Pub Date : 2025-01-17DOI: 10.1038/s12276-024-01376-y
Seon-Yeong Lee, Jeonghyeon Moon, A Ram Lee, Young-Mee Moon, Jeong Won Choi, Chae Rim Lee, Su Been Jeon, Hee Su Sohn, Jeehee Youn, Dongyun Shin, Sung-Hwan Park, Mi-La Cho
Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mitochondrial STAT3 (mitoSTAT3) in Th17 cells and fibroblast-like synoviocytes (FLSs) and analyzed the correlation of mitoSTAT3 with RA. We used a collagen-induced arthritis (CIA) mouse model to determine the effect of mitochondrial STAT3. We observed changes in the RA mouse model via the use of a mitochondrial STAT3-inducing vector and inhibitor. We observed the accumulation of abnormal autophagosomes, increased inflammatory cell death signaling, and decreased mitoSTAT3 activity in FLSs from both patients with RA and patients with IL-17-treated FLSs. We first discovered that IL-17 increased the accumulation of abnormal autophagosomes and the expression of inflammatory cell death factors in synovial fibroblasts and decreased mitoSTAT3 activation. In a mouse model of CIA, arthritis and joint inflammation were decreased by injection vectors that induced mitoSTAT3 overexpression. The abnormal accumulation of autophagosomes and the expression of inflammatory cell death factors were also decreased in these mice. In mouse and human immune cells, ZnSO4, an inducer of mitochondrial STAT3, decreases the production of reactive oxygen species, the IL-17 concentration, and differentiation into Th17 cells. However, mitoSTAT3 blockade accelerated the development of arthritis, inflammatory cell death, and abnormal autophagosome/autophagolysosome formation. Therefore, this study suggests a novel inhibitory mechanism of RA using mitoSTAT3 via the regulation of autophagy, Th17 differentiation, and inflammatory cell death. Rheumatoid arthritis is a long-term disease where the immune system attacks the joints, causing pain and swelling. Researchers have found that a protein called mitoSTAT3, located in the mitochondria, might help reduce inflammation in RA. Researchers used mice with arthritis and human cells to study mitoSTAT3’s role. They increased mitoSTAT3 levels in mice and observed less joint damage and inflammation and found that mitoSTAT3 helps control a process called autophagy. This is important because poor autophagy can worsen RA. The results showed that boosting mitoSTAT3 reduced inflammation and joint damage in mice. The researchers concluded that mitoSTAT3 could be a new target for RA treatment by improving cell cleanup processes and reducing harmful immune responses. In the future, therapies that increase mitoSTAT3 might help people with RA by reducing inflammation and joint damage. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"mtSTAT3 suppresses rheumatoid arthritis by regulating Th17 and synovial fibroblast inflammatory cell death with IL-17-mediated autophagy dysfunction","authors":"Seon-Yeong Lee, Jeonghyeon Moon, A Ram Lee, Young-Mee Moon, Jeong Won Choi, Chae Rim Lee, Su Been Jeon, Hee Su Sohn, Jeehee Youn, Dongyun Shin, Sung-Hwan Park, Mi-La Cho","doi":"10.1038/s12276-024-01376-y","DOIUrl":"10.1038/s12276-024-01376-y","url":null,"abstract":"Th17 cells are activated by STAT3 factors in the nucleus, and these factors are correlated with the pathologic progression of rheumatoid arthritis (RA). Recent studies have demonstrated the presence of STAT3 in mitochondria, but its function is unclear. We investigated the novel role of mitochondrial STAT3 (mitoSTAT3) in Th17 cells and fibroblast-like synoviocytes (FLSs) and analyzed the correlation of mitoSTAT3 with RA. We used a collagen-induced arthritis (CIA) mouse model to determine the effect of mitochondrial STAT3. We observed changes in the RA mouse model via the use of a mitochondrial STAT3-inducing vector and inhibitor. We observed the accumulation of abnormal autophagosomes, increased inflammatory cell death signaling, and decreased mitoSTAT3 activity in FLSs from both patients with RA and patients with IL-17-treated FLSs. We first discovered that IL-17 increased the accumulation of abnormal autophagosomes and the expression of inflammatory cell death factors in synovial fibroblasts and decreased mitoSTAT3 activation. In a mouse model of CIA, arthritis and joint inflammation were decreased by injection vectors that induced mitoSTAT3 overexpression. The abnormal accumulation of autophagosomes and the expression of inflammatory cell death factors were also decreased in these mice. In mouse and human immune cells, ZnSO4, an inducer of mitochondrial STAT3, decreases the production of reactive oxygen species, the IL-17 concentration, and differentiation into Th17 cells. However, mitoSTAT3 blockade accelerated the development of arthritis, inflammatory cell death, and abnormal autophagosome/autophagolysosome formation. Therefore, this study suggests a novel inhibitory mechanism of RA using mitoSTAT3 via the regulation of autophagy, Th17 differentiation, and inflammatory cell death. Rheumatoid arthritis is a long-term disease where the immune system attacks the joints, causing pain and swelling. Researchers have found that a protein called mitoSTAT3, located in the mitochondria, might help reduce inflammation in RA. Researchers used mice with arthritis and human cells to study mitoSTAT3’s role. They increased mitoSTAT3 levels in mice and observed less joint damage and inflammation and found that mitoSTAT3 helps control a process called autophagy. This is important because poor autophagy can worsen RA. The results showed that boosting mitoSTAT3 reduced inflammation and joint damage in mice. The researchers concluded that mitoSTAT3 could be a new target for RA treatment by improving cell cleanup processes and reducing harmful immune responses. In the future, therapies that increase mitoSTAT3 might help people with RA by reducing inflammation and joint damage. 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":"57 1","pages":"221-234"},"PeriodicalIF":9.5,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01376-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015513","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}
