Pub Date : 2025-01-25DOI: 10.1016/j.jare.2025.01.035
Ziyue Zhang, Wei Huang, Li Wang, Guanjun Li, Fang Xu, Pengfei Wu, Chuqiao Luo, Qian Huang, Wenhua Kuang, Zhengyong Liu, Ying Jiang, Xiaoling Zhao, Yayuan Zhang, Wencai Ye, Juan Li, Nan Ma, Jigang Wang
Introduction
Triple-negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer, and effective therapeutic strategies are needed. Estrogen-related receptor alpha (ERRα) is considered a promising target for managing TNBC.
Objectives
Here, we aimed to screen natural products to find downregulator of ERRα and elucidate its mechanism of action.
Methods
TNBC cells (MDA-MB-231, MDA-MB-468, MDA-MB-453, and BT-549) were used for in vitro studies, and a subcutaneous MDA-MB-231 tumor model was created for in vivo studies. Immunofluorescence assessed protein distribution, while competitive activity-based protein profiling identified potential target proteins. Co-immunoprecipitation detected protein interactions and modifications, and a luciferase reporter assay evaluated ERRα transcriptional activity.
Results
The natural product Ailanthone (AIL) effectively induced cell death in TNBC cells by reducing the protein level of ERRα. The mechanism of action involved AIL promoting the degradation of ERRα through the ubiquitin–proteasome system, consequently reducing its transcriptional activity. The competitive-ABPP method mapped the profile of target proteins for AIL, and OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) was identified as a pivotal target of AIL in regulating ERRα protein levels. OTUB1 was validated as a novel deubiquitinating enzyme for ERRα, with its C91 residue being crucial for this deubiquitination process. AIL was found to inhibit the enzyme activity of OTUB1 by interacting with the C91 residue and disrupt the interaction between OTUB1 and ERRα, ultimately leading to the inhibition of ERRα.
Conclusion
AIL is a promising downregulator of ERRα, and the mechanism of this downregulation has been elucidated. Additionally, a new regulatory relationship between ERRα and OTUB1 is identified. The research presented in this article is anticipated to yield potential lead compounds for ERRα regulatory agents and to stimulate the development of novel therapeutic strategies designed to modulate ERRα activity for the treatment of TNBC.
{"title":"Ailanthone induces triple-negative breast cancer cells death involving the inhibition of OTUB1-mediated ERRα deubiquitylation","authors":"Ziyue Zhang, Wei Huang, Li Wang, Guanjun Li, Fang Xu, Pengfei Wu, Chuqiao Luo, Qian Huang, Wenhua Kuang, Zhengyong Liu, Ying Jiang, Xiaoling Zhao, Yayuan Zhang, Wencai Ye, Juan Li, Nan Ma, Jigang Wang","doi":"10.1016/j.jare.2025.01.035","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.035","url":null,"abstract":"<h3>Introduction</h3>Triple-negative breast cancer (TNBC) remains the most aggressive subtype of breast cancer, and effective therapeutic strategies are needed. Estrogen-related receptor alpha (ERRα) is considered a promising target for managing TNBC.<h3>Objectives</h3>Here, we aimed to screen natural products to find downregulator of ERRα and elucidate its mechanism of action.<h3>Methods</h3>TNBC cells (MDA-MB-231, MDA-MB-468, MDA-MB-453, and BT-549) were used for in vitro studies, and a subcutaneous MDA-MB-231 tumor model was created for in vivo studies. Immunofluorescence assessed protein distribution, while competitive activity-based protein profiling identified potential target proteins. Co-immunoprecipitation detected protein interactions and modifications, and a luciferase reporter assay evaluated ERRα transcriptional activity.<h3>Results</h3>The natural product Ailanthone (AIL) effectively induced cell death in TNBC cells by reducing the protein level of ERRα. The mechanism of action involved AIL promoting the degradation of ERRα through the ubiquitin–proteasome system, consequently reducing its transcriptional activity. The competitive-ABPP method mapped the profile of target proteins for AIL, and OTU domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) was identified as a pivotal target of AIL in regulating ERRα protein levels. OTUB1 was validated as a novel deubiquitinating enzyme for ERRα, with its C91 residue being crucial for this deubiquitination process. AIL was found to inhibit the enzyme activity of OTUB1 by interacting with the C91 residue and disrupt the interaction between OTUB1 and ERRα, ultimately leading to the inhibition of ERRα.<h3>Conclusion</h3>AIL is a promising downregulator of ERRα, and the mechanism of this downregulation has been elucidated. Additionally, a new regulatory relationship between ERRα and OTUB1 is identified. The research presented in this article is anticipated to yield potential lead compounds for ERRα regulatory agents and to stimulate the development of novel therapeutic strategies designed to modulate ERRα activity for the treatment of TNBC.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"8 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.jare.2025.01.042
Chen Liang, Xiao Liu, Jie Yu, Lingyun Shi, Wenchao Wei, Yalu Zhu, Maoping Feng, Tingting Tang, Dameng Li, Tao Yang, Junnian Zheng, Bo Ma, Liang Wei
Introduction
Hypericin (HP), a natural photosensitizer, has demonstrated great efficacy in photodynamic therapy (PDT) for cancer treatment. In addition to the induction of apoptosis and necrosis through reactive oxygen species (ROS) generation, the therapeutic mechanisms and targets of PDT-HP remain unknown.
Objectives
To investigate the direct targets and mechanisms of action of photoactivated hypericin in the inhibition of triple-negative breast cancer (TNBC).
Methods
Cell pyroptosis was examined via LDH release, SYTOX Green staining, and ELISA. RNA sequencing, network pharmacology, drug affinity target stability (DARTS)-tandem mass spectrometry (MS/MS), and molecular docking were employed to identify drug targets. Furthermore, immunoblotting and flow cytometry were utilized to elucidate the mechanisms of drug action.
