Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01257-4
Minglong Qiu, Leilei Chang, Guoqing Tang, Wenkai Ye, Yiming Xu, Nijiati Tulufu, Zhou Dan, Jin Qi, Lianfu Deng, Changwei Li
The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic β cell from STZ-induced apoptosis, promotion of pancreatic β cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM. The skeleton isn’t just for support, it also helps control body functions. This research looked at how a specific process in bone-forming cells, called the hypoxia-inducible factor-1 alpha (HIF-1α) pathway, affects sugar breakdown and diabetes. The scientists discovered that triggering this process in these cells can help manage sugar levels in diabetes through a protein named RegIIIγ. They also found that a substance named SF-DFO, which imitates low oxygen conditions and focuses on bone tissue, can somewhat ease type 1 diabetes symptoms by triggering the HIF-1α-RegIIIγ process in the skeleton. This implies that this specific process in bone-forming cells could be a possible treatment for type 1 diabetes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Activation of the osteoblastic HIF-1α pathway partially alleviates the symptoms of STZ-induced type 1 diabetes mellitus via RegIIIγ","authors":"Minglong Qiu, Leilei Chang, Guoqing Tang, Wenkai Ye, Yiming Xu, Nijiati Tulufu, Zhou Dan, Jin Qi, Lianfu Deng, Changwei Li","doi":"10.1038/s12276-024-01257-4","DOIUrl":"10.1038/s12276-024-01257-4","url":null,"abstract":"The hypoxia-inducible factor-1α (HIF-1α) pathway coordinates skeletal bone homeostasis and endocrine functions. Activation of the HIF-1α pathway increases glucose uptake by osteoblasts, which reduces blood glucose levels. However, it is unclear whether activating the HIF-1α pathway in osteoblasts can help normalize glucose metabolism under diabetic conditions through its endocrine function. In addition to increasing bone mass and reducing blood glucose levels, activating the HIF-1α pathway by specifically knocking out Von Hippel‒Lindau (Vhl) in osteoblasts partially alleviated the symptoms of streptozotocin (STZ)-induced type 1 diabetes mellitus (T1DM), including increased glucose clearance in the diabetic state, protection of pancreatic β cell from STZ-induced apoptosis, promotion of pancreatic β cell proliferation, and stimulation of insulin secretion. Further screening of bone-derived factors revealed that islet regeneration-derived protein III gamma (RegIIIγ) is an osteoblast-derived hypoxia-sensing factor critical for protection against STZ-induced T1DM. In addition, we found that iminodiacetic acid deferoxamine (SF-DFO), a compound that mimics hypoxia and targets bone tissue, can alleviate symptoms of STZ-induced T1DM by activating the HIF-1α-RegIIIγ pathway in the skeleton. These data suggest that the osteoblastic HIF-1α-RegIIIγ pathway is a potential target for treating T1DM. The skeleton isn’t just for support, it also helps control body functions. This research looked at how a specific process in bone-forming cells, called the hypoxia-inducible factor-1 alpha (HIF-1α) pathway, affects sugar breakdown and diabetes. The scientists discovered that triggering this process in these cells can help manage sugar levels in diabetes through a protein named RegIIIγ. They also found that a substance named SF-DFO, which imitates low oxygen conditions and focuses on bone tissue, can somewhat ease type 1 diabetes symptoms by triggering the HIF-1α-RegIIIγ process in the skeleton. This implies that this specific process in bone-forming cells could be a possible treatment for type 1 diabetes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01258-3
Se-Ra Park, Myung Geun Kook, Soo-Rim Kim, Choon-Mi Lee, Jin Woo Lee, Jung-Kyu Park, Chan Hum Park, Byung-Chul Oh, YunJae Jung, In-Sun Hong
The reciprocal crosstalk between testicular Sertoli and Leydig cells plays a vital role in supporting germ cell development and maintaining testicular characteristics and spermatogenesis. Conventional 2D and the recent 3D assay systems fail to accurately replicate the dynamic interactions between these essential endocrine cells. Furthermore, most in vitro testicular tissue models lack the ability to capture the complex multicellular nature of the testis. To address these limitations, we developed a 3D multicellular testis-on-a-chip platform that effectively demonstrates the reciprocal crosstalk between Sertoli cells and the adjacent Leydig cells while incorporating various human testicular tissue constituent cells and various natural polymers infused with blood coagulation factors. Additionally, we identified SERPINB2 as a biomarker of male reproductive toxicity that is activated in both Sertoli and Leydig cells upon exposure to various toxicants. Leveraging this finding, we designed a fluorescent reporter-conjugated toxic biomarker detection system that enables both an intuitive and quantitative assessment of material toxicity by measuring the converted fluorescence intensity. By integrating this fluorescent reporter system into the Sertoli and Leydig cells within our 3D multicellular chip platform, we successfully developed a testis-on-chip model that can be utilized to evaluate the male reproductive toxicity of potential drug candidates. This innovative approach holds promise for advancing toxicity screening and reproductive research. Spermatogenesis, or sperm creation, happens in the testis and involves various cells, including Sertoli and Leydig cells. However, traditional single-cell-based 2D assay models (tests that measure the presence of a substance) don’t accurately show the complex interactions between these cells. To solve this, scientists created a ‘human testis-on-a-chip’ platform that imitates the complex cell interactions and hormone communication of seminiferous tubules (small tubes) in the testis. The chip was made using polydimethylsiloxane (a type of silicone) and included multiple testicular tissue cells. The scientists found that the chip could keep the cells alive and active for up to 28 days. Also, the chip was able to produce hormones and respond to hormonal stimulation. This study provides a useful tool for studying male reproductive biology and testing potential drugs. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Development of a novel testis-on-a-chip that demonstrates reciprocal crosstalk between Sertoli and Leydig cells in testicular tissue","authors":"Se-Ra Park, Myung Geun Kook, Soo-Rim Kim, Choon-Mi Lee, Jin Woo Lee, Jung-Kyu Park, Chan Hum Park, Byung-Chul Oh, YunJae Jung, In-Sun Hong","doi":"10.1038/s12276-024-01258-3","DOIUrl":"10.1038/s12276-024-01258-3","url":null,"abstract":"The reciprocal crosstalk between testicular Sertoli and Leydig cells plays a vital role in supporting germ cell development and maintaining testicular characteristics and spermatogenesis. Conventional 2D and the recent 3D assay systems fail to accurately replicate the dynamic interactions between these essential endocrine cells. Furthermore, most in vitro testicular tissue models lack the ability to capture the complex multicellular nature of the testis. To address these limitations, we developed a 3D multicellular testis-on-a-chip platform that effectively demonstrates the reciprocal crosstalk between Sertoli cells and the adjacent Leydig cells while incorporating various human testicular tissue constituent cells and various natural polymers infused with blood coagulation factors. Additionally, we identified SERPINB2 as a biomarker of male reproductive toxicity that is activated in both Sertoli and Leydig cells upon exposure to various toxicants. Leveraging this finding, we designed a fluorescent reporter-conjugated toxic biomarker detection system that enables both an intuitive and quantitative assessment of material toxicity by measuring the converted fluorescence intensity. By integrating this fluorescent reporter system into the Sertoli and Leydig cells within our 3D multicellular chip platform, we successfully developed a testis-on-chip model that can be utilized to evaluate the male reproductive toxicity of potential drug candidates. This innovative approach holds promise for advancing toxicity screening and reproductive research. Spermatogenesis, or sperm creation, happens in the testis and involves various cells, including Sertoli and Leydig cells. However, traditional single-cell-based 2D assay models (tests that measure the presence of a substance) don’t accurately show the complex interactions between these cells. To solve this, scientists created a ‘human testis-on-a-chip’ platform that imitates the complex cell interactions and hormone communication of seminiferous tubules (small tubes) in the testis. The chip was made using polydimethylsiloxane (a type of silicone) and included multiple testicular tissue cells. The scientists found that the chip could keep the cells alive and active for up to 28 days. Also, the chip was able to produce hormones and respond to hormonal stimulation. This study provides a useful tool for studying male reproductive biology and testing potential drugs. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01262-7
Nayeon Kim, Junyeong Ma, Wonjong Kim, Jungyeon Kim, Peter Belenky, Insuk Lee
Recent substantial evidence implicating commensal bacteria in human diseases has given rise to a new domain in biomedical research: microbiome medicine. This emerging field aims to understand and leverage the human microbiota and derivative molecules for disease prevention and treatment. Despite the complex and hierarchical organization of this ecosystem, most research over the years has relied on 16S amplicon sequencing, a legacy of bacterial phylogeny and taxonomy. Although advanced sequencing technologies have enabled cost-effective analysis of entire microbiota, translating the relatively short nucleotide information into the functional and taxonomic organization of the microbiome has posed challenges until recently. In the last decade, genome-resolved metagenomics, which aims to reconstruct microbial genomes directly from whole-metagenome sequencing data, has made significant strides and continues to unveil the mysteries of various human-associated microbial communities. There has been a rapid increase in the volume of whole metagenome sequencing data and in the compilation of novel metagenome-assembled genomes and protein sequences in public depositories. This review provides an overview of the capabilities and methods of genome-resolved metagenomics for studying the human microbiome, with a focus on investigating the prokaryotic microbiota of the human gut. Just as decoding the human genome and its variations marked the beginning of the genomic medicine era, unraveling the genomes of commensal microbes and their sequence variations is ushering us into the era of microbiome medicine. Genome-resolved metagenomics stands as a pivotal tool in this transition and can accelerate our journey toward achieving these scientific and medical milestones. The human body houses numerous microbes, tiny organisms, that are vital for our health. This research aims to overcome limitations using genome-resolved metagenomics, a method that assembles complete genomes from complex microbial communities without needing to grow the organisms in a lab. The study focuses on the gut microbiome, using advanced computer methods to build metagenome-assembled genomes from DNA sequencing data. The research successfully increased the genetic diversity of the human gut microbiome by adding many new genomes to the existing database. The main findings include identifying new microbial species and expanding the genetic repertoire of known species, providing deeper understanding of the microbial diversity within the human gut. Researchers conclude that genome-resolved metagenomics is a significant advancement in microbiome research, offering understanding of microbial communities and their functions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Genome-resolved metagenomics: a game changer for microbiome medicine","authors":"Nayeon Kim, Junyeong Ma, Wonjong Kim, Jungyeon Kim, Peter Belenky, Insuk Lee","doi":"10.1038/s12276-024-01262-7","DOIUrl":"10.1038/s12276-024-01262-7","url":null,"abstract":"Recent substantial evidence implicating commensal bacteria in human diseases has given rise to a new domain in biomedical research: microbiome medicine. This emerging field