Research on pancreatic cancer has transformed with the advent of organoid technology, providing a better platform that closely mimics cancer biology in vivo. This review highlights the critical advancements facilitated by pancreatic organoid models in understanding disease progression, evaluating therapeutic responses, and identifying biomarkers. These three-dimensional cultures enable the proper recapitulation of the cellular architecture and genetic makeup of the original tumors, providing insights into the complex molecular and cellular dynamics at various stages of pancreatic ductal adenocarcinoma (PDAC). We explore the applications of pancreatic organoids in dissecting the tumor microenvironment (TME); elucidating cancer progression, metastasis, and drug resistance mechanisms; and personalizing therapeutic strategies. By overcoming the limitations of traditional 2D cultures and animal models, the use of pancreatic organoids has significantly accelerated translational research, which is promising for improving diagnostic and therapeutic approaches in clinical settings, ultimately aiming to improve the outcomes of patients with pancreatic cancer. Pancreatic cancer is a challenging disease to study and treat. This article discusses how researchers have developed pancreatic organoids to better study this cancer. Organoids are created by growing cells in a specialized 3D matrix, allowing them to form structures that resemble tissues found in the body. This method is more effective than traditional 2D cultures because it better replicates the natural environment of the cells. Researchers use these organoids to study cancer progression, test new drugs, and understand genetic changes in tumors. They can be made from small tissue samples, making them useful for studying advanced cancer stages where tissue is scarce. The findings from organoid studies help identify potential new treatments and improve our understanding of pancreatic cancer biology. In conclusion, pancreatic organoids offer a promising tool for advancing cancer research and developing personalized treatments. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Advancing pancreatic cancer research and therapeutics: the transformative role of organoid technology","authors":"Jihao Xu, Minh Duc Pham, Vincenzo Corbo, Mariano Ponz-Sarvise, Tobiloba Oni, Daniel Öhlund, Chang-Il Hwang","doi":"10.1038/s12276-024-01378-w","DOIUrl":"10.1038/s12276-024-01378-w","url":null,"abstract":"Research on pancreatic cancer has transformed with the advent of organoid technology, providing a better platform that closely mimics cancer biology in vivo. This review highlights the critical advancements facilitated by pancreatic organoid models in understanding disease progression, evaluating therapeutic responses, and identifying biomarkers. These three-dimensional cultures enable the proper recapitulation of the cellular architecture and genetic makeup of the original tumors, providing insights into the complex molecular and cellular dynamics at various stages of pancreatic ductal adenocarcinoma (PDAC). We explore the applications of pancreatic organoids in dissecting the tumor microenvironment (TME); elucidating cancer progression, metastasis, and drug resistance mechanisms; and personalizing therapeutic strategies. By overcoming the limitations of traditional 2D cultures and animal models, the use of pancreatic organoids has significantly accelerated translational research, which is promising for improving diagnostic and therapeutic approaches in clinical settings, ultimately aiming to improve the outcomes of patients with pancreatic cancer. Pancreatic cancer is a challenging disease to study and treat. This article discusses how researchers have developed pancreatic organoids to better study this cancer. Organoids are created by growing cells in a specialized 3D matrix, allowing them to form structures that resemble tissues found in the body. This method is more effective than traditional 2D cultures because it better replicates the natural environment of the cells. Researchers use these organoids to study cancer progression, test new drugs, and understand genetic changes in tumors. They can be made from small tissue samples, making them useful for studying advanced cancer stages where tissue is scarce. The findings from organoid studies help identify potential new treatments and improve our understanding of pancreatic cancer biology. In conclusion, pancreatic organoids offer a promising tool for advancing cancer research and developing personalized 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":"57 1","pages":"50-58"},"PeriodicalIF":9.5,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01378-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015493","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 : 2025-01-08DOI: 10.1038/s12276-024-01384-y
Marissa A. Scavuzzo, Wojciech J. Szlachcic, Matthew C. Hill, Natalia M. Ziojla, Jessica Teaw, Jeffrey C. Carlson, Jonathan Tiessen, Jolanta Chmielowiec, James F. Martin, Malgorzata Borowiak
