Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory ce...Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.展开更多
Plasmonic nanostructure-mediated photothermal therapy(PTT) has proven to be a promising approach for cancer treatment,and new approaches for its effective delivery to tumor lesions are currently being developed.This s...Plasmonic nanostructure-mediated photothermal therapy(PTT) has proven to be a promising approach for cancer treatment,and new approaches for its effective delivery to tumor lesions are currently being developed.This study aimed to assess macrophage-mediated delivery of PTT using radioiodine-124-labeled gold nanoparticles with crushed gold shells(124I-Au@AuCBs) as a theranostic nanoplatform.124I-Au@AuCBs exhibited effective photothermal conversion effects both in vitro and in vivo and were efficiently taken up by macrophages without cytotoxicity.After the administration of 124I-Au@AuCB-labeled macrophages to colon tumors,intensive signals were observed at tumor lesions,and subsequent in vivo PTT with laser irradiation yielded potent antitumor effects.The results indicate the considerable potential of 124I-Au@AuCBs as novel theranostic nanomaterials and the prominent advantages of macrophage-mediated cellular therapies in treating cancer and other diseases.展开更多
Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that...Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that histone demethylases are implicated in osteoblastogenesis;however,little is known about the role of histone demethylases in osteoclast formation.Here,we identified KDM4B as an epigenetic regulator of osteoclast differentiation.Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells.Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency.Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex.Using genome-wide chromatin immunoprecipitation(ChIP)-sequencing,we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation.We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure(euchromatinization)near the promoters of osteoclast-related genes through H3K9 demethylation,leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65.Finally,small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model.Taken together,our findings establish KDM4B as a critical regulator of osteoclastogenesis,providing a potential therapeutic target for osteoporosis.展开更多
Cells orchestrate their processes through complex interactions,precisely organizing biomolecules in space and time.Recent discoveries have highlighted the crucial role of biomolecular condensates—membrane-less assemb...Cells orchestrate their processes through complex interactions,precisely organizing biomolecules in space and time.Recent discoveries have highlighted the crucial role of biomolecular condensates—membrane-less assemblies formed through the condensation of proteins,nucleic acids,and other molecules—in driving efficient and dynamic cellular processes.These condensates are integral to various physiological functions,such as gene expression and intracellular signal transduction,enabling rapid and finely tuned cellular responses.Their ability to regulate cellular signaling pathways is particularly significant,as it requires a careful balance between flexibility and precision.Disruption of this balance can lead to pathological conditions,including neurodegenerative diseases,cancer,and viral infections.Consequently,biomolecular condensates have emerged as promising therapeutic targets,with the potential to offer novel approaches to disease treatment.In this review,we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways,their roles in health and disease,and potential strategies for modulating condensate dynamics as a therapeutic approach.Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.展开更多
The demand for safe vaccines that ensure long-term and broad protection against multiple viral variants has dramatically increased after the emergence of catastrophic infectious diseases such as COVID-19.To ensure lon...The demand for safe vaccines that ensure long-term and broad protection against multiple viral variants has dramatically increased after the emergence of catastrophic infectious diseases such as COVID-19.To ensure long-term and broad protection against heterologous virus variants,antigen-specific polyfunctional T cells should be orchestrated with the activation of follicular helper T(TFH)cells and germinal center(GC)B cells.Herein,we suggest a novel engineered nanoadjuvant(SE(Trojan-TLR7/8a))that enhances the migration of nonexhausted antigen-presenting cells(APCs)into lymph nodes and elicits the activation of TFH cells,the generation of GC B cells,and polyfunctional T cells via multiscale dynamic immunomodulation through squalene nanoemulsion(SE)-mediated macroscopic control of vaccine delivery and Trojan-TLR7/8a-enabled dynamic and sustained activation of APCs at the cellular level.SE(Trojan-TLR7/8a)can be lyophilized,reduce systemic toxicity,and outperform current commercial vaccine adjuvants(Alum or AS03)and mRNA vaccines.SE(Trojan-TLR7/8a)ensures cross-protection against diverse influenza and SARS-CoV-2 variants,providing 100%protection while maintaining a healthy state.SE(Trojan-TLR7/8a)also sustains a potent T-cell response in an aged ferret model of SFTSV infection.SE(Trojan-TLR7/8a)suggested herein provides a novel vaccine design principle for dynamic modulation at the multiscale level and demonstrates long-term and broad protective immunity against emerging pandemic and endemic infectious viruses.展开更多
基金Supported by National Research Foundation of Korea grant funded by the Korea government No.2007-0056092
文摘Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.
基金supported by National Research Foundation of Korea(NRF) grants funded by the Korea Government(MSIP)a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI) funded by the Ministry of Health&Welfare,Republic of Korea(HI16C1501)+1 种基金a grant from the Medical Cluster R&D Support Project through the Daegu-Gyeongbuk Medical Innovation Foundation(DGMIF) funded by the Ministry of Health and Welfare(HT16C0001,HT16C0002,HT17C0009)a National Research Foundation of Korea(NRF) Grant funded by the Korea Government(MSIP)(2014R1A1A1003323,2017R1D1A1B03028340,2018R1D1AB07047417)
文摘Plasmonic nanostructure-mediated photothermal therapy(PTT) has proven to be a promising approach for cancer treatment,and new approaches for its effective delivery to tumor lesions are currently being developed.This study aimed to assess macrophage-mediated delivery of PTT using radioiodine-124-labeled gold nanoparticles with crushed gold shells(124I-Au@AuCBs) as a theranostic nanoplatform.124I-Au@AuCBs exhibited effective photothermal conversion effects both in vitro and in vivo and were efficiently taken up by macrophages without cytotoxicity.After the administration of 124I-Au@AuCB-labeled macrophages to colon tumors,intensive signals were observed at tumor lesions,and subsequent in vivo PTT with laser irradiation yielded potent antitumor effects.The results indicate the considerable potential of 124I-Au@AuCBs as novel theranostic nanomaterials and the prominent advantages of macrophage-mediated cellular therapies in treating cancer and other diseases.