Results
Our research revealed that PDT-HP can induce pyroptosis in TNBC cells. Further investigation revealed that PDT-HP induces endoplasmic reticulum stress, activating Caspase-3 and gasdermin E (GSDME) to trigger TNBC cell pyroptosis. RNA-seq, network pharmacology, and DARTS-MS/MS proteomic analyses revealed that the endoplasmic reticulum protein calreticulin (CALR) is a potential HP target and that interfering with CALR inhibited PDT-HP-induced pyroptosis. During PDT-HP treatment, the interaction between CALR and SERCA2 inactivates SERCA2, increasing the susceptibility of cells to increased intracellular Ca2+ levels under oxidative stress. This triggered endoplasmic reticulum stress and activated Caspase3, which further cleaved GSDME, releasing GSDME-N and ultimately leading to pyroptosis in TNBC cells.
Conclusion
In this study, we provide insight into the antitumor mechanism by examining the pharmacological mechanism by which PDT-HP regulates TNBC cell pyroptosis via the ROS/CALR/Caspase-3/GSDME signaling axis.
{"title":"Hypericin photoactivation induces triple-negative breast cancer cells pyroptosis by targeting the ROS/CALR/Caspase-3/GSDME pathway","authors":"Chen Liang, Xiao Liu, Jie Yu, Lingyun Shi, Wenchao Wei, Yalu Zhu, Maoping Feng, Tingting Tang, Dameng Li, Tao Yang, Junnian Zheng, Bo Ma, Liang Wei","doi":"10.1016/j.jare.2025.01.042","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.042","url":null,"abstract":"<h3>Introduction</h3>Hypericin (HP), a natural photosensitizer, has demonstrated great efficacy in photodynamic therapy (PDT) for cancer treatment. In addition to the induction of apoptosis and necrosis through reactive oxygen species (ROS) generation, the therapeutic mechanisms and targets of PDT-HP remain unknown.<h3>Objectives</h3>To investigate the direct targets and mechanisms of action of photoactivated hypericin in the inhibition of triple-negative breast cancer (TNBC).<h3>Methods</h3>Cell pyroptosis was examined via LDH release, SYTOX Green staining, and ELISA. RNA sequencing, network pharmacology, drug affinity target stability (DARTS)-tandem mass spectrometry (MS/MS), and molecular docking were employed to identify drug targets. Furthermore, immunoblotting and flow cytometry were utilized to elucidate the mechanisms of drug action.<h3>Results</h3>Our research revealed that PDT-HP can induce pyroptosis in TNBC cells. Further investigation revealed that PDT-HP induces endoplasmic reticulum stress, activating Caspase-3 and gasdermin E (GSDME) to trigger TNBC cell pyroptosis. RNA-seq, network pharmacology, and DARTS-MS/MS proteomic analyses revealed that the endoplasmic reticulum protein calreticulin (CALR) is a potential HP target and that interfering with CALR inhibited PDT-HP-induced pyroptosis. During PDT-HP treatment, the interaction between CALR and SERCA2 inactivates SERCA2, increasing the susceptibility of cells to increased intracellular Ca<sup>2+</sup> levels under oxidative stress. This triggered endoplasmic reticulum stress and activated Caspase3, which further cleaved GSDME, releasing GSDME-N and ultimately leading to pyroptosis in TNBC cells.<h3>Conclusion</h3>In this study, we provide insight into the antitumor mechanism by examining the pharmacological mechanism by which PDT-HP regulates TNBC cell pyroptosis via the ROS/CALR/Caspase-3/GSDME signaling axis.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"111 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.jare.2025.01.041
Raluca M. Boteanu, Viorel I. Suica, Elena Uyy, Luminita Ivan, Diana V. Uta, Razvan G. Mares, Maya Simionescu, Alexandru Schiopu, Felicia Antohe
Introduction
The infarcted heart is energetically compromised exhibiting a deficient production of adenosine triphosphate (ATP) and the ensuing impaired contractile function. Short-term blockade of the protein S100A9 improves cardiac performance in mice after myocardial infarction (MI). The implications upon ATP production during this process are not known.
Objectives
This study evaluates whether S100A9 blockade effects ATP synthesis and cardiac contractility in C57BL/6 mice at seven days post-MI.
Methods
Three experimental groups were used: (i) mice with MI, induced by permanent left coronary ligation, (ii) mice with MI, short-term treated with the S100A9 blocker ABR-238901, and (iii) sham (control) mice. After removing the left ventricle, mass spectrometry, pathway enrichment analysis, Western blot, RT-PCR and pharmacological network analysis were performed.
Results
A number of 600 differential abundance proteins (DAPs) was significantly altered by the S100A9 blocker in MI-treated mice compared with MI mice. Some of these proteins were associated with oxidative phosphorylation, citrate cycle (TCA), mitochondrial fatty acid beta-oxidation, glycolysis and cardiac muscle contraction pathways. In the ischemic ventricle, ABR-238901 treatment increased (1.8- to 38-fold) the abundance of proteins NDUFAB1, UQCRC1, HADHA, ACAA2, ALDOA, PKM1, DLD, DLAT, PDHX, ACO2, IDH3A, FH1, CKM, CKMT2, TNNC1, crucial for early cellular metabolic changes, ATP distribution and contractility. The cardiac level of ATP increased (1.8-fold, p < 0.05) in MI mice treated with ABR-238901 compared to MI mice. The network pharmacology analysis uncovered potential pharmacologic targets of ABR-238901 that may interact with DAPs related to ATP production and contractility.
Conclusion
Short-term S100A9 blockade effectively regulates the proteins implicated in ATP production and cardiac contractility post-MI, providing a framework for future cardiac energy metabolism studies.