aims to understand and leverage the human microbiota and derivative molecules for disease prevention and treatment. Despite the complex and hierarchical organization of this ecosystem, most research over the years has relied on 16S amplicon sequencing, a legacy of bacterial phylogeny and taxonomy. Although advanced sequencing technologies have enabled cost-effective analysis of entire microbiota, translating the relatively short nucleotide information into the functional and taxonomic organization of the microbiome has posed challenges until recently. In the last decade, genome-resolved metagenomics, which aims to reconstruct microbial genomes directly from whole-metagenome sequencing data, has made significant strides and continues to unveil the mysteries of various human-associated microbial communities. There has been a rapid increase in the volume of whole metagenome sequencing data and in the compilation of novel metagenome-assembled genomes and protein sequences in public depositories. This review provides an overview of the capabilities and methods of genome-resolved metagenomics for studying the human microbiome, with a focus on investigating the prokaryotic microbiota of the human gut. Just as decoding the human genome and its variations marked the beginning of the genomic medicine era, unraveling the genomes of commensal microbes and their sequence variations is ushering us into the era of microbiome medicine. Genome-resolved metagenomics stands as a pivotal tool in this transition and can accelerate our journey toward achieving these scientific and medical milestones. The human body houses numerous microbes, tiny organisms, that are vital for our health. This research aims to overcome limitations using genome-resolved metagenomics, a method that assembles complete genomes from complex microbial communities without needing to grow the organisms in a lab. The study focuses on the gut microbiome, using advanced computer methods to build metagenome-assembled genomes from DNA sequencing data. The research successfully increased the genetic diversity of the human gut microbiome by adding many new genomes to the existing database. The main findings include identifying new microbial species and expanding the genetic repertoire of known species, providing deeper understanding of the microbial diversity within the human gut. Researchers conclude that genome-resolved metagenomics is a significant advancement in microbiome research, offering understanding of microbial communities and their functions. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01264-5
Dong-Joon Lee, Pyunggang Kim, Hyun-Yi Kim, Jinah Park, Seung-Jun Lee, Haein An, Jin Sun Heo, Min-Jung Lee, Hayato Ohshima, Seiya Mizuno, Satoru Takahashi, Han-Sung Jung, Seong-Jin Kim
The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity. The research examines the function of MAST4, a protein, in tooth growth, particularly in creating enamel (the hard, outer layer of the tooth). Scientists discovered that mice without MAST4 had unusual enamel development in their front teeth, resulting in weaker teeth. The research showed that MAST4 is vital for preserving stem cells (cells that can develop into many different cell types) and controlling their transformation into ameloblasts (cells that create enamel). Without MAST4, this process was disrupted, causing early enamel release and incorrect maturation. The scientists also discovered that MAST4 controls the function of another protein, DLX3, necessary for enamel maturation. This research offers a new understanding of the molecular processes involved in tooth growth and could be significant for understanding and treating dental issues. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"MAST4 regulates stem cell maintenance with DLX3 for epithelial development and amelogenesis","authors":"Dong-Joon Lee, Pyunggang Kim, Hyun-Yi Kim, Jinah Park, Seung-Jun Lee, Haein An, Jin Sun Heo, Min-Jung Lee, Hayato Ohshima, Seiya Mizuno, Satoru Takahashi, Han-Sung Jung, Seong-Jin Kim","doi":"10.1038/s12276-024-01264-5","DOIUrl":"10.1038/s12276-024-01264-5","url":null,"abstract":"The asymmetric division of stem cells permits the maintenance of the cell population and differentiation for harmonious progress. Developing mouse incisors allows inspection of the role of the stem cell niche to provide specific insights into essential developmental phases. Microtubule-associated serine/threonine kinase family member 4 (Mast4) knockout (KO) mice showed abnormal incisor development with low hardness, as the size of the apical bud was decreased and preameloblasts were shifted to the apical side, resulting in amelogenesis imperfecta. In addition, Mast4 KO incisors showed abnormal enamel maturation, and stem cell maintenance was inhibited as amelogenesis was accelerated with Wnt signal downregulation. Distal-Less Homeobox 3 (DLX3), a critical factor in tooth amelogenesis, is considered to be responsible for the development of amelogenesis imperfecta in humans. MAST4 directly binds to DLX3 and induces phosphorylation at three residues within the nuclear localization site (NLS) that promotes the nuclear translocation of DLX3. MAST4-mediated phosphorylation of DLX3 ultimately controls the transcription of DLX3 target genes, which are carbonic anhydrase and ion transporter genes involved in the pH regulation process during ameloblast maturation. Taken together, our data reveal a novel role for MAST4 as a critical regulator of the entire amelogenesis process through its control of Wnt signaling and DLX3 transcriptional activity. The research examines the function of MAST4, a protein, in tooth growth, particularly in creating enamel (the hard, outer layer of the tooth). Scientists discovered that mice without MAST4 had unusual enamel development in their front teeth, resulting in weaker teeth. The research showed that MAST4 is vital for preserving stem cells (cells that can develop into many different cell types) and controlling their transformation into ameloblasts (cells that create enamel). Without MAST4, this process was disrupted, causing early enamel release and incorrect maturation. The scientists also discovered that MAST4 controls the function of another protein, DLX3, necessary for enamel maturation. This research offers a new understanding of the molecular processes involved in tooth growth and could be significant for understanding and treating dental issues. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01261-8