基金support of the National Research Foundation of Korea(2017R1C1B2008017,2020R1A6A1A06046235,and 2020R1A2C1008179 to K.K.,2019R1I1A1A01061125 to S.J.Y.).
文摘Bone undergoes a constant and continuous remodeling process that is tightly regulated by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts.Recent studies have shown that histone demethylases are implicated in osteoblastogenesis;however,little is known about the role of histone demethylases in osteoclast formation.Here,we identified KDM4B as an epigenetic regulator of osteoclast differentiation.Knockdown of KDM4B significantly blocked the formation of tartrate-resistant acid phosphatase-positive multinucleated cells.Mice with myeloid-specific conditional knockout of KDM4B showed an osteopetrotic phenotype due to osteoclast deficiency.Biochemical analysis revealed that KDM4B physically and functionally associates with CCAR1 and MED1 in a complex.Using genome-wide chromatin immunoprecipitation(ChIP)-sequencing,we revealed that the KDM4B–CCAR1–MED1 complex is localized to the promoters of several osteoclast-related genes upon receptor activator of NF-κB ligand stimulation.We demonstrated that the KDM4B–CCAR1–MED1 signaling axis induces changes in chromatin structure(euchromatinization)near the promoters of osteoclast-related genes through H3K9 demethylation,leading to NF-κB p65 recruitment via a direct interaction between KDM4B and p65.Finally,small molecule inhibition of KDM4B activity impeded bone loss in an ovariectomized mouse model.Taken together,our findings establish KDM4B as a critical regulator of osteoclastogenesis,providing a potential therapeutic target for osteoporosis.
基金supported by the National Research Foundation of Korea(NRF)grants NRF-2022R1A4A3024551 and RS-2024-00457141(to W.K.)the Bio&Medical Technology Development Program grant NRF-2022M3A9J3073020(to B.C.)funded by the Ministry of Science,ICT&Future Planning.Figures 1,3,4,5,6,7,8,9,10,and 11 were created using BioRender(http://biorender.com/).
文摘Cells orchestrate their processes through complex interactions,precisely organizing biomolecules in space and time.Recent discoveries have highlighted the crucial role of biomolecular condensates—membrane-less assemblies formed through the condensation of proteins,nucleic acids,and other molecules—in driving efficient and dynamic cellular processes.These condensates are integral to various physiological functions,such as gene expression and intracellular signal transduction,enabling rapid and finely tuned cellular responses.Their ability to regulate cellular signaling pathways is particularly significant,as it requires a careful balance between flexibility and precision.Disruption of this balance can lead to pathological conditions,including neurodegenerative diseases,cancer,and viral infections.Consequently,biomolecular condensates have emerged as promising therapeutic targets,with the potential to offer novel approaches to disease treatment.In this review,we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways,their roles in health and disease,and potential strategies for modulating condensate dynamics as a therapeutic approach.Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.
基金supported by National Research Foundation(NRF)grants funded by the Korean government(grant numbers RS-2025-00513566 and RS-2023-00218648),Republic of Korea(Prof.Yong Taik Lim)supported by NRF grants funded by Korean government(grant number 2021R1A6A1A03045495),Republic of Korea(Prof.Jong-Soo Lee)supported by the Institute for Basic Science(grant number IBS-R801-D1),Republic of Korea(Director Young Ki Choi).
文摘The demand for safe vaccines that ensure long-term and broad protection against multiple viral variants has dramatically increased after the emergence of catastrophic infectious diseases such as COVID-19.To ensure long-term and broad protection against heterologous virus variants,antigen-specific polyfunctional T cells should be orchestrated with the activation of follicular helper T(TFH)cells and germinal center(GC)B cells.Herein,we suggest a novel engineered nanoadjuvant(SE(Trojan-TLR7/8a))that enhances the migration of nonexhausted antigen-presenting cells(APCs)into lymph nodes and elicits the activation of TFH cells,the generation of GC B cells,and polyfunctional T cells via multiscale dynamic immunomodulation through squalene nanoemulsion(SE)-mediated macroscopic control of vaccine delivery and Trojan-TLR7/8a-enabled dynamic and sustained activation of APCs at the cellular level.SE(Trojan-TLR7/8a)can be lyophilized,reduce systemic toxicity,and outperform current commercial vaccine adjuvants(Alum or AS03)and mRNA vaccines.SE(Trojan-TLR7/8a)ensures cross-protection against diverse influenza and SARS-CoV-2 variants,providing 100%protection while maintaining a healthy state.SE(Trojan-TLR7/8a)also sustains a potent T-cell response in an aged ferret model of SFTSV infection.SE(Trojan-TLR7/8a)suggested herein provides a novel vaccine design principle for dynamic modulation at the multiscale level and demonstrates long-term and broad protective immunity against emerging pandemic and endemic infectious viruses.