{"title":"Cardiac ATP production and contractility are favorably regulated by short-term S100A9 blockade after myocardial infarction","authors":"Raluca M. Boteanu, Viorel I. Suica, Elena Uyy, Luminita Ivan, Diana V. Uta, Razvan G. Mares, Maya Simionescu, Alexandru Schiopu, Felicia Antohe","doi":"10.1016/j.jare.2025.01.041","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.041","url":null,"abstract":"<h3>Introduction</h3>The infarcted heart is energetically compromised exhibiting a deficient production of adenosine triphosphate (ATP) and the ensuing impaired contractile function. Short-term blockade of the protein S100A9 improves cardiac performance in mice after myocardial infarction (MI). The implications upon ATP production during this process are not known.<h3>Objectives</h3>This study evaluates whether S100A9 blockade effects ATP synthesis and cardiac contractility in C57BL/6 mice at seven days post-MI.<h3>Methods</h3>Three experimental groups were used: (i) mice with MI, induced by permanent left coronary ligation, (ii) mice with MI, short-term treated with the S100A9 blocker ABR-238901, and (iii) sham (control) mice. After removing the left ventricle, mass spectrometry, pathway enrichment analysis, Western blot, RT-PCR and pharmacological network analysis were performed.<h3>Results</h3>A number of 600 differential abundance proteins (DAPs) was significantly altered by the S100A9 blocker in MI-treated mice compared with MI mice. Some of these proteins were associated with oxidative phosphorylation, citrate cycle (TCA), mitochondrial fatty acid beta-oxidation, glycolysis and cardiac muscle contraction pathways. In the ischemic ventricle, ABR-238901 treatment increased (1.8- to 38-fold) the abundance of proteins NDUFAB1, UQCRC1, HADHA, ACAA2, ALDOA, PKM1, DLD, DLAT, PDHX, ACO2, IDH3A, FH1, CKM, CKMT2, TNNC1, crucial for early cellular metabolic changes, ATP distribution and contractility. The cardiac level of ATP increased (1.8-fold, p < 0.05) in MI mice treated with ABR-238901 compared to MI mice. The network pharmacology analysis uncovered potential pharmacologic targets of ABR-238901 that may interact with DAPs related to ATP production and contractility.<h3>Conclusion</h3>Short-term S100A9 blockade effectively regulates the proteins implicated in ATP production and cardiac contractility post-MI, providing a framework for future cardiac energy metabolism studies.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"35 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035071","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.jare.2025.01.036
Aya Osama, Ali Mostafa Anwar, Shahd Ezzeldin, Eman Ali Ahmed, Sebaey Mahgoub, Omneya Ibrahim, Sherif Abdelaziz Ibrahim, Ismail Abdelshafy Abdelhamid, Usama Bakry, Aya A. Diab, Ahmed A.Sayed, Sameh Magdeldin
Introduction
Gut microbiota alterations have been implicated in Autism Spectrum Disorder (ASD), yet the mechanisms linking these changes to ASD pathophysiology remain unclear.
Objectives
This study utilized a multi-omics approach to uncover mechanisms linking gut microbiota to ASD by examining microbial diversity, bacterial metaproteins, associated metabolic pathways and host proteome.
Methods
The gut microbiota of 30 children with severe ASD and 30 healthy controls was analyzed. Microbial diversity was assessed using 16S rRNA V3 and V4 sequencing. A novel metaproteomics pipeline identified bacterial proteins, while untargeted metabolomics explored altered metabolic pathways. Finally, multi-omics integration was employed to connect macromolecular changes to neurodevelopmental deficits.
Results
Children with ASD exhibited significant alterations in gut microbiota, including lower diversity and richness compared to controls. Tyzzerella was uniquely associated with the ASD group. Microbial network analysis revealed rewiring and reduced stability in ASD. Major metaproteins identified were produced by Bifidobacterium and Klebsiella (e.g., xylose isomerase and NADH peroxidase). Metabolomics profiling identified neurotransmitters (e.g., glutamate, DOPAC), lipids, and amino acids capable of crossing the blood–brain barrier, potentially contributing to neurodevelopmental and immune dysregulation. Host proteome analysis revealed altered proteins, including kallikrein (KLK1) and transthyretin (TTR), involved in neuroinflammation and immune regulation. Finally, multi-omics integration supported single-omics findings and reinforced the hypothesis that gut microbiota and their macromolecular products may contribute to ASD-associated symptoms.
Conclusions
The integration of multi-omics data provided critical evidence that alteration in gut microbiota and associated macromolecule production may play a role in ASD-related symptoms and co-morbidities. Key bacterial metaproteins and metabolites were identified as potential contributors to neurological and immune dysregulation in ASD, underscoring possible novel targets for therapeutic intervention.
