effects of botulinum toxin A on histological abnormalities, loss of ovarian reserve, and angiogenesis within the ovarian torsion–detorsion paradigm.

Methods

A total of 45 female Wistar albino rats were used for the study. The rats were randomly divided into five groups (n = 9 in each group): Control, Torsion, Torsion + Detorsion, Torsion + Detorsion + Botulinum toxin, and Botulinum toxin only. Follicular cell degeneration, vascular congestion, hemorrhage, inflammation, and vascular endothelial growth factor (VEGF) expression scores were compared histopathologically between the groups. Follicle numbers were compared. Anti-mullerian hormone levels were measured before and after torsion, detorsion, and treatments.

Results

Follicular cell degeneration, vascular congestion, hemorrhage, inflammation, and VEGF expression differed significantly between groups for each score (< 0.001). The VEGF expression score was found to increase more in the torsion + detorsion + botulinum toxin group than in the torsion + detorsion group (2.67 ± 0.71 and 2.22 ± 0.67, respectively). There was a significant difference between the groups in secondary follicle counts (p = 0.04). The groups showed statistically significant differences in their anti-mullerian hormone levels (< 0.001).

Conclusion

This initial investigation of the effects of botulinum toxin on ovarian torsion (OT) has shown that botulinum toxin type A has the potential to be a useful adjunct treatment for fertility preservation. Our results proved the ovarian protective effect of botulinum toxin type A in rats with OT. Therefore, botulinum toxin type A may be a potential preventive agent against ovarian damage caused by torsion in the future.

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引用次数: 0
期刊
American Journal of Reproductive Immunology
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