Rajath Ramachandran, Abdul Manan, Jei Kim, Sangdun Choi
Proinflammatory cytokines and chemokines play a crucial role in regulating the inflammatory response, which is essential for the proper functioning of our immune system. When infections or threats to the body’s defense mechanisms are detected, the innate immune system takes the lead. However, an excessive inflammatory response can lead to the production of high concentrations of cytotoxic molecules, resulting in tissue damage. Inflammasomes are significant contributors to innate immunity, and one of the most extensively studied inflammasome complexes is NOD-like receptor 3 (NLRP3). NLRP3 has a wide range of recognition mechanisms that streamline immune activation and eliminate pathogens. These cytosolic multiprotein complexes are composed of effector, adaptor, and sensor proteins, which are crucial for identifying intracellular bacterial breakdown products and initiating an innate immune cascade. To understand the diverse behavior of NLRP3 activation and its significance in the development of lifestyle-related diseases, one must delve into the study of the immune response and apoptosis mediated by the release of proinflammatory cytokines. In this review, we briefly explore the immune response in the context of lifestyle associated disorders such as obesity, hyperlipidemia, diabetes, chronic respiratory disease, oral disease, and cardiovascular disease. NOD-like receptors (NLRs - proteins that help our immune system fight off harmful invaders) are vital for our health. Their function in T and B cells (types of white blood cells) is less clear. Scientists have found 22 kinds of NLRs in humans, which start different immune and inflammation responses. This study is a detailed review of NLRs, examining their structure, how they are activated, and their role in diseases like obesity, diabetes, and heart problems. It emphasizes that NLRs, particularly the NLRP3 inflammasome (a protein complex involved in inflammation), are key in lifestyle diseases by causing inflammation. The review proposes that focusing on NLRP3 could lead to new treatments for these diseases. This research is a big step in understanding how our natural immune system contributes to chronic diseases and offers potential for new treatments. Future research could further explore the complexities of NLRs and their potential as treatment targets. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"NLRP3 inflammasome: a key player in the pathogenesis of life-style disorders","authors":"Rajath Ramachandran, Abdul Manan, Jei Kim, Sangdun Choi","doi":"10.1038/s12276-024-01261-8","DOIUrl":"10.1038/s12276-024-01261-8","url":null,"abstract":"Proinflammatory cytokines and chemokines play a crucial role in regulating the inflammatory response, which is essential for the proper functioning of our immune system. When infections or threats to the body’s defense mechanisms are detected, the innate immune system takes the lead. However, an excessive inflammatory response can lead to the production of high concentrations of cytotoxic molecules, resulting in tissue damage. Inflammasomes are significant contributors to innate immunity, and one of the most extensively studied inflammasome complexes is NOD-like receptor 3 (NLRP3). NLRP3 has a wide range of recognition mechanisms that streamline immune activation and eliminate pathogens. These cytosolic multiprotein complexes are composed of effector, adaptor, and sensor proteins, which are crucial for identifying intracellular bacterial breakdown products and initiating an innate immune cascade. To understand the diverse behavior of NLRP3 activation and its significance in the development of lifestyle-related diseases, one must delve into the study of the immune response and apoptosis mediated by the release of proinflammatory cytokines. In this review, we briefly explore the immune response in the context of lifestyle associated disorders such as obesity, hyperlipidemia, diabetes, chronic respiratory disease, oral disease, and cardiovascular disease. NOD-like receptors (NLRs - proteins that help our immune system fight off harmful invaders) are vital for our health. Their function in T and B cells (types of white blood cells) is less clear. Scientists have found 22 kinds of NLRs in humans, which start different immune and inflammation responses. This study is a detailed review of NLRs, examining their structure, how they are activated, and their role in diseases like obesity, diabetes, and heart problems. It emphasizes that NLRs, particularly the NLRP3 inflammasome (a protein complex involved in inflammation), are key in lifestyle diseases by causing inflammation. The review proposes that focusing on NLRP3 could lead to new treatments for these diseases. This research is a big step in understanding how our natural immune system contributes to chronic diseases and offers potential for new treatments. Future research could further explore the complexities of NLRs and their potential as treatment targets. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297159/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01270-7
Lin-Zhen Shu, Xian-Lei Zhang, Yi-Dan Ding, Hui Lin