{"title":"Integrative multi-omics analysis of autism spectrum disorder reveals unique microbial macromolecules interactions","authors":"Aya Osama, Ali Mostafa Anwar, Shahd Ezzeldin, Eman Ali Ahmed, Sebaey Mahgoub, Omneya Ibrahim, Sherif Abdelaziz Ibrahim, Ismail Abdelshafy Abdelhamid, Usama Bakry, Aya A. Diab, Ahmed A.Sayed, Sameh Magdeldin","doi":"10.1016/j.jare.2025.01.036","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.036","url":null,"abstract":"<h3>Introduction</h3>Gut microbiota alterations have been implicated in Autism Spectrum Disorder (ASD), yet the mechanisms linking these changes to ASD pathophysiology remain unclear.<h3>Objectives</h3>This study utilized a multi-omics approach to uncover mechanisms linking gut microbiota to ASD by examining microbial diversity, bacterial metaproteins, associated metabolic pathways and host proteome.<h3>Methods</h3>The gut microbiota of 30 children with severe ASD and 30 healthy controls was analyzed. Microbial diversity was assessed using 16S rRNA V3 and V4 sequencing. A novel metaproteomics pipeline identified bacterial proteins, while untargeted metabolomics explored altered metabolic pathways. Finally, multi-omics integration was employed to connect macromolecular changes to neurodevelopmental deficits.<h3>Results</h3>Children with ASD exhibited significant alterations in gut microbiota, including lower diversity and richness compared to controls. <em>Tyzzerella</em> was uniquely associated with the ASD group. Microbial network analysis revealed rewiring and reduced stability in ASD. Major metaproteins identified were produced by <em>Bifidobacterium</em> and <em>Klebsiella</em> (e.g., xylose isomerase and NADH peroxidase). Metabolomics profiling identified neurotransmitters (e.g., glutamate, DOPAC), lipids, and amino acids capable of crossing the blood–brain barrier, potentially contributing to neurodevelopmental and immune dysregulation. Host proteome analysis revealed altered proteins, including kallikrein (KLK1) and transthyretin (TTR), involved in neuroinflammation and immune regulation. Finally, multi-omics integration supported single-omics findings and reinforced the hypothesis that gut microbiota and their macromolecular products may contribute to ASD-associated symptoms.<h3>Conclusions</h3>The integration of multi-omics data provided critical evidence that alteration in gut microbiota and associated macromolecule production may play a role in ASD-related symptoms and co-morbidities. Key bacterial metaproteins and metabolites were identified as potential contributors to neurological and immune dysregulation in ASD, underscoring possible novel targets for therapeutic intervention.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"113 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031104","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1016/j.jare.2025.01.037
Yeye Kuang, Yijian Yu, Chan Wang, Hui Li, Yiru Zhou, Lijuan Pan, Yi Zhang, Xiaoqing Cheng, Zhinong Jiang, Xiaotong Hu
Introduction
Tumor suppressor gene (TSG) inactivation by epigenetic modifications contributes to the carcinogenesis and progression of colorectal cancer (CRC). Expression profiling and CpG methylomics revealed that a forkhead-box transcriptional factor, FOXS1, is downregulated and methylated in CRC.
Objectives
To assess the biological functions and underlying mechanisms of FOXS1 in colorectal cancer.
Methods
Public databases, semi-quantitative RT-PCR, immunohistochemistry, MSP, and BGS were used to analyze FOXS1 expression and promoter methylation in CRC. Stable FOXS1-overexpressing or knockdown cell lines were established. Cell growth, colony formation, flow cytometry, GFP-LC3 puncta detection, Ad-mCherry-GFP-LC3B, qPCR, in vivo subcutaneous tumor model, RNA-seq, western blotting, immunofluorescence, Co-IP assays, and protein stability analysis were performed to investigate the underlying molecular mechanisms of FOXS1.
Results
In CRC, FOXS1 was frequently downregulated due to promoter CpG methylation, acting as an independent prognostic marker. Moreover, FOXS1 exerts inhibitory effects on the growth of CRC cells in vitro and in vivo, while concurrently promoting CRC cell autophagy. Intriguingly, we found that FOXS1 interacted with transforming growth factor beta induced (TGFBI) and FOXS1 promoted TGFBI degradation through the autophagy–lysosome pathway rather than the ubiquitin–proteasome system. FOXS1 was also found to facilitate the interaction between TGFBI and lysosomal associated membrane protein 2A (LAMP2A), leading to the translocation of TGFBI into lysosomes for degradation. Additionally, FOXS1 regulates AKT phosphorylation and FOXO3a nuclear translocation, promoting the transcription of autophagy-related genes downstream of FOXO3a. Restoration of TGFBI expression reversed the suppressive effect exerted by FOXS1 on the growth of colorectal cancer cells.
Conclusion
FOXS1 functions as a tumor suppressor that is methylated in CRC and promotes the lysosomal degradation of TGFBI, regulates cell growth and promotes autophagy in CRC through the TGFBI/AKT/FOXO3a signaling pathway. These findings indicate that FOXS1 exhibits potential as a promising biomarker and therapeutic target for colorectal cancer.
{"title":"FOXS1, frequently inactivated by promoter methylation, inhibited colorectal cancer cell growth by promoting TGFBI degradation through autophagy-lysosome pathway","authors":"Yeye Kuang, Yijian Yu, Chan Wang, Hui Li, Yiru Zhou, Lijuan Pan, Yi Zhang, Xiaoqing Cheng, Zhinong Jiang, Xiaotong Hu","doi":"10.1016/j.jare.2025.01.037","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.037","url":null,"abstract":"<h3>Introduction</h3>Tumor suppressor gene (TSG) inactivation by epigenetic modifications contributes to the carcinogenesis and progression of colorectal cancer (CRC). Expression profiling and CpG methylomics revealed that a forkhead-box transcriptional factor, FOXS1, is downregulated and methylated in CRC.<h3>Objectives</h3>To assess the biological functions and underlying mechanisms of FOXS1 in colorectal cancer<strong>.</strong><h3>Methods</h3>Public databases, semi-quantitative RT-PCR, immunohistochemistry, MSP, and BGS were used to analyze FOXS1 expression and promoter methylation in CRC. Stable FOXS1-overexpressing or knockdown cell lines were established. Cell growth, colony formation, flow cytometry, GFP-LC3 puncta detection, Ad-mCherry-GFP-LC3B, qPCR, <em>in vivo</em> subcutaneous tumor model, RNA-seq, western blotting, immunofluorescence, Co-IP assays, and protein stability analysis were performed to investigate the underlying molecular mechanisms of FOXS1.<h3>Results</h3>In CRC, FOXS1 was frequently downregulated due to promoter CpG methylation, acting as an independent prognostic marker. Moreover, FOXS1 exerts inhibitory effects on the growth of CRC cells <em>in vitro</em> and <em>in vivo</em>, while concurrently promoting CRC cell autophagy. Intriguingly, we found that FOXS1 interacted with transforming growth factor beta induced (TGFBI) and FOXS1 promoted TGFBI degradation through the autophagy–lysosome pathway rather than the ubiquitin–proteasome system. FOXS1 was also found to facilitate the interaction between TGFBI and lysosomal associated membrane protein 2A (LAMP2A), leading to the translocation of TGFBI into lysosomes for degradation. Additionally, FOXS1 regulates AKT phosphorylation and FOXO3a nuclear translocation, promoting the transcription of autophagy-related genes downstream of FOXO3a. Restoration of TGFBI expression reversed the suppressive effect exerted by FOXS1 on the growth of colorectal cancer cells.<h3>Conclusion</h3>FOXS1 functions as a tumor suppressor that is methylated in CRC and promotes the lysosomal degradation of TGFBI, regulates cell growth and promotes autophagy in CRC through the TGFBI/AKT/FOXO3a signaling pathway. These findings indicate that FOXS1 exhibits potential as a promising biomarker and therapeutic target for colorectal cancer.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"58 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.jare.2025.01.030
Mei Chen, Jiahui Shi, Tianyao Liu, Jiayin Liu, Yulong Liu, Jianghui Li, Yi Luo, Jing Luo, Xin Li, Hong Gong, Xiaotang Fan
Introduction
Autism spectrum disorder (ASD) represents a multifaceted set of neurodevelopmental conditions marked by social deficits and repetitive behaviors. Astragaloside IV (ASIV), a natural compound derived from the traditional Chinese herb Astragali Radix, exhibits robust neuroprotective effects. However, whether ASIV can ameliorate behavioral deficits in ASD remains unknown.
