Pub Date : 2024-08-01DOI: 10.1038/s12276-024-01283-2
Yuri Seo, Yejin Jang, Seon-gyeong Lee, Joon Ho Rhlee, Sukyeong Kong, Thi Tuyet Hanh Vo, Myung hun Kim, Myoung Kyu Lee, Byungil Kim, Sung You Hong, Meehyein Kim, Joo-Yong Lee, Kyungjae Myung
The SARS-CoV-2 pandemic has had an unprecedented impact on global public health and the economy. Although vaccines and antivirals have provided effective protection and treatment, the development of new small molecule-based antiviral candidates is imperative to improve clinical outcomes against SARS-CoV-2. In this study, we identified UNI418, a dual PIKfyve and PIP5K1C inhibitor, as a new chemical agent that inhibits SARS-CoV-2 entry into host cells. UNI418 inhibited the proteolytic activation of cathepsins, which is regulated by PIKfyve, resulting in the inhibition of cathepsin L-dependent proteolytic cleavage of the SARS-CoV-2 spike protein into its mature form, a critical step for viral endosomal escape. We also demonstrated that UNI418 prevented ACE2-mediated endocytosis of the virus via PIP5K1C inhibition. Our results identified PIKfyve and PIP5K1C as potential antiviral targets and UNI418 as a putative therapeutic compound against SARS-CoV-2. The COVID-19 pandemic, triggered by the SARS-CoV-2 virus, underscores the immediate need for effective treatments, particularly for severe cases. Even with vaccines, treatments that block the virus’s entry into cells are vital. SARS-CoV-2 enters host cells by attaching to the ACE2 receptor, a process that is a prime target for intervention. This research concentrates on blocking the virus’s entry into cells as a potential treatment method. The study is an experiment using cellular models to assess the effectiveness of a new compound, UNI418, in preventing SARS-CoV-2 infection. UNI418 targets enzymes involved in cell membrane dynamics, essential for the virus’s entry. The researchers conclude that UNI418, by blocking PIP5K1C and PIKfyve, offers a promising approach to preventing SARS-CoV-2 infection and emphasizes the importance of targeting the virus’s entry process as a treatment strategy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells","authors":"Yuri Seo, Yejin Jang, Seon-gyeong Lee, Joon Ho Rhlee, Sukyeong Kong, Thi Tuyet Hanh Vo, Myung hun Kim, Myoung Kyu Lee, Byungil Kim, Sung You Hong, Meehyein Kim, Joo-Yong Lee, Kyungjae Myung","doi":"10.1038/s12276-024-01283-2","DOIUrl":"10.1038/s12276-024-01283-2","url":null,"abstract":"The SARS-CoV-2 pandemic has had an unprecedented impact on global public health and the economy. Although vaccines and antivirals have provided effective protection and treatment, the development of new small molecule-based antiviral candidates is imperative to improve clinical outcomes against SARS-CoV-2. In this study, we identified UNI418, a dual PIKfyve and PIP5K1C inhibitor, as a new chemical agent that inhibits SARS-CoV-2 entry into host cells. UNI418 inhibited the proteolytic activation of cathepsins, which is regulated by PIKfyve, resulting in the inhibition of cathepsin L-dependent proteolytic cleavage of the SARS-CoV-2 spike protein into its mature form, a critical step for viral endosomal escape. We also demonstrated that UNI418 prevented ACE2-mediated endocytosis of the virus via PIP5K1C inhibition. Our results identified PIKfyve and PIP5K1C as potential antiviral targets and UNI418 as a putative therapeutic compound against SARS-CoV-2. The COVID-19 pandemic, triggered by the SARS-CoV-2 virus, underscores the immediate need for effective treatments, particularly for severe cases. Even with vaccines, treatments that block the virus’s entry into cells are vital. SARS-CoV-2 enters host cells by attaching to the ACE2 receptor, a process that is a prime target for intervention. This research concentrates on blocking the virus’s entry into cells as a potential treatment method. The study is an experiment using cellular models to assess the effectiveness of a new compound, UNI418, in preventing SARS-CoV-2 infection. UNI418 targets enzymes involved in cell membrane dynamics, essential for the virus’s entry. The researchers conclude that UNI418, by blocking PIP5K1C and PIKfyve, offers a promising approach to preventing SARS-CoV-2 infection and emphasizes the importance of targeting the virus’s entry process as a treatment strategy. 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":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01283-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861524","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 : 2024-08-01DOI: 10.1038/s12276-024-01273-4
Kyung Chul Shin, Houda Yasmine Ali Moussa, Yongsoo Park
The brain contains the highest concentration of cholesterol in the human body, which emphasizes the importance of cholesterol in brain physiology. Cholesterol is involved in neurogenesis and synaptogenesis, and age-related reductions in cholesterol levels can lead to synaptic loss and impaired synaptic plasticity, which potentially contribute to neurodegeneration. The maintenance of cholesterol homeostasis in the neuronal plasma membrane is essential for normal brain function, and imbalances in cholesterol distribution are associated with various neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This review aims to explore the molecular and pathological mechanisms by which cholesterol imbalance can lead to neurotransmission defects and neurodegeneration, focusing on four key mechanisms: (1) synaptic dysfunction, (2) alterations in membrane structure and protein clustering, (3) oligomers of amyloid beta (Aβ) protein, and (4) α-synuclein aggregation. Cholesterol, a