The spatial organization of cells within a tissue is dictated throughout dynamic developmental processes. We sought to understand whether cells geometrically coordinate with one another throughout development to achieve their organization. The pancreas is a complex cellular organ with a particular spatial organization. Signals from the mesenchyme, neurons, and endothelial cells instruct epithelial cell differentiation during pancreatic development. To understand the cellular diversity and spatial organization of the developing pancreatic niche, we mapped the spatial relationships between single cells over time. We found that four transcriptionally unique subtypes of mesenchyme in the developing pancreas spatially coordinate throughout development, with each subtype at fixed locations in space and time in relation to other cells, including beta cells, vasculature, and epithelial cells. Our work provides insight into the mechanisms of pancreatic development by showing that cells are organized in a space and time manner. This study explores how different types of cells, called mesenchyme, help form the pancreas during development. Researchers used various techniques to study mouse embryos and human fetal tissue. They identified several subtypes of mesenchyme in the developing pancreas and found that these subtypes are not randomly distributed; instead, they occupy specific locations. The study involved analyzing single-cell RNA sequencing data (a method to study gene expression in individual cells) and using advanced imaging techniques to map the positions of these cells. The researchers discovered that different mesenchyme subtypes have unique roles, such as supporting blood vessel formation or nerve development. These findings suggest that understanding mesenchyme organization could improve regenerative medicine approaches for diseases like diabetes. Future research may explore how these cells interact with other pancreatic components over time. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Pancreatic organogenesis mapped through space and time","authors":"Marissa A. Scavuzzo, Wojciech J. Szlachcic, Matthew C. Hill, Natalia M. Ziojla, Jessica Teaw, Jeffrey C. Carlson, Jonathan Tiessen, Jolanta Chmielowiec, James F. Martin, Malgorzata Borowiak","doi":"10.1038/s12276-024-01384-y","DOIUrl":"10.1038/s12276-024-01384-y","url":null,"abstract":"The spatial organization of cells within a tissue is dictated throughout dynamic developmental processes. We sought to understand whether cells geometrically coordinate with one another throughout development to achieve their organization. The pancreas is a complex cellular organ with a particular spatial organization. Signals from the mesenchyme, neurons, and endothelial cells instruct epithelial cell differentiation during pancreatic development. To understand the cellular diversity and spatial organization of the developing pancreatic niche, we mapped the spatial relationships between single cells over time. We found that four transcriptionally unique subtypes of mesenchyme in the developing pancreas spatially coordinate throughout development, with each subtype at fixed locations in space and time in relation to other cells, including beta cells, vasculature, and epithelial cells. Our work provides insight into the mechanisms of pancreatic development by showing that cells are organized in a space and time manner. This study explores how different types of cells, called mesenchyme, help form the pancreas during development. Researchers used various techniques to study mouse embryos and human fetal tissue. They identified several subtypes of mesenchyme in the developing pancreas and found that these subtypes are not randomly distributed; instead, they occupy specific locations. The study involved analyzing single-cell RNA sequencing data (a method to study gene expression in individual cells) and using advanced imaging techniques to map the positions of these cells. The researchers discovered that different mesenchyme subtypes have unique roles, such as supporting blood vessel formation or nerve development. These findings suggest that understanding mesenchyme organization could improve regenerative medicine approaches for diseases like diabetes. Future research may explore how these cells interact with other pancreatic components over time. 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":"57 1","pages":"204-220"},"PeriodicalIF":9.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01384-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958279","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 : 2025-01-08DOI: 10.1038/s12276-024-01382-0
Won-Gun Yun, Daeun Kim, Youngmin Han, Wooil Kwon, Seong-Geun Lee, Jin-Young Jang, Daechan Park
Most cancer mutation profiling studies are laboratory-based and lack direct clinical application. For clinical use, it is necessary to focus on key genes and integrate them with relevant clinical variables. We aimed to evaluate the prognostic value of the dosage of the KRAS G12 mutation, a key pancreatic ductal adenocarcinoma (PDAC) variant and to investigate the biological mechanism of the prognosis associated with the dosage of the KRAS G12 mutation. In this retrospective cohort study, we analyzed 193 surgically treated patients with PDAC between 2009 and 2016. RNA, whole-exome, and KRAS-targeted sequencing data were used to estimate the dosage of the KRAS G12 mutant. Our prognostic scoring system included the mutation dosage from targeted sequencing ( > 0.195, 1 point), maximal tumor diameter at preoperative imaging ( > 20 mm, 1 point), and carbohydrate antigen 19-9 levels ( > 150 U/mL, 1 point). The KRAS mutation dosage exhibited comparable performance with clinical variables for survival prediction. High KRAS mutation dosages activated the cell cycle, leading to high mutation rates and poor prognosis. According to prognostic scoring systems that integrate mutation dosage with clinical factors, patients with 0 points had superior median overall survival of 97.0 months and 1-year, 3-year, and 5-year overall survival rates of 95.8%, 70.8%, and 66.4%, respectively. In contrast, patients with 3 points had worse median overall survival of only 16.0 months and 1-year, 3-year, and 5-year overall survival rates of 65.2%, 8.7%, and 8.7%, respectively. The incorporation of the KRAS G12 mutation dosage variable into prognostic scoring systems can improve clinical variable-based survival prediction, highlighting the feasibility of an integrated scoring system with clinical significance. Pancreatic ductal adenocarcinoma (PDAC) is a severe health issue with low survival rates. This study is aimed to improve PDAC treatment by examining the KRAS gene mutation, which is common in these tumors. The study involved 193 patients who had surgery for PDAC. Researchers used different sequencing methods to measure the KRAS mutation levels and compared these with clinical data. They found that higher KRAS mutation levels were linked to faster tumor growth and earlier recurrence after surgery. By combining KRAS mutation data with clinical factors like tumor size and a blood marker, they developed a scoring system to predict patient outcomes. This system could help doctors tailor treatments more effectively. The study suggests that using KRAS mutation levels can improve predictions about PDAC progression and guide personalized treatment plans in the future. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Multiomic quantification of the KRAS mutation dosage improves the preoperative prediction of survival and recurrence in patients with pancreatic ductal adenocarcinoma","authors":"Won-Gun Yun, Daeun Kim, Youngmin Han, Wooil Kwon, Seong-Geun Lee, Jin-Young Jang, Daechan Park","doi":"10.1038/s12276-024-01382-0","DOIUrl":"10.1038/s12276-024-01382-0","url":null,"abstract":"Most cancer mutation profiling studies are laboratory-based and lack direct clinical application. For clinical use, it is necessary to focus on key genes and integrate them with relevant clinical variables. We aimed to evaluate the prognostic value of the dosage of the KRAS G12 mutation, a key pancreatic ductal adenocarcinoma (PDAC) variant and to investigate the biological mechanism of the prognosis associated with the dosage of the KRAS G12 mutation. In this retrospective cohort study, we analyzed 193 surgically treated patients with PDAC between 2009 and 2016. RNA, whole-exome, and KRAS-targeted sequencing data were used to estimate the dosage of the KRAS G12 mutant. Our prognostic scoring system included the mutation dosage from targeted sequencing ( > 0.195, 1 point), maximal tumor diameter at preoperative imaging ( > 20 mm, 1 point), and carbohydrate antigen 19-9 levels ( > 150 U/mL, 1 point). The KRAS mutation dosage exhibited comparable performance with clinical variables for survival prediction. High KRAS mutation dosages activated the cell cycle, leading to high mutation rates and poor prognosis. According to prognostic scoring systems that integrate mutation dosage with clinical factors, patients with 0 points had superior median overall survival of 97.0 months and 1-year, 3-year, and 5-year overall survival rates of 95.8%, 70.8%, and 66.4%, respectively. In contrast, patients with 3 points had worse median overall survival of only 16.0 months and 1-year, 3-year, and 5-year overall survival rates of 65.2%, 8.7%, and 8.7%, respectively. The incorporation of the KRAS G12 mutation dosage variable into prognostic scoring systems can improve clinical variable-based survival prediction, highlighting the feasibility of an integrated scoring system with clinical significance. Pancreatic ductal adenocarcinoma (PDAC) is a severe health issue with low survival rates. This study is aimed to improve PDAC treatment by examining the KRAS gene mutation, which is common in these tumors. The study involved 193 patients who had surgery for PDAC. Researchers used different sequencing methods to measure the KRAS mutation levels and compared these with clinical data. They found that higher KRAS mutation levels were linked to faster tumor growth and earlier recurrence after surgery. By combining KRAS mutation data with clinical factors like tumor size and a blood marker, they developed a scoring system to predict patient outcomes. This system could help doctors tailor treatments more effectively. The study suggests that using KRAS mutation levels can improve predictions about PDAC progression and guide personalized treatment plans in the future. 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":"57 1","pages":"193-203"},"PeriodicalIF":9.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01382-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958278","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 : 2025-01-08DOI: 10.1038/s12276-024-01385-x
Donghoon Lee
In response to extra- and intracellular stimuli that constantly challenge and disturb the proteome, cells rapidly change their proteolytic capacity to maintain proteostasis. Failure of such efforts often becomes a major cause of diseases or is associated with exacerbation. Increase in protein breakdown occurs at multiple steps in the ubiquitin-proteasome system, and the regulation of ubiquitination has been extensively studied. However, the activities of the 26S proteasome are also stimulated, especially under highly catabolic conditions such as those associated with atrophying skeletal muscle, proteotoxic stress such as heat shock and arsenite, or hormonal cues such as cAMP or cGMP agonists. Among the proteins that enhance proteasomal degradation are the PKA, PKG, UBL-UBA proteins and the Zn finger AN1-type domain (ZFAND) family proteins. ZFAND proteins are of particular interest because of their inducible expression in response to various stimuli and their abilities to control protein quality by stimulating the 26S proteasome and p97/VCP. The regulatory roles of ZFAND proteins appear to be important not only for the control of protein degradation but also for other cellular processes, such as mRNA stability and signaling pathways. This review summarizes the known functions of proteasome activators and discusses their possible roles in regulating proteostasis and other cellular processes. For many years, scientists have studied how cells break down proteins using a proteolytic complex like the proteasome. The proteasome is a complex machine that degrades majority of intracellular proteins. However, its activation mechanism under stresses is not fully understood. Researchers explored proteins called ZFANDs, which can activate the proteasome. The studies used various methods to understand how ZFAND proteins work and found that ZFAND5, as an example, helps the proteasome break down proteins more efficiently. This is important because it can help cells manage stresses by removing unwanted proteins. The results showed that ZFAND5 binds to the proteasome and enhances its activity, especially in stresses causing muscle wasting. This discovery helps us understand how cells adapt to stresses and could lead to new treatments for diseases where protein breakdown is disrupted. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Activators of the 26S proteasome when protein degradation increases","authors":"Donghoon Lee","doi":"10.1038/s12276-024-01385-x","DOIUrl":"10.1038/s12276-024-01385-x","url":null,"abstract":"In response to extra- and intracellular stimuli that constantly challenge and disturb the proteome, cells rapidly change their proteolytic capacity to maintain proteostasis. Failure of such efforts often becomes a major cause of diseases or is associated with exacerbation. Increase in protein breakdown occurs at multiple steps in the ubiquitin-proteasome system, and the regulation of ubiquitination has been extensively studied. However, the activities of the 26S proteasome are also stimulated, especially under highly catabolic conditions such as those associated with atrophying skeletal muscle, proteotoxic stress such as heat shock and arsenite, or hormonal cues such as cAMP or cGMP agonists. Among the proteins that enhance proteasomal degradation are the PKA, PKG, UBL-UBA proteins and the Zn finger AN1-type domain (ZFAND) family proteins. ZFAND proteins are of particular interest because of their inducible expression in response to various stimuli and their abilities to control protein quality by stimulating the 26S proteasome and p97/VCP. The regulatory roles of ZFAND proteins appear to be important not only for the control of protein degradation but also for other cellular processes, such as mRNA stability and signaling pathways. This review summarizes the known functions of proteasome activators and discusses their possible roles in regulating proteostasis and other cellular processes. For many years, scientists have studied how cells break down proteins using a proteolytic complex like the proteasome. The proteasome is a complex machine that degrades majority of intracellular proteins. However, its activation mechanism under stresses is not fully understood. Researchers explored proteins called ZFANDs, which can activate the proteasome. The studies used various methods to understand how ZFAND proteins work and found that ZFAND5, as an example, helps the proteasome break down proteins more efficiently. This is important because it can help cells manage stresses by removing unwanted proteins. The results showed that ZFAND5 binds to the proteasome and enhances its activity, especially in stresses causing muscle wasting. This discovery helps us understand how cells adapt to stresses and could lead to new treatments for diseases where protein breakdown is disrupted. 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":"57 1","pages":"41-49"},"PeriodicalIF":9.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01385-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958277","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 : 2025-01-07DOI: 10.1038/s12276-024-01386-w
Hyung-Goo Kim, Clara Berdasco, Angus C. Nairn, Yong Kim
Actin polymerization and depolymerization are fundamental cellular processes required not only for the embryonic and postnatal development of the brain but also for the maintenance of neuronal plasticity and survival in the adult and aging brain. The orchestrated organization of actin filaments is controlled by various actin regulatory proteins. Wiskott‒Aldrich syndrome protein-family verprolin-homologous protein (WAVE) members are key activators of ARP2/3 complex-mediated actin polymerization. WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1. The activity of the WAVE complex is tightly regulated by extracellular cues and intracellular signaling to execute its roles in specific intracellular events in brain cells. Notably, dysregulation of the WAVE complex and WAVE complex-mediated cellular processes confers vulnerability to a variety of brain disorders. De novo mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders such as intellectual disability, epileptic seizures, schizophrenia, and/or autism spectrum disorder. In addition, alterations in the WAVE complex are implicated in the pathophysiology of Alzheimer’s disease and Parkinson’s disease, as well as in behavioral adaptations to psychostimulants or maladaptive feeding. The WAVE complex is a group of proteins that work together to regulate actin, an essential component of the cell cytoskeleton. This article reviews how changes in the WAVE complex can affect brain function and contribute to various brain disorders. It summarizes how different parts of the WAVE complex interact with other proteins to regulate actin polymerization. This regulation is crucial for programming brain cell growth, migration, and synaptic formation and function. This article also explores recent studies on genetic changes in the WAVE complex and their links to developmental and adult brain disorders. Key findings suggest disruptions in the WAVE complex can lead to conditions like intellectual disabilities, autism, and neurodegenerative diseases such as Alzheimer’s. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"The WAVE complex in developmental and adulthood brain disorders","authors":"Hyung-Goo Kim, Clara Berdasco, Angus C. Nairn, Yong Kim","doi":"10.1038/s12276-024-01386-w","DOIUrl":"10.1038/s12276-024-01386-w","url":null,"abstract":"Actin polymerization and depolymerization are fundamental cellular processes required not only for the embryonic and postnatal development of the brain but also for the maintenance of neuronal plasticity and survival in the adult and aging brain. The orchestrated organization of actin filaments is controlled by various actin regulatory proteins. Wiskott‒Aldrich syndrome protein-family verprolin-homologous protein (WAVE) members are key activators of ARP2/3 complex-mediated actin polymerization. WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1. The activity of the WAVE complex is tightly regulated by extracellular cues and intracellular signaling to execute its roles in specific intracellular events in brain cells. Notably, dysregulation of the WAVE complex and WAVE complex-mediated cellular processes confers vulnerability to a variety of brain disorders. De novo mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders such as intellectual disability, epileptic seizures, schizophrenia, and/or autism spectrum disorder. In addition, alterations in the WAVE complex are implicated in the pathophysiology of Alzheimer’s disease and Parkinson’s disease, as well as in behavioral adaptations to psychostimulants or maladaptive feeding. The WAVE complex is a group of proteins that work together to regulate actin, an essential component of the cell cytoskeleton. This article reviews how changes in the WAVE complex can affect brain function and contribute to various brain disorders. It summarizes how different parts of the WAVE complex interact with other proteins to regulate actin polymerization. This regulation is crucial for programming brain cell growth, migration, and synaptic formation and function. This article also explores recent studies on genetic changes in the WAVE complex and their links to developmental and adult brain disorders. Key findings suggest disruptions in the WAVE complex can lead to conditions like intellectual disabilities, autism, and neurodegenerative diseases such as Alzheimer’s. 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":"57 1","pages":"13-29"},"PeriodicalIF":9.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01386-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142957149","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 : 2025-01-07DOI: 10.1038/s12276-024-01387-9
Muhammad Sufyan bin Masroni, Evelyn Siew-Chuan Koay, Victor Kwan Min Lee, Siok Bian Ng, Soo Yong Tan, Karen Meiling Tan, Marco Archetti, Sai Mun Leong
Altruism, an act of benefiting others at a cost to the self, challenges our understanding of evolution. This Perspective delves into the importance of altruism in cancer cells and its implications for therapy. Against the backdrop of existing knowledge on various social organisms found in nature, we explore the mechanisms underlying the manifestation of altruism within breast tumors, revealing a complex interplay of seemingly counteracting cancer signaling pathways and processes that orchestrate the delicate balance between cost and benefit underlying altruistic cooperation. We also discuss how evolutionary game theory, coupled with contemporary molecular tools, may shed light on understudied mechanisms governing the dynamics of altruistic cooperation in cancer cells. Finally, we discuss how molecular insights gleaned from these mechanistic dissections may fuel advancements in our comprehension of altruism among cancer cells, with implications across multiple disciplines, offering innovative prospects for therapeutic strategies, molecular discoveries, and evolutionary investigations. Altruism, or selfless behavior, has puzzled scientists for years, especially in the context of evolution. Traditionally, cancer cells are seen as selfish, growing uncontrollably. However, recent research suggests some cancer cells might act altruistically. They found that certain breast cancer cells produce substances that help neighboring cells survive chemotherapy, even though this slows their own growth. The study used breast cancer cell lines to observe these interactions. Researchers identified a subpopulation of cells with high levels of a molecule called miR-125b. These cells secrete proteins that protect other cells but grow more slowly themselves. This behavior fits the definition of biological altruism, where one organism incurs a cost to benefit others. The findings suggest that understanding these altruistic behaviors in cancer could lead to new treatment strategies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Sociobiology meets oncology: unraveling altruistic cooperation in cancer cells and its implications","authors":"Muhammad Sufyan bin Masroni, Evelyn Siew-Chuan Koay, Victor Kwan Min Lee, Siok Bian Ng, Soo Yong Tan, Karen Meiling Tan, Marco Archetti, Sai Mun Leong","doi":"10.1038/s12276-024-01387-9","DOIUrl":"10.1038/s12276-024-01387-9","url":null,"abstract":"Altruism, an act of benefiting others at a cost to the self, challenges our understanding of evolution. This Perspective delves into the importance of altruism in cancer cells and its implications for therapy. Against the backdrop of existing knowledge on various social organisms found in nature, we explore the mechanisms underlying the manifestation of altruism within breast tumors, revealing a complex interplay of seemingly counteracting cancer signaling pathways and processes that orchestrate the delicate balance between cost and benefit underlying altruistic cooperation. We also discuss how evolutionary game theory, coupled with contemporary molecular tools, may shed light on understudied mechanisms governing the dynamics of altruistic cooperation in cancer cells. Finally, we discuss how molecular insights gleaned from these mechanistic dissections may fuel advancements in our comprehension of altruism among cancer cells, with implications across multiple disciplines, offering innovative prospects for therapeutic