Objectives
This work aimed to determine the efficacy and molecular mechanisms of ASIV in ASD.
Methods
The autistic BTBR T + tf/J (BTBR) mice were used in this study. Behavioral tests were performed to assess the ASD-like phenotypes. The neurotransmitter levels and synaptic transmission were evaluated by high-performance liquid chromatography and whole-cell patch-clamp recordings, respectively. Molecular biological techniques, immunostaining, and RNA-sequencing (RNA-seq) were combined to uncover the underlying molecular mechanisms.
Results
Our study showed that both social impairment and repetitive behaviors were significantly improved after ASIV treatment in a dose-dependent manner in BTBR mice. The ASIV treatment normalized the neurotransmitter levels (GABA and glutamate) and their corresponding vesicular transporters (vGAT, vGLUT1) in the medial prefrontal cortex (mPFC). Furthermore, the excitation-inhibition imbalance in layer V of mPFC was reversed after ASIV administration. Mechanistically, bulk RNA-seq and PPI network analysis identified Camk2n2 as the crucial bridging gene regulating oxidative phosphorylation and neurotransmission. Camk2n2 overexpression in the mPFC abolished the beneficial effects of ASIV on autistic symptoms in BTBR mice via the Camk2/CREB pathway.
Conclusion
The evidence demonstrates that ASIV may become a promising treatment option for ASD and implies that targeting the Camk2n2/Camk2/CREB axis is warranted to investigate these ASD individuals further.
自闭症谱系障碍（ASD）代表了以社会缺陷和重复行为为特征的多方面的神经发育状况。黄芪甲苷（Astragaloside IV， ASIV）是一种从传统中药黄芪中提取的天然化合物，具有强大的神经保护作用。然而，asv是否可以改善ASD的行为缺陷仍然未知。目的探讨asv治疗ASD的疗效及分子机制。方法采用自闭BTBR T + tf/J （BTBR）小鼠。行为测试评估asd样表型。分别用高效液相色谱法和全细胞膜片钳法测定神经递质水平和突触传递。结合分子生物学技术，免疫染色和rna测序（RNA-seq）来揭示潜在的分子机制。结果BTBR小鼠经asv治疗后，社交障碍和重复行为均有剂量依赖性改善。asv治疗使内侧前额叶皮层（mPFC）的神经递质（GABA和谷氨酸）及其相应的囊泡转运蛋白（vGAT, vGLUT1）水平正常化。此外，注射asv后，mPFC第V层的兴奋-抑制不平衡被逆转。在机制上，大量RNA-seq和PPI网络分析发现Camk2n2是调节氧化磷酸化和神经传递的关键桥接基因。mPFC中的Camk2n2过表达通过Camk2/CREB途径消除了asv对BTBR小鼠自闭症症状的有益作用。结论有证据表明，asv可能成为ASD的一种有前景的治疗选择，并表明靶向Camk2n2/Camk2/CREB轴是进一步研究这些ASD个体的必要条件。
{"title":"Astragaloside IV ameliorates autism-like behaviors in BTBR mice by modulating Camk2n2-dependent OXPHOS and neurotransmission in the mPFC","authors":"Mei Chen, Jiahui Shi, Tianyao Liu, Jiayin Liu, Yulong Liu, Jianghui Li, Yi Luo, Jing Luo, Xin Li, Hong Gong, Xiaotang Fan","doi":"10.1016/j.jare.2025.01.030","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.030","url":null,"abstract":"<h3>Introduction</h3>Autism spectrum disorder (ASD) represents a multifaceted set of neurodevelopmental conditions marked by social deficits and repetitive behaviors. Astragaloside IV (ASIV), a natural compound derived from the traditional Chinese herb Astragali Radix, exhibits robust neuroprotective effects. However, whether ASIV can ameliorate behavioral deficits in ASD remains unknown.<h3>Objectives</h3>This work aimed to determine the efficacy and molecular mechanisms of ASIV in ASD.<h3>Methods</h3>The autistic BTBR T + tf/J (BTBR) mice were used in this study. Behavioral tests were performed to assess the ASD-like phenotypes. The neurotransmitter levels and synaptic transmission were evaluated by high-performance liquid chromatography and whole-cell patch-clamp recordings, respectively. Molecular biological techniques, immunostaining, and RNA-sequencing (RNA-seq) were combined to uncover the underlying molecular mechanisms.<h3>Results</h3>Our study showed that both social impairment and repetitive behaviors were significantly improved after ASIV treatment in a dose-dependent manner in BTBR mice. The ASIV treatment normalized the neurotransmitter levels (GABA and glutamate) and their corresponding vesicular transporters (vGAT, vGLUT1) in the medial prefrontal cortex (mPFC). Furthermore, the excitation-inhibition imbalance in layer V of mPFC was reversed after ASIV administration. Mechanistically, bulk RNA-seq and PPI network analysis identified Camk2n2 as the crucial bridging gene regulating oxidative phosphorylation and neurotransmission. Camk2n2 overexpression in the mPFC abolished the beneficial effects of ASIV on autistic symptoms in BTBR mice via the Camk2/CREB pathway.<h3>Conclusion</h3>The evidence demonstrates that ASIV may become a promising treatment option for ASD and implies that targeting the Camk2n2/Camk2/CREB axis is warranted to investigate these ASD individuals further.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"27 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Periodontal diseases are prevalent among middle-aged and elderly individuals. There’s still no satisfactory solution for tooth loss caused by periodontal diseases. Human periodontal ligament stem cells (hPDLSCs) is a distinctive subgroup of mesenchymal stem cells, which play a crucial role in periodontal supportive tissues, but their application value hasn’t been fully explored yet. As a regulatory subunit of PI3K, PIK3R3′s role in stem cell regulation remains poorly comprehended.