substance crucial for the brain, can lead to diseases like Alzheimer’s and Parkinson’s when imbalanced. This review investigates how this imbalance causes brain cell degeneration, focusing on issues like communication breakdown and harmful protein build-up. The study combines findings from different experiments to understand cholesterol’s role in the brain. The review emphasizes the need for cholesterol balance for brain health and identifies potential treatment targets for neurodegenerative diseases. The main findings suggest that cholesterol imbalance disrupts brain cell communication and leads to harmful protein build-up, causing brain cell degeneration. The researchers conclude that focusing on cholesterol metabolism and distribution could lead to new treatments for these conditions. Future research may lead to treatments that correct cholesterol imbalances, possibly slowing or preventing neurodegenerative diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Cholesterol imbalance and neurotransmission defects in neurodegeneration","authors":"Kyung Chul Shin, Houda Yasmine Ali Moussa, Yongsoo Park","doi":"10.1038/s12276-024-01273-4","DOIUrl":"10.1038/s12276-024-01273-4","url":null,"abstract":"The brain contains the highest concentration of cholesterol in the human body, which emphasizes the importance of cholesterol in brain physiology. Cholesterol is involved in neurogenesis and synaptogenesis, and age-related reductions in cholesterol levels can lead to synaptic loss and impaired synaptic plasticity, which potentially contribute to neurodegeneration. The maintenance of cholesterol homeostasis in the neuronal plasma membrane is essential for normal brain function, and imbalances in cholesterol distribution are associated with various neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. This review aims to explore the molecular and pathological mechanisms by which cholesterol imbalance can lead to neurotransmission defects and neurodegeneration, focusing on four key mechanisms: (1) synaptic dysfunction, (2) alterations in membrane structure and protein clustering, (3) oligomers of amyloid beta (Aβ) protein, and (4) α-synuclein aggregation. Cholesterol, a substance crucial for the brain, can lead to diseases like Alzheimer’s and Parkinson’s when imbalanced. This review investigates how this imbalance causes brain cell degeneration, focusing on issues like communication breakdown and harmful protein build-up. The study combines findings from different experiments to understand cholesterol’s role in the brain. The review emphasizes the need for cholesterol balance for brain health and identifies potential treatment targets for neurodegenerative diseases. The main findings suggest that cholesterol imbalance disrupts brain cell communication and leads to harmful protein build-up, causing brain cell degeneration. The researchers conclude that focusing on cholesterol metabolism and distribution could lead to new treatments for these conditions. Future research may lead to treatments that correct cholesterol imbalances, possibly slowing or preventing neurodegenerative 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":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01273-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861484","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}
Human interleukin-33 (IL-33) is a 270 amino acid protein that belongs to the IL-1 cytokine family and plays an important role in various inflammatory disorders. Neutrophil proteases (Cathepsin G and Elastase) and mast cell proteases (tryptase and chymase) regulate the activity of IL-33 by processing full-length IL-33 into its mature form. There is little evidence on the role of these mature forms of IL-33 in retinal endothelial cell signaling and pathological retinal angiogenesis. Here, we cloned, expressed, and purified the various mature forms of human IL-33 and then evaluated the effects of IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 on angiogenesis in human retinal microvascular endothelial cells (HRMVECs). We observed that IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 significantly induced HRMVEC migration, tube formation and sprouting angiogenesis. However, only IL-3399-270 could induce HRMVEC proliferation. We used a murine model of oxygen-induced retinopathy (OIR) to assess the role of these mature forms of IL-33 in pathological retinal neovascularization. Our 3′-mRNA sequencing and signaling studies indicated that IL-3399-270 and IL-33109-270 were more potent at inducing endothelial cell activation and angiogenesis than the other mature forms. We found that genetic deletion of IL-33 significantly reduced OIR-induced retinal neovascularization in the mouse retina and that intraperitoneal administration of mature forms of IL-33, mainly IL-3399–270 and IL-33109–270, significantly restored ischemia-induced angiogenic sprouting and tuft formation in the hypoxic retinas of IL-33–/– mice. Thus, our study results suggest that blockade or inhibition of IL-33 cleavage by neutrophil proteases could help mitigate pathological angiogenesis in proliferative retinopathies. Interleukin-33 plays a role in many diseases and biological processes. This study investigates how various IL-33 mature forms affects blood vessel creation in the eye, especially in eye diseases. The researchers used genetic and drug-related methods to study the effects of IL-33 on blood vessel formation in the eye, focusing on how it regulates cellular signaling. The research used both in vitro and in vivo methods to understand IL-33’s role in abnormal blood vessel