strategies, molecular discoveries, and evolutionary investigations. Altruism, or selfless behavior, has puzzled scientists for years, especially in the context of evolution. Traditionally, cancer cells are seen as selfish, growing uncontrollably. However, recent research suggests some cancer cells might act altruistically. They found that certain breast cancer cells produce substances that help neighboring cells survive chemotherapy, even though this slows their own growth. The study used breast cancer cell lines to observe these interactions. Researchers identified a subpopulation of cells with high levels of a molecule called miR-125b. These cells secrete proteins that protect other cells but grow more slowly themselves. This behavior fits the definition of biological altruism, where one organism incurs a cost to benefit others. The findings suggest that understanding these altruistic behaviors in cancer could lead to new treatment strategies. 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":"57 1","pages":"30-40"},"PeriodicalIF":9.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01387-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958280","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 : 2025-01-06DOI: 10.1038/s12276-024-01375-z
Do-Hun Kim, Sang-Hwi Choi, Jin Jea Sung, Sieun Kim, Hanui Yi, Sanghyun Park, Chan Wook Park, Young Woo Oh, Jungil Lee, Dae-Sung Kim, Jong-Hoon Kim, Chul-Yong Park, Dong-Wook Kim
Hemophilia A (HA) is caused by mutations in coagulation factor VIII (FVIII). Genome editing in conjunction with patient-derived induced pluripotent stem cells (iPSCs) is a promising cell therapy strategy, as it replaces dysfunctional proteins resulting from genetic mutations with normal proteins. However, the low expression level and short half-life of FVIII still remain significant limiting factors in the efficacy of these approaches in HA. Here, we constructed a functionally enhanced FVIII variant, F309S/E1984V-mutated B domain-deleted (BDD)-FVIII (FE-FVIII), with increased activity and stability. We inserted FE-FVIII with a human elongation factor-1 alpha (EF1α) promoter into the AAVS1 locus of HA patient-derived iPSCs via CRISPR/Cas9 (D10A) nickase to ensure expression in any cell type. FE-FVIII was expressed not only in undifferentiated FE-FVIII-inserted (FE-KI) iPSCs but also in endothelial cells (ECs) differentiated from them in vitro. Compared with mice transplanted with wild-type BDD-FVIII-containing ECs, immunocompetent HA mice intravenously transplanted with FE-KI ECs presented a 2.12-fold increase in FVIII activity in the blood and an approximately 20% greater survival rate after hemorrhagic tail injury. For sustained efficacy, FE-KI ECs were subcutaneously transplanted into immunodeficient HA mice, resulting in amelioration of the hemophilia phenotype for more than 3 months. This strategy can improve FVIII function and may provide a universal therapeutic approach for treating HA. Hemophilia A is a genetic disorder that causes bleeding due to a faulty gene on the X chromosome. Researchers explored a new approach using stem cells and gene editing to improve treatment. They used induced pluripotent stem cells, which can become any cell type, from HA patients. By editing these cells with CRISPR/Cas9, they inserted a modified version of the faulty gene into a safe spot in the DNA. This study involved lab experiments and tests on mice to see if the edited cells could produce the necessary protein, Factor VIII, more effectively. The modified FVIII showed better activity and stability than the regular version. Mice treated with these cells had improved blood clotting and survival rates after injury. The researchers concluded that this method could be a promising step toward better treatments for HA. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Long-term correction of hemophilia A via integration of a functionally enhanced FVIII gene into the AAVS1 locus by nickase in patient-derived iPSCs","authors":"Do-Hun Kim, Sang-Hwi Choi, Jin Jea Sung, Sieun Kim, Hanui Yi, Sanghyun Park, Chan Wook Park, Young Woo Oh, Jungil Lee, Dae-Sung Kim, Jong-Hoon Kim, Chul-Yong Park, Dong-Wook Kim","doi":"10.1038/s12276-024-01375-z","DOIUrl":"10.1038/s12276-024-01375-z","url":null,"abstract":"Hemophilia A (HA) is caused by mutations in coagulation factor VIII (FVIII). Genome editing in conjunction with patient-derived induced pluripotent stem cells (iPSCs) is a promising cell therapy strategy, as it replaces dysfunctional proteins resulting from genetic mutations with normal proteins. However, the low expression level and short half-life of FVIII still remain significant limiting factors in the efficacy of these approaches in HA. Here, we constructed a functionally enhanced FVIII variant, F309S/E1984V-mutated B domain-deleted (BDD)-FVIII (FE-FVIII), with increased activity and stability. We inserted FE-FVIII with a human elongation factor-1 alpha (EF1α) promoter into the AAVS1 locus of HA patient-derived iPSCs via CRISPR/Cas9 (D10A) nickase to ensure expression in any cell type. FE-FVIII was expressed not only in undifferentiated FE-FVIII-inserted (FE-KI) iPSCs but also in endothelial cells (ECs) differentiated from them in vitro. Compared with mice transplanted with wild-type BDD-FVIII-containing ECs, immunocompetent HA mice intravenously transplanted with FE-KI ECs presented a 2.12-fold increase in FVIII activity in the blood and an approximately 20% greater survival rate after hemorrhagic tail injury. For sustained efficacy, FE-KI ECs were subcutaneously transplanted into immunodeficient HA mice, resulting in amelioration of the hemophilia phenotype for more than 3 months. This strategy can improve FVIII function and may provide a universal therapeutic approach for treating HA. Hemophilia A is a genetic disorder that causes bleeding due to a faulty gene on the X chromosome. Researchers explored a new approach using stem cells and gene editing to improve treatment. They used induced pluripotent stem cells, which can become any cell type, from HA patients. By editing these cells with CRISPR/Cas9, they inserted a modified version of the faulty gene into a safe spot in the DNA. This study involved lab experiments and tests on mice to see if the edited cells could produce the necessary protein, Factor VIII, more effectively. The modified FVIII showed better activity and stability than the regular version. Mice treated with these cells had improved blood clotting and survival rates after injury. The researchers concluded that this method could be a promising step toward better treatments for HA. 