Objectives
This study aims to explore the regulatory effect of PIK3R3 on differentiation and senescence of hPDLSCs and the underlying mechanism, as well as whether overexpression of PIK3R3 mitigate alveolar bone loss in aged rats.
Methods
Human PDLSC lines with both PIK3R3 knockdown and overexpression are established. Osteogenic, adipogenic, chondrogenic and senescent induction are used to test the effect of PIK3R3 on senescence in vitro. Model of alveolar bone loss in aged mice is used to reveal the effect of PIK3R3 in vivo. FOXO1 siRNA is used for mechanism exploration.
Results
Knockdown of PIK3R3 inhibits the mRNA and protein expression of markers in osteogenic, adipogenic, and chondrogenic differentiation of hPDLSCs but promotes in vitro senescence of hPDLSCs, including cell proliferation, senescence markers expression, telomerase density and reactive oxygen species. Overexpression of PIK3R3 has the opposite effect. Furthermore, the result of Micro-CT and tissue section shows that overexpression of PIK3R3 in elder rats mitigates alveolar bone loss. Mechanistically, PIK3R3 regulates senescence of hPDLSCs through modulating FOXO1 expression. Expression of FOXO1 is altered when PIK3R3 is knocked down or overexpressed in senescent medium. Knockdown of FOXO1 promotes senescence of hPDLSCs and the senescence promoting effect of knocking down PIK3R3 is weakened when FOXO1 is highly expressed.
Conclusion
These findings indicate that PIK3R3 modulates senescence of MSCs by regulating FOXO1 expression and shows promise as a therapeutic target for mitigating age-related alveolar bone loss.
{"title":"PIK3R3 regulates differentiation and senescence of periodontal ligament stem cells and mitigates age-related alveolar bone loss by modulating FOXO1 expression","authors":"Xuenan Liu, Donghao Wei, Feilong Wang, Fanyu Yan, Xiao Zhang, Yongsheng Zhou, Ping Zhang, Yunsong Liu","doi":"10.1016/j.jare.2025.01.031","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.031","url":null,"abstract":"<h3>Introduction</h3>Periodontal diseases are prevalent among middle-aged and elderly individuals. There’s still no satisfactory solution for tooth loss caused by periodontal diseases. Human periodontal ligament stem cells (hPDLSCs) is a distinctive subgroup of mesenchymal stem cells, which play a crucial role in periodontal supportive tissues, but their application value hasn’t been fully explored yet. As a regulatory subunit of PI3K, PIK3R3′s role in stem cell regulation remains poorly comprehended.<h3>Objectives</h3>This study aims to explore the regulatory effect of PIK3R3 on differentiation and senescence of hPDLSCs and the underlying mechanism, as well as whether overexpression of PIK3R3 mitigate alveolar bone loss in aged rats.<h3>Methods</h3>Human PDLSC lines with both <em>PIK3R3</em> knockdown and overexpression are established. Osteogenic, adipogenic, chondrogenic and senescent induction are used to test the effect of PIK3R3 on senescence <em>in vitro</em>. Model of alveolar bone loss in aged mice is used to reveal the effect of PIK3R3 <em>in vivo</em>. FOXO1 siRNA is used for mechanism exploration.<h3>Results</h3>Knockdown of <em>PIK3R3</em> inhibits the mRNA and protein expression of markers in osteogenic, adipogenic, and chondrogenic differentiation of hPDLSCs but promotes <em>in vitro</em> senescence of hPDLSCs, including cell proliferation, senescence markers expression, telomerase density and reactive oxygen species. Overexpression of <em>PIK3R3</em> has the opposite effect. Furthermore, the result of Micro-CT and tissue section shows that overexpression of <em>PIK3R3</em> in elder rats mitigates alveolar bone loss. Mechanistically, PIK3R3 regulates senescence of hPDLSCs through modulating FOXO1 expression. Expression of FOXO1 is altered when <em>PIK3R3</em> is knocked down or overexpressed in senescent medium. Knockdown of FOXO1 promotes senescence of hPDLSCs and the senescence promoting effect of knocking down <em>PIK3R3</em> is weakened when FOXO1 is highly expressed.<h3>Conclusion</h3>These findings indicate that PIK3R3 modulates senescence of MSCs by regulating FOXO1 expression and shows promise as a therapeutic target for mitigating age-related alveolar bone loss.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"13 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143026617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1016/j.jare.2025.01.032
Jie Wang, Ting Gao, Dongmei Zhang, Yufeng Tang, Junlian Gu
Background
Phospholipase C epsilon 1 (PLCε1) can hydrolyze phosphatidylinositol-4,5-bisphosphate and phosphatidylinositol-4-phosphate at the plasma membrane and perinuclear membrane in the cardiovascular system, producing lipid-derived second messengers. These messengers are considered prominent triggers for various signal transduction processes. Notably, diverse cardiac phenotypes have been observed in cardiac-specific and global Plce1 knockout mice under conditions of pathological stress. It is well established that the cardiac-specific Plce1 knockout confers cardioprotective benefits. Therefore, the development of tissue/cell-specific targeting approaches is critical for advancing therapeutic interventions.