growth, specifically in oxygen-induced eye disease, a model for diseases like premature retinopathy and some aspects of diabetic retinopathy. The research concludes that IL-33, especially its enzyme-processed forms, plays a key role in the development of proliferative retinopathies by promoting abnormal blood vessel growth in the eye. This new understanding of IL-33’s function could lead to new treatments for proliferative retinopathies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"A neutrophil elastase-generated mature form of IL-33 is a potent regulator of endothelial cell activation and proliferative retinopathy","authors":"Shivantika Bisen, Shailendra Kumar Verma, Chandra Sekhar Mukhopadhyay, Nikhlesh K. Singh","doi":"10.1038/s12276-024-01279-y","DOIUrl":"10.1038/s12276-024-01279-y","url":null,"abstract":"Human interleukin-33 (IL-33) is a 270 amino acid protein that belongs to the IL-1 cytokine family and plays an important role in various inflammatory disorders. Neutrophil proteases (Cathepsin G and Elastase) and mast cell proteases (tryptase and chymase) regulate the activity of IL-33 by processing full-length IL-33 into its mature form. There is little evidence on the role of these mature forms of IL-33 in retinal endothelial cell signaling and pathological retinal angiogenesis. Here, we cloned, expressed, and purified the various mature forms of human IL-33 and then evaluated the effects of IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 on angiogenesis in human retinal microvascular endothelial cells (HRMVECs). We observed that IL-3395-270, IL-3399-270, IL-33109-270, and IL-33112-270 significantly induced HRMVEC migration, tube formation and sprouting angiogenesis. However, only IL-3399-270 could induce HRMVEC proliferation. We used a murine model of oxygen-induced retinopathy (OIR) to assess the role of these mature forms of IL-33 in pathological retinal neovascularization. Our 3′-mRNA sequencing and signaling studies indicated that IL-3399-270 and IL-33109-270 were more potent at inducing endothelial cell activation and angiogenesis than the other mature forms. We found that genetic deletion of IL-33 significantly reduced OIR-induced retinal neovascularization in the mouse retina and that intraperitoneal administration of mature forms of IL-33, mainly IL-3399–270 and IL-33109–270, significantly restored ischemia-induced angiogenic sprouting and tuft formation in the hypoxic retinas of IL-33–/– mice. Thus, our study results suggest that blockade or inhibition of IL-33 cleavage by neutrophil proteases could help mitigate pathological angiogenesis in proliferative retinopathies. Interleukin-33 plays a role in many diseases and biological processes. This study investigates how various IL-33 mature forms affects blood vessel creation in the eye, especially in eye diseases. The researchers used genetic and drug-related methods to study the effects of IL-33 on blood vessel formation in the eye, focusing on how it regulates cellular signaling. The research used both in vitro and in vivo methods to understand IL-33’s role in abnormal blood vessel growth, specifically in oxygen-induced eye disease, a model for diseases like premature retinopathy and some aspects of diabetic retinopathy. The research concludes that IL-33, especially its enzyme-processed forms, plays a key role in the development of proliferative retinopathies by promoting abnormal blood vessel growth in the eye. This new understanding of IL-33’s function could lead to new treatments for proliferative retinopathies. 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":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01279-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861525","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 : 2024-08-01DOI: 10.1038/s12276-024-01290-3
Shenzheng Mo, Min Kyung Kim, Ji Sun Jang, Seung Hye Lee, Seo Jin Hong, Suhan Jung, Hong-Hee Kim
Bone homeostasis is maintained by an intricate balance between osteoclasts and osteoblasts, which becomes disturbed in osteoporosis. Metallothioneins (MTs) are major contributors in cellular zinc regulation. However, the role of MTs in bone cell regulation has remained unexplored. Single-cell RNA sequencing analysis discovered that, unlike the expression of other MT members, the expression of MT3 was unique to osteoclasts among various macrophage populations and was highly upregulated during osteoclast differentiation. This unique MT3 upregulation was validated experimentally and supported by ATAC sequencing data analyses. Downregulation of MT3 by gene knockdown or knockout resulted in excessive osteoclastogenesis and exacerbated bone loss in ovariectomy-induced osteoporosis. Transcriptome sequencing of MT3 knockdown osteoclasts and gene set enrichment analysis indicated that the oxidative stress and redox pathways were enriched, which was verified by MT3-dependent regulation of reactive oxygen species (ROS). In addition, MT3 deficiency increased the transcriptional activity of SP1 in a manner dependent on intracellular zinc levels. This MT3-zinc-SP1 axis was crucial for the control of osteoclasts, as zinc chelation and SP1 knockdown abrogated the promotion of SP1 activity and osteoclastogenesis by MT3 deletion. Moreover, SP1 bound to the NFATc1 promoter, and overexpression of an inactive SP1 mutant negated the effects of MT3 deletion on NFATc1 and osteoclastogenesis. In conclusion, MT3 plays a pivotal role in controlling osteoclastogenesis and bone metabolism via dual axes involving ROS and SP1. The present study demonstrated that MT3 elevation is a potential therapeutic strategy for