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":"57 1","pages":"184-192"},"PeriodicalIF":9.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01375-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121562","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}
FHIT is a fragile site tumor suppressor that is primarily inactivated upon tobacco smoking. FHIT loss is frequently observed in lung cancer, making it an important biomarker for the development of targeted therapy for lung cancer. Here, we report that inhibitors of glycogen synthase kinase 3 beta (GSK3β) and the homologous recombination DNA repair (HRR) pathway are synthetic lethal with FHIT loss in lung cancer. Pharmacological inhibition or siRNA depletion of GSK3β selectively suppressed the growth of FHIT-deficient lung cancer tumors in vitro and in animal models. We further showed that FHIT inactivation leads to the activation of DNA damage repair pathways, including the HRR and NHEJ pathways, in lung cancer cells. Conversely, FHIT-deficient cells are highly dependent on HRR for survival under DNA damage stress. The inhibition of GSK3β in FHIT-deficient cells suppressed the ATR/BRCA1/RAD51 axis in HRR signaling via two distinct pathways and suppressed DNA double-strand break repair, leading to the accumulation of DNA damage and apoptosis. Small molecule inhibitors of HRR, but not NHEJ or PARP, induced synthetic lethality in FHIT-deficient lung cancer cells. The findings of this study suggest that the GSK3β and HRR pathways are potential drug targets in lung cancer patients with FHIT loss. Lung cancer is a major cause of cancer deaths, often due to smoking. Despite progress, death rates remain high. Researchers found a gap in targeting FHIT, a tumor suppressor gene often missing in lung cancer. The study used synthetic lethality (a genetic interaction where two gene mutations cause cell death) to target FHIT loss. They tested drugs on lung cancer cells and discovered that blocking GSK3β (an enzyme involved in various cell processes) killed FHIT-deficient cells. This study used cell cultures and mice, focusing on DNA repair pathways vital for cancer cell survival. Results showed that inhibiting GSK3β increased DNA damage and cell death in FHIT-deficient cells. The study suggests that targeting GSK3β could lead to new treatments for lung cancer with FHIT loss, offering hope for better therapies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
{"title":"Inhibition of GSK3β is synthetic lethal with FHIT loss in lung cancer by blocking homologous recombination repair","authors":"Shishi Tao, Yue Pu, Eun Ju Yang, Guowen Ren, Changxiang Shi, Li-Jie Chen, Liang Chen, Joong Sup Shim","doi":"10.1038/s12276-024-01374-0","DOIUrl":"10.1038/s12276-024-01374-0","url":null,"abstract":"FHIT is a fragile site tumor suppressor that is primarily inactivated upon tobacco smoking. FHIT loss is frequently observed in lung cancer, making it an important biomarker for the development of targeted therapy for lung cancer. Here, we report that inhibitors of glycogen synthase kinase 3 beta (GSK3β) and the homologous recombination DNA repair (HRR) pathway are synthetic lethal with FHIT loss in lung cancer. Pharmacological inhibition or siRNA depletion of GSK3β selectively suppressed the growth of FHIT-deficient lung cancer tumors in vitro and in animal models. We further showed that FHIT inactivation leads to the activation of DNA damage repair pathways, including the HRR and NHEJ pathways, in lung cancer cells. Conversely, FHIT-deficient cells are highly dependent on HRR for survival under DNA damage stress. The inhibition of GSK3β in FHIT-deficient cells suppressed the ATR/BRCA1/RAD51 axis in HRR signaling via two distinct pathways and suppressed DNA double-strand break repair, leading to the accumulation of DNA damage and apoptosis. Small molecule inhibitors of HRR, but not NHEJ or PARP, induced synthetic lethality in FHIT-deficient lung cancer cells. The findings of this study suggest that the GSK3β and HRR pathways are potential drug targets in lung cancer patients with FHIT loss. Lung cancer is a major cause of cancer deaths, often due to smoking. Despite progress, death rates remain high. Researchers found a gap in targeting FHIT, a tumor suppressor gene often missing in lung cancer. The study used synthetic lethality (a genetic interaction where two gene mutations cause cell death) to target FHIT loss. They tested drugs on lung cancer cells and discovered that blocking GSK3β (an enzyme involved in various cell processes) killed FHIT-deficient cells. This study used cell cultures and mice, focusing on DNA repair pathways vital for cancer cell survival. Results showed that inhibiting GSK3β increased DNA damage and cell death in FHIT-deficient cells. The study suggests that targeting GSK3β could lead to new treatments for lung cancer with FHIT loss, offering hope for better therapies. 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":"57 1","pages":"167-183"},"PeriodicalIF":9.5,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01374-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121626","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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