Neutrophils are emerging as an important player in skeletal muscle injury and repair. Neutrophils accumulate in injured tissue, thus releasing inflammatory factors, proteases and neutrophil extracellular traps (NETs) to clear muscle debris and pathogens when skeletal muscle is damaged. During the process of muscle repair, neutrophils can promote self-renewal and angiogenesis in satellite cells. When neutrophils are abnormally overactivated, neutrophils cause collagen deposition, functional impairment of satellite cells, and damage to the skeletal muscle vascular endothelium. Heterotopic ossification (HO) refers to abnormal bone formation in soft tissue. Skeletal muscle injury is one of the main causes of traumatic HO (tHO). Neutrophils play a pivotal role in activating BMPs and TGF-β signals, thus promoting the differentiation of mesenchymal stem cells and progenitor cells into osteoblasts or osteoclasts to facilitate HO. Furthermore, NETs are specifically localized at the site of HO, thereby accelerating the formation of HO. Additionally, the overactivation of neutrophils contributes to the disruption of immune homeostasis to trigger HO. An understanding of the diverse roles of neutrophils will not only provide more information on the pathogenesis of skeletal muscle injury for repair and HO but also provides a foundation for the development of more efficacious treatment modalities for HO. Skeletal muscle, the body’s most common tissue, often gets injured and lacks highly effective treatments. This review investigates the complex relationship between skeletal muscle and neutrophils during injury and healing. Researchers study how neutrophils can both worsen muscle damage and assist in tissue repair. It looks at how neutrophil activity affects muscle repair, explaining the processes of inflammation, tissue regeneration, and the factors causing heterotopic ossification. It also emphasizes the significance of controlling neutrophil activity for effective muscle healing and avoiding complications. Key findings show that neutrophils are crucial in both harming and repairing skeletal muscle. Overactive neutrophils can cause extended inflammation, hindering the healing process, while controlled activity aids tissue regeneration. The researchers suggest that focusing on neutrophil activity could be a promising method for treating muscle injuries and preventing heterotopic ossification. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"From inflammation to bone formation: the intricate role of neutrophils in skeletal muscle injury and traumatic heterotopic ossification","authors":"Lin-Zhen Shu, Xian-Lei Zhang, Yi-Dan Ding, Hui Lin","doi":"10.1038/s12276-024-01270-7","DOIUrl":"10.1038/s12276-024-01270-7","url":null,"abstract":"Neutrophils are emerging as an important player in skeletal muscle injury and repair. Neutrophils accumulate in injured tissue, thus releasing inflammatory factors, proteases and neutrophil extracellular traps (NETs) to clear muscle debris and pathogens when skeletal muscle is damaged. During the process of muscle repair, neutrophils can promote self-renewal and angiogenesis in satellite cells. When neutrophils are abnormally overactivated, neutrophils cause collagen deposition, functional impairment of satellite cells, and damage to the skeletal muscle vascular endothelium. Heterotopic ossification (HO) refers to abnormal bone formation in soft tissue. Skeletal muscle injury is one of the main causes of traumatic HO (tHO). Neutrophils play a pivotal role in activating BMPs and TGF-β signals, thus promoting the differentiation of mesenchymal stem cells and progenitor cells into osteoblasts or osteoclasts to facilitate HO. Furthermore, NETs are specifically localized at the site of HO, thereby accelerating the formation of HO. Additionally, the overactivation of neutrophils contributes to the disruption of immune homeostasis to trigger HO. An understanding of the diverse roles of neutrophils will not only provide more information on the pathogenesis of skeletal muscle injury for repair and HO but also provides a foundation for the development of more efficacious treatment modalities for HO. Skeletal muscle, the body’s most common tissue, often gets injured and lacks highly effective treatments. This review investigates the complex relationship between skeletal muscle and neutrophils during injury and healing. Researchers study how neutrophils can both worsen muscle damage and assist in tissue repair. It looks at how neutrophil activity affects muscle repair, explaining the processes of inflammation, tissue regeneration, and the factors causing heterotopic ossification. It also emphasizes the significance of controlling neutrophil activity for effective muscle healing and avoiding complications. Key findings show that neutrophils are crucial in both harming and repairing skeletal muscle. Overactive neutrophils can cause extended inflammation, hindering the healing process, while controlled activity aids tissue regeneration. The researchers suggest that focusing on neutrophil activity could be a promising method for treating muscle injuries and preventing heterotopic ossification. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01260-9
Seong Hun Lim, Hyesung Lee, Hyun Ji Lee, Kuglae Kim, Junjeong Choi, Jung Min Han, Do Sik Min
The development of chemoresistance is a major challenge in the treatment of several types of cancers in clinical settings. Stemness and chemoresistance are the chief causes of poor clinical outcomes. In this context, we hypothesized that understanding the signaling pathways responsible for chemoresistance in cancers is crucial for the development of novel targeted therapies to overcome drug resistance. Among the aberrantly activated pathways, the PI3K-Akt/Wnt/β-catenin signaling pathway is clinically implicated in malignancies such as colorectal cancer (CRC) and glioblastoma multiforme (GBM). Aberrant dysregulation of phospholipase D (PLD) has been implicated in several malignancies, and oncogenic activation of this pathway facilitates tumor proliferation, stemness, and chemoresistance. Crosstalk involving the PLD and Wnt/β-catenin pathways promotes the progression of CRC and GBM and reduces the sensitivity of cancer cells to standard therapies. Notably, both pathways are tightly regulated and connected at multiple levels by upstream and downstream effectors. Thus, gaining deeper insights into the interactions between these pathways would help researchers discover unique therapeutic targets for the management of drug-resistant cancers. Here, we review the molecular mechanisms by which PLD signaling stimulates stemness and chemoresistance in CRC and GBM. Thus, the current review aims to address the importance of PLD as a central player coordinating cross-talk between the PI3K/Akt and Wnt/β-catenin pathways and proposes the possibility of targeting these pathways to improve