osteolytic bone disorders, and it established for the first time that MT3 is a crucial bone mass regulator. Bone diseases such as osteoporosis often result from imbalances in bone remodeling, a process involving bone breakdown by cells called osteoclasts and formation by cells called osteoblasts. This study examines the role of Metallothionein 3, a protein that binds to zinc, in osteoclasts. Using a mix of single-cell RNA sequencing database and knockout mouse models, the study investigates how MT3 affects osteoclast development and activity. The researchers used various methods, including gene knockdown and overexpression techniques, to alter MT3 levels in cells and observed the effects on osteoclast formation and bone breakdown. The results indicate that MT3 inhibits osteoclast development and decreases bone loss, suggesting its potential as a treatment target for bone diseases. The study concludes that MT3 plays a crucial role in bone remodeling by controlling osteoclast activity. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Unique expression and critical role of metallothionein 3 in the control of osteoclastogenesis and osteoporosis","authors":"Shenzheng Mo, Min Kyung Kim, Ji Sun Jang, Seung Hye Lee, Seo Jin Hong, Suhan Jung, Hong-Hee Kim","doi":"10.1038/s12276-024-01290-3","DOIUrl":"10.1038/s12276-024-01290-3","url":null,"abstract":"Bone homeostasis is maintained by an intricate balance between osteoclasts and osteoblasts, which becomes disturbed in osteoporosis. Metallothioneins (MTs) are major contributors in cellular zinc regulation. However, the role of MTs in bone cell regulation has remained unexplored. Single-cell RNA sequencing analysis discovered that, unlike the expression of other MT members, the expression of MT3 was unique to osteoclasts among various macrophage populations and was highly upregulated during osteoclast differentiation. This unique MT3 upregulation was validated experimentally and supported by ATAC sequencing data analyses. Downregulation of MT3 by gene knockdown or knockout resulted in excessive osteoclastogenesis and exacerbated bone loss in ovariectomy-induced osteoporosis. Transcriptome sequencing of MT3 knockdown osteoclasts and gene set enrichment analysis indicated that the oxidative stress and redox pathways were enriched, which was verified by MT3-dependent regulation of reactive oxygen species (ROS). In addition, MT3 deficiency increased the transcriptional activity of SP1 in a manner dependent on intracellular zinc levels. This MT3-zinc-SP1 axis was crucial for the control of osteoclasts, as zinc chelation and SP1 knockdown abrogated the promotion of SP1 activity and osteoclastogenesis by MT3 deletion. Moreover, SP1 bound to the NFATc1 promoter, and overexpression of an inactive SP1 mutant negated the effects of MT3 deletion on NFATc1 and osteoclastogenesis. In conclusion, MT3 plays a pivotal role in controlling osteoclastogenesis and bone metabolism via dual axes involving ROS and SP1. The present study demonstrated that MT3 elevation is a potential therapeutic strategy for osteolytic bone disorders, and it established for the first time that MT3 is a crucial bone mass regulator. Bone diseases such as osteoporosis often result from imbalances in bone remodeling, a process involving bone breakdown by cells called osteoclasts and formation by cells called osteoblasts. This study examines the role of Metallothionein 3, a protein that binds to zinc, in osteoclasts. Using a mix of single-cell RNA sequencing database and knockout mouse models, the study investigates how MT3 affects osteoclast development and activity. The researchers used various methods, including gene knockdown and overexpression techniques, to alter MT3 levels in cells and observed the effects on osteoclast formation and bone breakdown. The results indicate that MT3 inhibits osteoclast development and decreases bone loss, suggesting its potential as a treatment target for bone diseases. The study concludes that MT3 plays a crucial role in bone remodeling by controlling osteoclast activity. 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":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01290-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861492","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 : 2024-08-01DOI: 10.1038/s12276-024-01285-0
Qian-Yun Wu, Lian-Hong Lin, Kun Lu, Si-Fu Deng, Wei-Min Li, Yuan Xu, Bin Zhang, Ji-Hong Liu
NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders. Understanding how our brains learn and remember is intriguing. As we age, our learning and memory abilities can alter, and scientists are trying to understand why. A recent study investigates this by studying a specific brain receptor, the 5-HT1A receptor, and its effect on learning and memory in mice. The team focused on a process called long-term depression. They found that the ability to induce LTD changes with age and that the 5-HT1A receptor plays a key role in this. They discovered that the activity of 5-HT1A receptors in certain brain cells, astrocytes, is necessary for LTD and influences fear memory extinction. The researchers conclude that the 5-HT1A receptor in astrocytes plays a crucial role in regulating learning and memory processes related to LTD. This discovery could lead to new treatments for memory-related disorders. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Astrocytic 5-HT1A receptor mediates age-dependent hippocampal LTD and fear memory extinction in male mice","authors":"Qian-Yun Wu, Lian-Hong Lin, Kun Lu, Si-Fu Deng, Wei-Min Li, Yuan Xu, Bin Zhang, Ji-Hong Liu","doi":"10.1038/s12276-024-01285-0","DOIUrl":"10.1038/s12276-024-01285-0","url":null,"abstract":"NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. Although the underlying mechanisms remain unclear, this form of LTD cannot be induced by low-frequency stimulation (LFS) in adult mice. In this study, we found that LFS-induced LTD was not easily induced in adult animals and was age dependent. Interestingly, the level of the 5-HT1A receptor was correspondingly increased and exhibited an inverse correlation with the magnitude of LFS-LTD during development. Knockout or pharmacological inhibition of the 5-HT1A receptor reversed impaired LFS-LTD in adult mice (P60), while activation or inhibition of this receptor disturbed or enhanced LFS-LTD in adolescent mice (P21), respectively. Furthermore, the astrocytic 5-HT1A receptor in the hippocampus predominantly mediated age-dependent LFS-LTD through enhancing GABAergic neurotransmission. Finally, fear memory extinction differed among the above conditions. These observations enrich our knowledge of LTD at the cellular level and suggest a therapeutic approach for LTD-related psychiatric disorders. Understanding how our brains learn and remember is intriguing. As we age, our learning and memory abilities can alter, and scientists are trying to understand why. A recent study investigates this by studying a specific brain receptor, the 5-HT1A receptor, and its effect on learning and memory in mice. The team focused on a process called long-term depression. They found that the ability to induce LTD changes with age and that the 5-HT1A receptor plays a key role in this. They discovered that the activity of 5-HT1A receptors in certain brain cells, astrocytes, is necessary for LTD and influences fear memory extinction. The researchers conclude that the 5-HT1A receptor in astrocytes plays a crucial role in regulating learning and memory processes related to LTD. This discovery could lead to new treatments for memory-related disorders. 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":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01285-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861483","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 : 2024-08-01DOI: 10.1038/s12276-024-01292-1
Htoo A. Wai, Eliska Svobodova, Natalia Romero Herrera, Andrew G. L. Douglas, John W. Holloway, Francisco E. Baralle, Marco Baralle, Diana Baralle
Effective translation of rare disease diagnosis knowledge into therapeutic applications is achievable within a reasonable timeframe; where mutations are amenable to current antisense oligonucleotide technology. In our study, we identified five distinct types of abnormal splice-causing mutations in patients with rare genetic disorders and developed a tailored antisense oligonucleotide for each mutation type using phosphorodiamidate morpholino oligomers with or without octa-guanidine dendrimers and 2′-O-methoxyethyl phosphorothioate. We observed variations in treatment effects and efficiencies, influenced by both the chosen chemistry and the specific nature of the aberrant splicing patterns targeted for correction. Our study demonstrated the successful correction of all five different types of aberrant splicing. Our findings reveal that effective correction of aberrant splicing can depend on altering the chemical composition of oligonucleotides and suggest a fast, efficient, and feasible approach for developing personalized therapeutic interventions for genetic disorders within short time frames. Millions globally suffer from rare diseases, often genetic and affecting children. This study explores using antisense oligonucleotides to fix incorrect RNA splicing, a common result of disease-causing genetic mutations. The results showed that tailored ASOs could correct incorrect splicing for various mutation types, showing this technology′s potential in treating rare genetic diseases. The team chose five mutation types disrupting normal splicing and created specific ASOs to correct these errors in cell models. They created minigenes to simulate the mutations and tested different ASOs′ effectiveness. This method was key to understanding ASOs′ ability to restore normal gene function, crucial for developing targeted treatments for rare genetic disorders. This research could lead to new, targeted treatments for rare genetic disorders, offering hope to millions of patients and their families facing limited treatment options. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Tailored antisense oligonucleotides designed to correct aberrant splicing reveal actionable groups of mutations for rare genetic disorders","authors":"Htoo A. Wai, Eliska Svobodova, Natalia Romero Herrera, Andrew G. L. Douglas, John W. Holloway, Francisco E. Baralle, Marco Baralle, Diana Baralle","doi":"10.1038/s12276-024-01292-1","DOIUrl":"10.1038/s12276-024-01292-1","url":null,"abstract":"Effective translation of rare disease diagnosis knowledge into therapeutic applications is achievable within a reasonable timeframe; where mutations are amenable to current antisense oligonucleotide technology. In our study, we identified five distinct types of abnormal splice-causing mutations in patients with rare genetic disorders and developed a tailored antisense oligonucleotide for each mutation type using phosphorodiamidate morpholino oligomers with or without octa-guanidine dendrimers and 2′-O-methoxyethyl phosphorothioate. We observed variations in treatment effects and efficiencies, influenced by both the chosen chemistry and the specific nature of the aberrant splicing patterns targeted for correction. Our study demonstrated the successful