Aim of Review:
This review aims to distill the foundational biology and functional significance of PLCε1 in cardiovascular diseases, as well as to explore potential avenues for research and the development of novel therapeutic strategies targeting PLCε1.
Key Scientific Concepts of Review:
Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, with incidence rates escalating annually. A comprehensive understanding of the multifaceted role of PLCε1 is essential for enhancing the diagnosis, management, and prognostic assessment of patients suffering from cardiovascular diseases.
{"title":"Phospholipase C epsilon 1 as a therapeutic target in cardiovascular diseases","authors":"Jie Wang, Ting Gao, Dongmei Zhang, Yufeng Tang, Junlian Gu","doi":"10.1016/j.jare.2025.01.032","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.032","url":null,"abstract":"<h3>Background</h3>Phospholipase C epsilon 1 (PLCε1) can hydrolyze phosphatidylinositol-4,5-bisphosphate and phosphatidylinositol-4-phosphate at the plasma membrane and perinuclear membrane in the cardiovascular system, producing lipid-derived second messengers. These messengers are considered prominent triggers for various signal transduction processes. Notably, diverse cardiac phenotypes have been observed in cardiac-specific and global <em>Plce1</em> knockout mice under conditions of pathological stress. It is well established that the cardiac-specific <em>Plce1</em> knockout confers cardioprotective benefits. Therefore, the development of tissue/cell-specific targeting approaches is critical for advancing therapeutic interventions.<h3>Aim of Review:</h3>This review aims to distill the foundational biology and functional significance of PLCε1 in cardiovascular diseases, as well as to explore potential avenues for research and the development of novel therapeutic strategies targeting PLCε1.<h3>Key Scientific Concepts of Review:</h3>Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide, with incidence rates escalating annually. A comprehensive understanding of the multifaceted role of PLCε1 is essential for enhancing the diagnosis, management, and prognostic assessment of patients suffering from cardiovascular diseases.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"18 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142992625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-22DOI: 10.1016/j.jare.2025.01.033
Zipeng Jiang, Weifa Su, Mingzhi Yang, Jie Fu, Tao Gong, Wentao Li, Chaoyue Wen, Xinxia Wang, Fengqin Wang, Mingliang Jin, Yizhen Wang, Zeqing Lu
Introduction
Clostridium perfringens (C. perfringens) can cause necrotic enteritis and higher mortality rates in piglets, by impairing the intestinal barrier function. Bacillus amyloliquefaciens 40 (BA40) has showed potential ability to reduce C. perfringens infections, but the mechanisms responsible for its effectiveness remain unclear.
Objectives
This study aims to evaluate the impact of BA40 on inflammation induced by C. perfringens and to explain the mechanisms underlying its therapeutic effects. We aim to show how BA40 can bolster piglet health by strengthening the intestinal barrier and regulating immune responses.
Methods
We used piglets and cellular models, alongside microbiomics, metabolomic, and transcriptomic analyses, to investigate BA40′s impact on C. perfringens-induced inflammation. A model of C. perfringens infection was constructed using piglets and cells to investigate the effect of BA40 on its phenotype. Microbiomics, metabolomics, and transcriptomics analyses were subsequently used to investigate the mechanisms of protection and immune response to BA40 on the intestinal barrier of piglets.
Results
Our study revealed significant improvements in piglet health following BA40 administration. Notably, BA40 strengthened the intestinal mucosal barrier and mitigated the inflammatory response triggered by C. perfringens BA40 decreased harmful bacteria and increased beneficial bacteria. Metabolite profiles improved, showing a reduction in harmful substances. Transscriptomics analysis indicated BA40′s role in TNF/NF-κB signaling pathway, hinting at its ability to regulate immune responses and reduce intestinal inflammation. Cellular assays further confirmed BA40′s capacity to diminish inflammatory cytokine release and encourage the differentiation of anti-inflammatory macrophages.
Conclusion
Datasets from the present study demonstrate that BA40 modulates gut microbes and metabolites, inhibits inflammation-related signaling pathways, and maintains gut barrier function. Our findings not only deepen our understanding of the therapeutic capacity of BA40 but also provide a theoretical foundation for the development of probiotics and alternative therapies aimed at improving piglet gut health.
