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}
Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/β-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process. Calcific aortic valve disease (CAVD, a common heart condition) currently has no effective treatments. This research aimed to examine the role of non-coding RNAs (molecules that control gene activity) in CAVD, particularly circHIPK3 and miR-182-5p. Experiments were conducted on human heart valve cells and mice, showing that circHIPK3 can prevent heart valve hardening, while miR-182-5p can trigger a process that encourages hardening. The research also discovered a protein, Krm1, that can stop this hardening process. These results suggest that focusing on these non-coding RNAs and proteins could offer a new way to treat CAVD. However, more research is needed to fully comprehend these processes and their potential treatment implications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Noncoding RNA regulates the expression of Krm1 and Dkk2 to synergistically affect aortic valve lesions","authors":"Gaopeng Xian, Rong Huang, Minhui Xu, Hengli Zhao, Xingbo Xu, Yangchao Chen, Hao Ren, Dingli Xu, Qingchun Zeng","doi":"10.1038/s12276-024-01256-5","DOIUrl":"10.1038/s12276-024-01256-5","url":null,"abstract":"Calcific aortic valve disease (CAVD) is becoming an increasingly important global medical problem, but effective pharmacological treatments are lacking. Noncoding RNAs play a pivotal role in the progression of cardiovascular diseases, but their relationship with CAVD remains unclear. Sequencing data revealed differential expression of many noncoding RNAs in normal and calcified aortic valves, with significant differences in circHIPK3 and miR-182-5p expression. Overexpression of circHIPK3 ameliorated aortic valve lesions in a CAVD mouse model. In vitro experiments demonstrated that circHIPK3 inhibits the osteogenic response of aortic valve interstitial cells. Mechanistically, DEAD-box helicase 5 (DDX5) recruits methyltransferase 3 (METTL3) to promote the N6-methyladenosine (m6A) modification of circHIPK3. Furthermore, m6A-modified circHIPK3 increases the stability of Kremen1 (Krm1) mRNA, and Krm1 is a negative regulator of the Wnt/β-catenin pathway. Additionally, miR-182-5p suppresses the expression of Dickkopf2 (Dkk2), the ligand of Krm1, and attenuates the Krm1-mediated inhibition of Wnt signaling. Activation of the Wnt signaling pathway significantly contributes to the promotion of aortic valve calcification. Our study describes the role of the Krm1-Dkk2 axis in inhibiting Wnt signaling in aortic valves and suggests that noncoding RNAs are upstream regulators of this process. Calcific aortic valve disease (CAVD, a common heart condition) currently has no effective treatments. This research aimed to examine the role of non-coding RNAs (molecules that control gene activity) in CAVD, particularly circHIPK3 and miR-182-5p. Experiments were conducted on human heart valve cells and mice, showing that circHIPK3 can prevent heart valve hardening, while miR-182-5p can trigger a process that encourages hardening. The research also discovered a protein, Krm1, that can stop this hardening process. These results suggest that focusing on these non-coding RNAs and proteins could offer a new way to treat CAVD. However, more research is needed to fully comprehend these processes and their potential treatment implications. 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/PMC11297286/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141472202","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 : 2024-06-14DOI: 10.1038/s12276-024-01220-3
Hyun Jung Hwang, Yoon Ki Kim
Circular RNAs (circRNAs) are covalently closed single-stranded RNAs without a 5′ cap structure and a 3′ poly(A) tail typically present in linear mRNAs of eukaryotic cells. CircRNAs are predominantly generated through a back-splicing process within the nucleus. CircRNAs have long been considered non-coding RNAs seemingly devoid of protein-coding potential. However, many recent studies have challenged this idea and have provided substantial evidence that a subset of circRNAs can associate with polysomes and indeed be translated. Therefore, in this review, we primarily highlight the 5’ cap-independent internal initiation of translation that occurs on circular RNAs. Several molecular features of circRNAs, including the internal ribosome entry site, N6-methyladenosine modification, and the exon junction complex deposited around the back-splicing junction after back-splicing event, play pivotal roles in their efficient internal translation. We also propose a possible relationship between the translatability of circRNAs and their stability, with a focus on nonsense-mediated mRNA decay and nonstop decay, both of which are well-characterized mRNA surveillance mechanisms. An in-depth understanding of circRNA translation will reshape and expand our current knowledge of proteomics. This research delves into the intricate realm of circular RNAs (circRNAs), a kind of RNA molecule that forms a covalently closed circular structure, making it more stable than its linear counterparts. Despite being plentiful in cells, the role of circRNAs is largely a mystery. The researchers provide a summary of the various ways circRNAs are created and outline the different functions they can have. They also explore the molecular specifics of how circRNAs are translated and consider the potential interaction between this translation and their stability. The research is a review, summarizing and analyzing existing studies on the subject and highlighting the role and potential impact of circRNAs in the regulation of gene expression. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Molecular mechanisms of circular RNA translation","authors":"Hyun Jung Hwang, Yoon Ki Kim","doi":"10.1038/s12276-024-01220-3","DOIUrl":"10.1038/s12276-024-01220-3","url":null,"abstract":"Circular RNAs (circRNAs) are covalently closed single-stranded RNAs without a 5′ cap structure and a 3′ poly(A) tail typically present in linear mRNAs of eukaryotic cells. CircRNAs are predominantly generated through a back-splicing process within the nucleus. CircRNAs have long been considered non-coding RNAs seemingly devoid of protein-coding potential. However, many recent studies have challenged this idea and have provided substantial evidence that a subset of circRNAs can associate with polysomes and indeed be translated. Therefore, in this review, we primarily highlight the 5’ cap-independent internal initiation of translation that occurs on circular RNAs. Several molecular features of circRNAs, including the internal ribosome entry site, N6-methyladenosine modification, and the exon junction complex deposited around the back-splicing junction after back-splicing event, play pivotal roles in their efficient internal translation. We also propose a possible relationship between the translatability of circRNAs and their stability, with a focus on nonsense-mediated mRNA decay and nonstop decay, both of which are well-characterized mRNA surveillance mechanisms. An in-depth understanding of circRNA translation will reshape and expand our current knowledge of proteomics. This research delves into the intricate realm of circular RNAs (circRNAs), a kind of RNA molecule that forms a covalently closed circular structure, making it more stable than its linear counterparts. Despite being plentiful in cells, the role of circRNAs is largely a mystery. The researchers provide a summary of the various ways circRNAs are created and outline the different functions they can have. They also explore the molecular specifics of how circRNAs are translated and consider the potential interaction between this translation and their stability. The research is a review, summarizing and analyzing existing studies on the subject and highlighting the role and potential impact of circRNAs in the regulation of gene expression. 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":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318884","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 : 2024-06-14DOI: 10.1038/s12276-024-01267-2
TaeSoo Kim, Tae-Kyung Kim
{"title":"Regulatory RNA: from molecular insights to therapeutic frontiers","authors":"TaeSoo Kim, Tae-Kyung Kim","doi":"10.1038/s12276-024-01267-2","DOIUrl":"10.1038/s12276-024-01267-2","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11263535/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141318886","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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