correction of all five different types of aberrant splicing. Our findings reveal that effective correction of aberrant splicing can depend on altering the chemical composition of oligonucleotides and suggest a fast, efficient, and feasible approach for developing personalized therapeutic interventions for genetic disorders within short time frames. Millions globally suffer from rare diseases, often genetic and affecting children. This study explores using antisense oligonucleotides to fix incorrect RNA splicing, a common result of disease-causing genetic mutations. The results showed that tailored ASOs could correct incorrect splicing for various mutation types, showing this technology′s potential in treating rare genetic diseases. The team chose five mutation types disrupting normal splicing and created specific ASOs to correct these errors in cell models. They created minigenes to simulate the mutations and tested different ASOs′ effectiveness. This method was key to understanding ASOs′ ability to restore normal gene function, crucial for developing targeted treatments for rare genetic disorders. This research could lead to new, targeted treatments for rare genetic disorders, offering hope to millions of patients and their families facing limited treatment options. 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":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01292-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861490","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 : 2024-08-01DOI: 10.1038/s12276-024-01284-1
Il Bin Kim, Myeong-Heui Kim, Saehoon Jung, Woo Kyeong Kim, Junehawk Lee, Young Seok Ju, Maree J. Webster, Sanghyeon Kim, Ja Hye Kim, Hyun Jung Kim, Junho Kim, Sangwoo Kim, Jeong Ho Lee
Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12–14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology. Autism Spectrum Disorder is a complex condition influenced by various genetic factors, including inherited traits and new changes in genes. This study investigates the role of low-level brain somatic mutations in ASD. The researchers analyzed brain tissues from deceased individuals, both with and without ASD, using high-depth whole-exome sequencing. The results showed that low-level brain somatic mutations, along with inherited genetic variations, contribute to ASD’s genetic makeup. These mutations were found in genes linked to brain development and function. The study emphasizes the need to consider both inherited and somatic mutations to understand ASD’s genetic complexity. Researchers conclude that the interaction between somatic and inherited mutations is crucial in ASD, providing new insights into its genetic basis. This study enhances our understanding of ASD’s genetic diversity and suggests a multifaceted genetic contribution to the disorder. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Low-level brain somatic mutations in exonic regions are collectively implicated in autism with germline mutations in autism risk genes","authors":"Il Bin Kim, Myeong-Heui Kim, Saehoon Jung, Woo Kyeong Kim, Junehawk Lee, Young Seok Ju, Maree J. Webster, Sanghyeon Kim, Ja Hye Kim, Hyun Jung Kim, Junho Kim, Sangwoo Kim, Jeong Ho Lee","doi":"10.1038/s12276-024-01284-1","DOIUrl":"10.1038/s12276-024-01284-1","url":null,"abstract":"Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12–14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology. Autism Spectrum Disorder is a complex condition influenced by various genetic factors, including inherited traits and new changes in genes. This study investigates the role of low-level brain somatic mutations in ASD. The researchers analyzed brain tissues from deceased individuals, both with and without ASD, using high-depth whole-exome sequencing. The results showed that low-level brain somatic mutations, along with inherited genetic variations, contribute to ASD’s genetic makeup. These mutations were found in genes linked to brain development and function. The study emphasizes the need to consider both inherited and somatic mutations to understand ASD’s genetic complexity. Researchers conclude that the interaction between somatic and inherited mutations is crucial in ASD, providing new insights into its genetic basis. This study enhances our understanding of ASD’s genetic diversity and suggests a multifaceted genetic contribution to the disorder. 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":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01284-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861487","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 development of unstable carotid atherosclerotic plaques is associated with the induction of neutrophil extracellular traps (NETs) via the activation of diverse inflammatory mediators in the circulating bloodstream. However, the underlying mechanisms through which NETs influence the microenvironment of atherosclerotic plaques and contribute to the development of unstable carotid plaques remain largely elusive. The objective of this study was to elucidate the role of myeloid differentiation protein 1 (MD-1, LY86)-induced NETs underlying the crosstalk between unstable plaque formation and the plaque microenvironment. We employed bioinformatics analysis to identify key genes associated with carotid-unstable plaque, followed by comprehensive validation using various experimental approaches on tissue specimens and plasma samples classified based on pathological characteristics. Patients with carotid-unstable plaques exhibited elevated plasma concentrations of MD-1 (LY86), while patients with stable plaques