{"title":"Integrated multi-omics reveals the Bacillus amyloliquefaciens BA40 against Clostridium perfringens infection in weaned piglets","authors":"Zipeng Jiang, Weifa Su, Mingzhi Yang, Jie Fu, Tao Gong, Wentao Li, Chaoyue Wen, Xinxia Wang, Fengqin Wang, Mingliang Jin, Yizhen Wang, Zeqing Lu","doi":"10.1016/j.jare.2025.01.033","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.033","url":null,"abstract":"<h3>Introduction</h3><em>Clostridium perfringens</em> (<em>C. perfringens</em>) can cause necrotic enteritis and higher mortality rates in piglets, by impairing the intestinal barrier function. <em>Bacillus amyloliquefaciens</em> 40 (BA40) has showed potential ability to reduce <em>C. perfringens</em> infections, but the mechanisms responsible for its effectiveness remain unclear.<h3>Objectives</h3>This study aims to evaluate the impact of BA40 on inflammation induced by <em>C. perfringens</em> and to explain the mechanisms underlying its therapeutic effects. We aim to show how BA40 can bolster piglet health by strengthening the intestinal barrier and regulating immune responses.<h3>Methods</h3>We used piglets and cellular models, alongside microbiomics, metabolomic, and transcriptomic analyses, to investigate BA40′s impact on <em>C. perfringens</em>-induced inflammation. A model of <em>C. perfringens</em> infection was constructed using piglets and cells to investigate the effect of BA40 on its phenotype. Microbiomics, metabolomics, and transcriptomics analyses were subsequently used to investigate the mechanisms of protection and immune response to BA40 on the intestinal barrier of piglets.<h3>Results</h3>Our study revealed significant improvements in piglet health following BA40 administration. Notably, BA40 strengthened the intestinal mucosal barrier and mitigated the inflammatory response triggered by <em>C. perfringens</em> BA40 decreased harmful bacteria and increased beneficial bacteria. Metabolite profiles improved, showing a reduction in harmful substances. Transscriptomics analysis indicated BA40′s role in TNF/NF-κB signaling pathway, hinting at its ability to regulate immune responses and reduce intestinal inflammation. Cellular assays further confirmed BA40′s capacity to diminish inflammatory cytokine release and encourage the differentiation of anti-inflammatory macrophages.<h3>Conclusion</h3>Datasets from the present study demonstrate that BA40 modulates gut microbes and metabolites, inhibits inflammation-related signaling pathways, and maintains gut barrier function. Our findings not only deepen our understanding of the therapeutic capacity of BA40 but also provide a theoretical foundation for the development of probiotics and alternative therapies aimed at improving piglet gut health.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"33 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143020923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Despite of numerous studies of the placenta, some molecular and cellular characteristics, particularly the relationship among different cell types, have not been well understood. We aim to investigate the basic and intricate details of cellular and molecular elements in early and late phase placentas to gain better understanding of the immune regulation of human reproductive process.
Methods
A novel combination of techniques of spatial transcriptomics(ST), multiple immunohistochemistry, and a dual labeling combining immunohistochemistry and (fluorescence in situ hybridization) FISH on normal and ectopic pregnancy and animal models was employed to investigate the placenta at tissue, cell, protein and molecular levels and to trace the fetal and maternal origin of every cell in early and late placentas.
Results
Original discoveries include early expression of immune checkpoint proteins in embryo trophoblasts even before implantation. The detailed distributional relationships among different cell types of fetal and maternal origins in placenta and decidua indicate an immune rejection of the mother towards the fetus and this was counterbalanced by immune inhibitory proteins and blocking antibody Immunoglobulin G4 (IgG4) at the junction between the fetus and the mother. In contrary to common believe, we found that vascular endothelial and glandular epithelial cells in the decidua remain maternal in origin and were not replaced by fetal cells. At term placenta, fetal immune cells infiltrated into the maternal side of the decidus and vice versa indicating a possible immune reaction between fetal and maternal immune systems and suggesting a possible immune mechanism for trigger of parturition. The ability of trophoblasts to create an immune suppressed environment was also supported by findings in ectopic pregnancy and the animal models.
Conclusion
The findings indicate a fetus-driven mechanism of immune balance involving both cellular and humoral immunity in human reproduction.
{"title":"Molecular and cellular morphology of placenta unveils new mechanisms of reproductive immunology","authors":"Penghao Li, Liting Zeng, Xiaomiao Yan, Ziqi Zhu, Qiaoxiu Gu, Xuqing He, Sujuan Zhang, Rurong Mao, Jingliang Xu, Fengshan Xie, Hui Wang, Ziteng Li, Jing Shu, Weifeng Zhang, Yulin Sha, Jin Huang, Meng Su, Qu Zheng, Jian Ma, Xiaolin Zhou, Jiang Gu","doi":"10.1016/j.jare.2025.01.025","DOIUrl":"https://doi.org/10.1016/j.jare.2025.01.025","url":null,"abstract":"<h3>Introduction</h3>Despite of numerous studies of the placenta, some molecular and cellular characteristics, particularly the relationship among different cell types, have not been well understood. We aim to investigate the basic and intricate details of cellular and molecular elements in early and late phase placentas to gain better understanding of the immune regulation of human reproductive process.<h3>Methods</h3>A novel combination of techniques of spatial transcriptomics(ST), multiple immunohistochemistry, and a dual labeling combining immunohistochemistry and (fluorescence in situ hybridization) FISH on normal and ectopic pregnancy and animal models was employed to investigate the placenta at tissue, cell, protein and molecular levels and to trace the fetal and maternal origin of every cell in early and late placentas.<h3>Results</h3>Original discoveries include early expression of immune checkpoint proteins in embryo trophoblasts even before implantation. The detailed distributional relationships among different cell types of fetal and maternal origins in placenta and decidua indicate an immune rejection of the mother towards the fetus and this was counterbalanced by immune inhibitory proteins and blocking antibody Immunoglobulin G4 (IgG4) at the junction between the fetus and the mother. In contrary to common believe, we found that vascular endothelial and glandular epithelial cells in the decidua remain maternal in origin and were not replaced by fetal cells. At term placenta, fetal immune cells infiltrated into the maternal side of the decidus and vice versa indicating a possible immune reaction between fetal and maternal immune systems and suggesting a possible immune mechanism for trigger of parturition. The ability of trophoblasts to create an immune suppressed environment was also supported by findings in ectopic pregnancy and the animal models.<h3>Conclusion</h3>The findings indicate a fetus-driven mechanism of immune balance involving both cellular and humoral immunity in human reproduction.","PeriodicalId":14952,"journal":{"name":"Journal of Advanced Research","volume":"49 1","pages":""},"PeriodicalIF":10.7,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142991052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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