cancer therapy and overcome drug resistance. Cancer coming back after it seemed to have gone away is a big problem in treating cancers like colorectal cancer and a brain cancer called glioblastoma multiforme. This research looks at the part played by cancer stem cells (CSCs - cells within a tumor that can self-renew and cause the cancer to grow and come back) in cancer coming back and not responding to treatment. The scientists found that a pathway in the cells, called the Wnt/β-catenin signaling pathway, is important for keeping CSCs going. They also found that an enzyme (a type of protein that speeds up reactions in the body) called phospholipase D1 (PLD1) helps control this pathway. By stopping PLD1, they could lower the ability of CSCs to keep renewing themselves and make them more responsive to chemotherapy. This means that focusing on PLD1 could be a new way to treat cancers that don’t respond to existing treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"PLD1 is a key player in cancer stemness and chemoresistance: Therapeutic targeting of cross-talk between the PI3K/Akt and Wnt/β-catenin pathways","authors":"Seong Hun Lim, Hyesung Lee, Hyun Ji Lee, Kuglae Kim, Junjeong Choi, Jung Min Han, Do Sik Min","doi":"10.1038/s12276-024-01260-9","DOIUrl":"10.1038/s12276-024-01260-9","url":null,"abstract":"The development of chemoresistance is a major challenge in the treatment of several types of cancers in clinical settings. Stemness and chemoresistance are the chief causes of poor clinical outcomes. In this context, we hypothesized that understanding the signaling pathways responsible for chemoresistance in cancers is crucial for the development of novel targeted therapies to overcome drug resistance. Among the aberrantly activated pathways, the PI3K-Akt/Wnt/β-catenin signaling pathway is clinically implicated in malignancies such as colorectal cancer (CRC) and glioblastoma multiforme (GBM). Aberrant dysregulation of phospholipase D (PLD) has been implicated in several malignancies, and oncogenic activation of this pathway facilitates tumor proliferation, stemness, and chemoresistance. Crosstalk involving the PLD and Wnt/β-catenin pathways promotes the progression of CRC and GBM and reduces the sensitivity of cancer cells to standard therapies. Notably, both pathways are tightly regulated and connected at multiple levels by upstream and downstream effectors. Thus, gaining deeper insights into the interactions between these pathways would help researchers discover unique therapeutic targets for the management of drug-resistant cancers. Here, we review the molecular mechanisms by which PLD signaling stimulates stemness and chemoresistance in CRC and GBM. Thus, the current review aims to address the importance of PLD as a central player coordinating cross-talk between the PI3K/Akt and Wnt/β-catenin pathways and proposes the possibility of targeting these pathways to improve cancer therapy and overcome drug resistance. Cancer coming back after it seemed to have gone away is a big problem in treating cancers like colorectal cancer and a brain cancer called glioblastoma multiforme. This research looks at the part played by cancer stem cells (CSCs - cells within a tumor that can self-renew and cause the cancer to grow and come back) in cancer coming back and not responding to treatment. The scientists found that a pathway in the cells, called the Wnt/β-catenin signaling pathway, is important for keeping CSCs going. They also found that an enzyme (a type of protein that speeds up reactions in the body) called phospholipase D1 (PLD1) helps control this pathway. By stopping PLD1, they could lower the ability of CSCs to keep renewing themselves and make them more responsive to chemotherapy. This means that focusing on PLD1 could be a new way to treat cancers that don’t respond to existing treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01268-1
Chae Min Lee, Yeseong Hwang, Minki Kim, Ye-Chan Park, Hyeonhui Kim, Sungsoon Fang
Serine is a key contributor to the generation of one-carbon units for DNA synthesis during cellular proliferation. In addition, it plays a crucial role in the production of antioxidants that prevent abnormal proliferation and stress in cancer cells. In recent studies, the relationship between cancer metabolism and the serine biosynthesis pathway has been highlighted. In this context, 3-phosphoglycerate dehydrogenase (PHGDH) is notable as a key enzyme that functions as the primary rate-limiting enzyme in the serine biosynthesis pathway, facilitating the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate. Elevated PHGDH activity in diverse cancer cells is mediated through genetic amplification, posttranslational modification, increased transcription, and allosteric regulation. Ultimately, these characteristics allow PHGDH to not only influence the growth and progression of cancer but also play an important role in metastasis and drug resistance. Consequently, PHGDH has emerged as a crucial focal point in cancer research. In this review, the structural aspects of PHGDH and its involvement in one-carbon metabolism are investigated, and PHGDH is proposed as a potential therapeutic target in diverse cancers. By elucidating how PHGDH expression promotes cancer growth, the goal of this review is to provide insight into innovative treatment strategies. This paper aims to reveal how PHGDH inhibitors can overcome resistance mechanisms, contributing to the development of effective cancer treatments. Serine is important in DNA copying and cancer cell growth as it helps produce antioxidants and other substances. This detailed review explores the role of 3-phosphoglycerate dehydrogenase, an enzyme, in cancer, particularly its role in serine creation and its potential as a treatment target. The review combines results from different studies, using various experimental methods to understand how PHGDH affects cancer cell behavior and treatment responses. Researchers suggest that targeting PHGDH could be a promising strategy for cancer treatment, potentially improving outcomes for patients with tumors that overproduce PHGDH. The authors call for more research to fully understand PHGDH’s role in cancer and to develop effective inhibitors that could be used in clinical settings. This work advances our understanding of cancer metabolism and opens new possibilities for treatment. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"PHGDH: a novel therapeutic target in cancer","authors":"Chae Min Lee, Yeseong Hwang, Minki Kim, Ye-Chan Park, Hyeonhui Kim, Sungsoon Fang","doi":"10.1038/s12276-024-01268-1","DOIUrl":"10.1038/s12276-024-01268-1","url":null,"abstract":"Serine is a key contributor to the generation of one-carbon units for DNA synthesis during cellular proliferation. In addition, it plays a crucial role in the production of antioxidants that prevent abnormal proliferation and stress in cancer cells. In recent studies, the relationship between cancer metabolism and the serine biosynthesis pathway has been highlighted. In this context, 3-phosphoglycerate dehydrogenase (PHGDH) is notable as a key enzyme that functions as the primary rate-limiting enzyme in the serine biosynthesis pathway, facilitating the conversion of 3-phosphoglycerate to 3-phosphohydroxypyruvate. Elevated PHGDH activity in diverse cancer cells is mediated through genetic amplification, posttranslational modification, increased transcription, and allosteric regulation. Ultimately, these characteristics allow PHGDH to not only influence the growth and progression of cancer but also play an important role in metastasis and drug resistance. Consequently, PHGDH has emerged as a crucial focal point in cancer research. In this review, the structural aspects of PHGDH and its involvement in one-carbon metabolism are investigated, and PHGDH is proposed as a potential therapeutic target in diverse cancers. By elucidating how PHGDH expression promotes cancer growth, the goal of this review is to provide insight into innovative treatment strategies. This paper aims to reveal how PHGDH inhibitors can overcome resistance mechanisms, contributing to the development of effective cancer treatments. Serine is important in DNA copying and cancer cell growth as it helps produce antioxidants and other substances. This detailed review explores the role of 3-phosphoglycerate dehydrogenase, an enzyme, in cancer, particularly its role in serine creation and its potential as a treatment target. The review combines results from different studies, using various experimental methods to understand how PHGDH affects cancer cell behavior and treatment responses. Researchers suggest that targeting PHGDH could be a promising strategy for cancer treatment, potentially improving outcomes for patients with tumors that overproduce PHGDH. The authors call for more research to fully understand PHGDH’s role in cancer and to develop effective inhibitors that could be used in clinical settings. This work advances our understanding of cancer metabolism and opens new possibilities for treatment. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297271/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The senescence of alveolar type II (AT2) cells impedes self-repair of the lung epithelium and contributes to lung injury in the setting of idiopathic pulmonary fibrosis (IPF). Yes-associated protein 1 (YAP1) is essential for cell growth and organ development; however, the role of YAP1 in AT2 cells during pulmonary fibrosis is still unclear. YAP1 expression was found to be downregulated in the AT2 cells of PF patients. Deletion of YAP1 in AT2 cells resulted in lung injury, exacerbated extracellular matrix (ECM) deposition, and worsened lung function. In contrast, overexpression of YAP1 in AT2 cells promoted alveolar regeneration, mitigated pulmonary fibrosis, and improved lung function. In addition, overexpression of YAP1 alleviated bleomycin (BLM) -induced senescence of alveolar epithelial cells both in vivo and in vitro. Moreover, YAP1 promoted the expression of peroxiredoxin 3 (Prdx3) by directly interacting with TEAD1. Forced expression of Prdx3 inhibited senescence and improved mitochondrial dysfunction in BLM-treated MLE-12 cells, whereas depletion of Prdx3 partially abrogated the protective effect of YAP1. Furthermore, overexpression of Prdx3 facilitated self-repair of the injured lung and reduced ECM deposition, while silencing Prdx3 attenuated the antifibrotic effect of YAP1. In conclusion, this study demonstrated that YAP1 alleviates lung injury and pulmonary fibrosis by regulating Prdx3 expression to improve mitochondrial dysfunction and block senescence in AT2 cells, revealing a potential novel therapeutic strategy for pulmonary fibrosis. Idiopathic pulmonary fibrosis is still not fully understood, and effective treatments are scarce. This study investigates the role of a protein, YAP1, in lung fibrosis. Researchers used mice and human lung samples to study how YAP1 influences lung cell aging and lung structure. The findings showed that increasing YAP1 levels in alveolar type II cells reduced lung fibrosis by improving the function of mitochondria and decreasing cell aging. Specifically, YAP1 worked through a pathway involving a molecule, Prdx3. However, reducing YAP1 levels worsened lung fibrosis. The researchers suggest that enhancing YAP1 activity in lung cells could be a potential treatment for lung fibrosis. This method targets lung cell aging and promotes healthy lung tissue repair. The results pave the way for developing treatments for IPF and possibly other similar lung diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"YAP1 inhibits the senescence of alveolar epithelial cells by targeting Prdx3 to alleviate pulmonary fibrosis","authors":"Wei Su, Yingying Guo, Qianqian Wang, Lu Ma, Qing Zhang, Yuhan Zhang, Yiding Geng, Tongzhu Jin, Jiayu Guo, Ruoxuan Yang, Zhihui Niu, Lingxue Ren, Yan Wang, Zhiwei Ning, Wenyue Li, Wenxin He, Jian Sun, Tianyu Li, Zhixin Li, Hongli Shan, Haihai Liang","doi":"10.1038/s12276-024-01277-0","DOIUrl":"10.1038/s12276-024-01277-0","url":null,"abstract":"The senescence of alveolar type II (AT2) cells impedes self-repair of the lung epithelium and contributes to lung injury in the setting of idiopathic pulmonary fibrosis (IPF). Yes-associated protein 1 (YAP1) is essential for cell growth and organ development; however, the role of