demonstrated comparatively lower levels. Furthermore, soluble MD-1 was found to induce the formation of NETs through activation of Toll-like receptor signaling pathway. The proliferative and immature vascularization effects of NETs on endothelial cells, as well as their inhibitory impact on cell migration, are directly correlated with the concentration of NETs. Additionally, NETs were found to activate the NF-κB signaling pathway, thereby upregulating ICAM1, VCAM1, MMP14, VEGFA, and IL6 expression in both Human umbilical vein endothelial cells (HUVECs) and HAECs. Subsequently, a significant increase in intraplaque neovascularization by NETs results in poor carotid plaque stability, and NETs in turn stimulate macrophages to produce more MD-1, generating a harmful positive feedback loop. Our findings suggest that soluble MD-1 in the bloodstream triggers the production of NETs through activation of the Toll-like receptor signaling pathway and further indicate NETs mediate a crosstalk between the microenvironment of the carotid plaque and the neovascularization of the intraplaque region. Inhibiting NETs formation or MD-1 secretion may represent a promising strategy to effectively suppress the development of unstable carotid plaques. Atherosclerosis, a disease where arteries get blocked with fat, is a main cause of heart disease and stroke. Predicting which atherosclerotic plaques will cause heart attacks is hard. Researchers analyzed gene data from unstable and stable carotid plaques, focusing on neutrophils and a protein called MD-1. The study involved 30 patients and 10 healthy volunteers to understand how MD-1 and neutrophils contribute to plaque instability. The main finding is that MD-1 could be a biomarker for unstable plaques, offering a new target for therapies to prevent major heart events. This progress in understanding the molecular mechanisms behind plaque instability could lead to better prevention strategies for heart disease. Future re
{"title":"Neutrophil extracellular traps mediate the crosstalk between plaque microenvironment and unstable carotid plaque formation","authors":"Yu Cao, Minghui Chen, Xinyu Jiao, Shuijie Li, Dong Wang, Yongxuan Zhan, Jiaju Li, Zhongfei Hao, Qingbin Li, Yang Liu, Yan Feng, Ruiyan Li, Hongjun Wang, Mingli Liu, Qiang Fu, Yongli Li","doi":"10.1038/s12276-024-01281-4","DOIUrl":"10.1038/s12276-024-01281-4","url":null,"abstract":"The development of unstable carotid atherosclerotic plaques is associated with the induction of neutrophil extracellular traps (NETs) via the activation of diverse inflammatory mediators in the circulating bloodstream. However, the underlying mechanisms through which NETs influence the microenvironment of atherosclerotic plaques and contribute to the development of unstable carotid plaques remain largely elusive. The objective of this study was to elucidate the role of myeloid differentiation protein 1 (MD-1, LY86)-induced NETs underlying the crosstalk between unstable plaque formation and the plaque microenvironment. We employed bioinformatics analysis to identify key genes associated with carotid-unstable plaque, followed by comprehensive validation using various experimental approaches on tissue specimens and plasma samples classified based on pathological characteristics. Patients with carotid-unstable plaques exhibited elevated plasma concentrations of MD-1 (LY86), while patients with stable plaques demonstrated comparatively lower levels. Furthermore, soluble MD-1 was found to induce the formation of NETs through activation of Toll-like receptor signaling pathway. The proliferative and immature vascularization effects of NETs on endothelial cells, as well as their inhibitory impact on cell migration, are directly correlated with the concentration of NETs. Additionally, NETs were found to activate the NF-κB signaling pathway, thereby upregulating ICAM1, VCAM1, MMP14, VEGFA, and IL6 expression in both Human umbilical vein endothelial cells (HUVECs) and HAECs. Subsequently, a significant increase in intraplaque neovascularization by NETs results in poor carotid plaque stability, and NETs in turn stimulate macrophages to produce more MD-1, generating a harmful positive feedback loop. Our findings suggest that soluble MD-1 in the bloodstream triggers the production of NETs through activation of the Toll-like receptor signaling pathway and further indicate NETs mediate a crosstalk between the microenvironment of the carotid plaque and the neovascularization of the intraplaque region. Inhibiting NETs formation or MD-1 secretion may represent a promising strategy to effectively suppress the development of unstable carotid plaques. Atherosclerosis, a disease where arteries get blocked with fat, is a main cause of heart disease and stroke. Predicting which atherosclerotic plaques will cause heart attacks is hard. Researchers analyzed gene data from unstable and stable carotid plaques, focusing on neutrophils and a protein called MD-1. The study involved 30 patients and 10 healthy volunteers to understand how MD-1 and neutrophils contribute to plaque instability. The main finding is that MD-1 could be a biomarker for unstable plaques, offering a new target for therapies to prevent major heart events. This progress in understanding the molecular mechanisms behind plaque instability could lead to better prevention strategies for heart disease. Future re","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01281-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861488","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 : 2024-08-01DOI: 10.1038/s12276-024-01282-3
Young Hyun Jung, Chang Woo Chae, Ho Jae Han
Although the role of gut microbiota (GMB)-derived metabolites in mitochondrial and endolysosomal dysfunction in Alzheimer’s disease (AD) under metabolic syndrome remains unclear, deciphering these host–metabolite interactions represents a major public health challenge. Dysfunction of mitochondria and endolysosomal networks (ELNs) plays a crucial role in metabolic syndrome and can exacerbate AD progression, highlighting the need to study their reciprocal regulation for a better understanding of how AD is linked to metabolic syndrome. Concurrently, metabolic disorders are associated with alterations in the composition of the GMB. Recent evidence suggests that changes in the composition of the GMB and its metabolites may be involved in AD pathology. This review highlights the mechanisms of metabolic syndrome-mediated AD development, focusing on the interconnected roles of mitochondrial dysfunction, ELN abnormalities, and changes in the GMB and its metabolites. We also discuss the pathophysiological role of GMB-derived metabolites, including amino acids, fatty acids, other metabolites, and extracellular vesicles, in mediating their effects on mitochondrial and ELN dysfunction. Finally, this review proposes therapeutic strategies for AD by directly modulating mitochondrial and ELN functions through targeting GMB metabolites under metabolic syndrome. Although mitochondrial and endolysosomal network (ELN) impairment in metabolic syndrome is considered a risk factor for neurodegenerative diseases, the regulatory role of gut microbiota (GMB)-derived metabolites in this dysfunction remains unclear. This research explores the roles and molecular mechanisms of mitochondrial dysfunction, ELN abnormalities, dysregulation of mitochondria-ELN crosstalk, and changes in GMB and its metabolites in metabolic syndrome, especially in relation to Alzheimer’s disease (AD). The researchers conclude by highlighting the potential of targeting GMB and its metabolites to develop new AD treatments, especially for those with metabolic syndrome. They suggest that understanding and modulating the links between gut health, mitochondrial function, and ELN activity could lead to new management strategies for AD in the context of gut microbiota and its metabolites. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
虽然肠道微生物群（GMB）产生的代谢物在代谢综合征下阿尔茨海默病（AD）的线粒体和内溶酶体功能障碍中的作用仍不清楚，但破译这些宿主-代谢物之间的相互作用是一项重大的公共卫生挑战。线粒体和内溶酶体网络（ELNs）的功能障碍在代谢综合征中起着至关重要的作用，并可加剧阿尔茨海默病的进展，这突出表明有必要研究它们之间的相互调控，以更好地了解阿尔茨海默病如何与代谢综合征联系在一起。同时，代谢紊乱与 GMB 组成的改变有关。最近的证据表明，GMB及其代谢物的组成变化可能与AD病理有关。本综述强调了代谢综合征介导的 AD 发病机制，重点是线粒体功能障碍、ELN 异常和 GMB 及其代谢物变化的相互关联作用。我们还讨论了 GMB 衍生代谢物（包括氨基酸、脂肪酸、其他代谢物和细胞外囊泡）在介导线粒体和 ELN 功能障碍方面的病理生理作用。最后，本综述提出了针对代谢综合征的 GMB 代谢物直接调节线粒体和 ELN 功能的 AD 治疗策略。
{"title":"The potential role of gut microbiota-derived metabolites as regulators of metabolic syndrome-associated mitochondrial and endolysosomal dysfunction in Alzheimer’s disease","authors":"Young Hyun Jung, Chang Woo Chae, Ho Jae Han","doi":"10.1038/s12276-024-01282-3","DOIUrl":"10.1038/s12276-024-01282-3","url":null,"abstract":"Although the role of gut microbiota (GMB)-derived metabolites in mitochondrial and endolysosomal dysfunction in Alzheimer’s disease (AD) under metabolic syndrome remains unclear, deciphering these host–metabolite interactions represents a major public health challenge. Dysfunction of mitochondria and endolysosomal networks (ELNs) plays a crucial role in metabolic syndrome and can exacerbate AD progression, highlighting the need to study their reciprocal regulation for a better understanding of how AD is linked to metabolic syndrome. Concurrently, metabolic disorders are associated with alterations in the composition of the GMB. Recent evidence suggests that changes in the composition of the GMB and its metabolites may be involved in AD pathology. This review highlights the mechanisms of metabolic syndrome-mediated AD development, focusing on the interconnected roles of mitochondrial dysfunction, ELN abnormalities, and changes in the GMB and its metabolites. We also discuss the pathophysiological role of GMB-derived metabolites, including amino acids, fatty acids, other metabolites, and extracellular vesicles, in mediating their effects on mitochondrial and ELN dysfunction. Finally, this review proposes therapeutic strategies for AD by directly modulating mitochondrial and ELN functions through targeting GMB metabolites under metabolic syndrome. Although mitochondrial and endolysosomal network (ELN) impairment in metabolic syndrome is considered a risk factor for neurodegenerative diseases, the regulatory role of gut microbiota (GMB)-derived metabolites in this dysfunction remains unclear. This research explores the roles and molecular mechanisms of mitochondrial dysfunction, ELN abnormalities, dysregulation of mitochondria-ELN crosstalk, and changes in GMB and its metabolites in metabolic syndrome, especially in relation to Alzheimer’s disease (AD). The researchers conclude by highlighting the potential of targeting GMB and its metabolites to develop new AD treatments, especially for those with metabolic syndrome. They suggest that understanding and modulating the links between gut health, mitochondrial function, and ELN activity could lead to new management strategies for AD in the context of gut microbiota and its metabolites. 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":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01282-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861491","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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