YAP1 in AT2 cells during pulmonary fibrosis is still unclear. YAP1 expression was found to be downregulated in the AT2 cells of PF patients. Deletion of YAP1 in AT2 cells resulted in lung injury, exacerbated extracellular matrix (ECM) deposition, and worsened lung function. In contrast, overexpression of YAP1 in AT2 cells promoted alveolar regeneration, mitigated pulmonary fibrosis, and improved lung function. In addition, overexpression of YAP1 alleviated bleomycin (BLM) -induced senescence of alveolar epithelial cells both in vivo and in vitro. Moreover, YAP1 promoted the expression of peroxiredoxin 3 (Prdx3) by directly interacting with TEAD1. Forced expression of Prdx3 inhibited senescence and improved mitochondrial dysfunction in BLM-treated MLE-12 cells, whereas depletion of Prdx3 partially abrogated the protective effect of YAP1. Furthermore, overexpression of Prdx3 facilitated self-repair of the injured lung and reduced ECM deposition, while silencing Prdx3 attenuated the antifibrotic effect of YAP1. In conclusion, this study demonstrated that YAP1 alleviates lung injury and pulmonary fibrosis by regulating Prdx3 expression to improve mitochondrial dysfunction and block senescence in AT2 cells, revealing a potential novel therapeutic strategy for pulmonary fibrosis. Idiopathic pulmonary fibrosis is still not fully understood, and effective treatments are scarce. This study investigates the role of a protein, YAP1, in lung fibrosis. Researchers used mice and human lung samples to study how YAP1 influences lung cell aging and lung structure. The findings showed that increasing YAP1 levels in alveolar type II cells reduced lung fibrosis by improving the function of mitochondria and decreasing cell aging. Specifically, YAP1 worked through a pathway involving a molecule, Prdx3. However, reducing YAP1 levels worsened lung fibrosis. The researchers suggest that enhancing YAP1 activity in lung cells could be a potential treatment for lung fibrosis. This method targets lung cell aging and promotes healthy lung tissue repair. The results pave the way for developing treatments for IPF and possibly other similar lung diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-01DOI: 10.1038/s12276-024-01274-3
Dong Kyu Kim, Kyujin Suh, Junho Park, Sang-Eun Lee, Jihui Han, Sunghoe Chang, Youngsoo Kim, Inhee Mook-Jung
The amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer’s disease (AD). However, the underlying mechanisms through which Aβ contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aβ induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aβ accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aβ-induced tau uptake in AD. Alzheimer’s disease (AD), the most common dementia leading to progressive memory loss and cognitive decline, is characterized by the accumulation of two pathological proteins in the brain: amyloid beta(Aβ) and tau. A recent study found that Aβ accelerates tau pathology in the brain, worsening AD. Using mice models, research showed that fibroblast growth factor receptor 3 (FGFR3) can act as tau receptor, and Aβ increases the tau uptake and aggregation by FGFR3 in brain cells. The findings suggest that decreasing FGFR3 could significantly lessen tau toxicity in brain cells. This could provide a new approach to slow down AD progression by targeting the early stages of tau accumulation. The study paves the way for potential treatments that could delay or prevent AD progression by targeting the early interaction between Aβ and tau. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
淀粉样蛋白级联假说认为，淀粉样蛋白β（Aβ）有助于引发阿尔茨海默病（AD）随后的tau病理变化。然而，人们对 Aβ 促进 tau 吸收和传播的潜在机制仍然知之甚少。在这里，我们发现，先前存在的淀粉样病理学会加速细胞外 tau 被神经元吸收。通过对内含囊泡进行定量蛋白质组学分析，我们发现 Aβ 能诱导成纤维细胞生长因子受体 3（FGFR3）的内化。细胞外 tau 与 FGFR3 的细胞外结构域结合，并被 FGFR3 配体成纤维细胞生长因子 2（FGF2）内化。Aβ 可加速神经元分泌 FGF2，从而诱导 tau 连接的 FGFR3 内化。敲除海马中的 FGFR3 可减少 tau 摄取，从而减少 tau 聚集，并改善 AD 模型小鼠的记忆功能。这些数据表明，神经元中的FGFR3是一种新型tau受体，也是AD中Aβ诱导tau吸收的关键介质。
{"title":"FGFR3 drives Aβ-induced tau uptake","authors":"Dong Kyu Kim, Kyujin Suh, Junho Park, Sang-Eun Lee, Jihui Han, Sunghoe Chang, Youngsoo Kim, Inhee Mook-Jung","doi":"10.1038/s12276-024-01274-3","DOIUrl":"10.1038/s12276-024-01274-3","url":null,"abstract":"The amyloid cascade hypothesis suggests that amyloid beta (Aβ) contributes to initiating subsequent tau pathology in Alzheimer’s disease (AD). However, the underlying mechanisms through which Aβ contributes to tau uptake and propagation remain poorly understood. Here, we show that preexisting amyloid pathology accelerates the uptake of extracellular tau into neurons. Using quantitative proteomic analysis of endocytic vesicles, we reveal that Aβ induces the internalization of fibroblast growth factor receptor 3 (FGFR3). Extracellular tau binds to the extracellular domain of FGFR3 and is internalized by the FGFR3 ligand, fibroblast growth factor 2 (FGF2). Aβ accelerates FGF2 secretion from neurons, thereby inducing the internalization of tau-attached FGFR3. Knockdown of FGFR3 in the hippocampus reduces tau aggregation by decreasing tau uptake and improving memory function in AD model mice. These data suggest FGFR3 in neurons as a novel tau receptor and a key mediator of Aβ-induced tau uptake in AD. Alzheimer’s disease (AD), the most common dementia leading to progressive memory loss and cognitive decline, is characterized by the accumulation of two pathological proteins in the brain: amyloid beta(Aβ) and tau. A recent study found that Aβ accelerates tau pathology in the brain, worsening AD. Using mice models, research showed that fibroblast growth factor receptor 3 (FGFR3) can act as tau receptor, and Aβ increases the tau uptake and aggregation by FGFR3 in brain cells. The findings suggest that decreasing FGFR3 could significantly lessen tau toxicity in brain cells. This could provide a new approach to slow down AD progression by targeting the early stages of tau accumulation. The study paves the way for potential treatments that could delay or prevent AD progression by targeting the early interaction between Aβ and tau. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141477875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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