Experimental and Molecular Medicine最新文献

{"title":"IKKε-deficient macrophages impede cardiac repair after myocardial infarction by enhancing the macrophage–myofibroblast transition","authors":"Hyang Hee Cho, Siyeon Rhee, Dong Im Cho, Ju Hee Jun, HyoJung Heo, Su Han Cho, Dohyup Kim, Mingqiang Wang, Bo Gyeong Kang, Soo Ji Yoo, Meeyoung Cho, Soo yeon Lim, Jae Yeong Cho, In Seok Jeong, Yong Sook Kim, Youngkeun Ahn","doi":"10.1038/s12276-024-01304-0","DOIUrl":"10.1038/s12276-024-01304-0","url":null,"abstract":"The regulatory role of the inhibitor of NF-kB kinase ε (IKKε) in postmyocardial infarction (MI) inflammation remains uncertain. Using an MI mouse model, we examined the cardiac outcomes of IKKε knockout (KO) mice and wild-type mice. We employed single-cell RNA sequencing (scRNA-seq) and phosphorylated protein array techniques to profile cardiac macrophages. IKKε KO mice exhibited compromised survival, heightened inflammation, pronounced cardiac fibrosis, and a reduced ejection fraction. A distinct cardiac macrophage subset in IKKε KO mice exhibited increased fibrotic marker expression and decreased phosphorylated p38 (p-p38) levels, indicating an enhanced macrophage–myofibroblast transition (MMT) post-MI. While cardiac inflammation is crucial for initiating compensatory pathways, the timely resolution of inflammation was impaired in the IKKε KO group, while the MMT in macrophages accelerated post-MI, leading to cardiac failure. Additionally, our study highlighted the potential of 5-azacytidine (5-Aza), known for its anti-inflammatory and cardioprotective effects, in restoring p-p38 levels in stimulated macrophages. The administration of 5-Aza significantly reduced the MMT in cardiac macrophages from the IKKε KO group. These findings underscore the regulation of the inflammatory response and macrophage transition by the IKKε-p38 axis, indicating that the MMT is a promising therapeutic target for ischemic heart disease. Heart attacks can result in heart failure due to ongoing inflammation and scarring. This research investigates how a specific protein, IKKε, affects inflammation in heart cells. Researchers used genetically altered mice and sophisticated genetic methods to study IKKε‘s role in heart disease. They analyzed heart tissue after inducing heart attacks in the mice, focusing on how cells involved in inflammation and scarring behave differently when the IKKε protein is changed. Macrophage-myofibroblast transition (MMT) is a process in which macrophages acquire characteristics similar to myofibroblasts, potentially contributing to tissue fibrosis. The main discovery is that blocking IKKε causes more scarring by encouraging excessive MMT, suggesting it could be a target for heart disease treatment. The researchers believe that controlling the MMT process could be a new method to enhance heart health after a heart attack by reducing harmful scarring. 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":"56 9","pages":"2052-2064"},"PeriodicalIF":9.5,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01304-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142191252","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}

{"title":"Author Correction: Generation of a lethal mouse model expressing human ACE2 and TMPRSS2 for SARS-CoV-2 infection and pathogenesis","authors":"Gi Uk Jeong, Insu Hwang, Wooseong Lee, Ji Hyun Choi, Gun Young Yoon, Hae Soo Kim, Jeong-Sun Yang, Kyung-Chang Kim, Joo-Yeon Lee, Seong-Jun Kim, Young-Chan Kwon, Kyun-Do Kim","doi":"10.1038/s12276-024-01305-z","DOIUrl":"10.1038/s12276-024-01305-z","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 9","pages":"2096-2096"},"PeriodicalIF":9.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01305-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127226","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}

{"title":"Immunoliposome-based targeted delivery of the CRISPR/Cas9gRNA-IL30 complex inhibits prostate cancer and prolongs survival","authors":"Cristiano Fieni, Carlo Sorrentino, Stefania Livia Ciummo, Antonella Fontana, Lavinia Vittoria Lotti, Sofia Scialis, Darien Calvo Garcia, Massimo Caulo, Emma Di Carlo","doi":"10.1038/s12276-024-01310-2","DOIUrl":"10.1038/s12276-024-01310-2","url":null,"abstract":"The development of selective and nontoxic immunotherapy targeting prostate cancer (PC) is challenging. Interleukin (IL)30 plays immunoinhibitory and oncogenic roles in PC, and its tumor-specific suppression may have significant clinical implications. CRISPR/Cas9-mediated IL30 gene deletion in PC xenografts using anti-PSCA antibody-driven lipid nanocomplexes (Cas9gRNA-hIL30-PSCA NxPs) revealed significant genome editing efficiency and circulation stability without off-target effects or organ toxicity. Biweekly intravenous administration of Cas9gRNA-hIL30-PSCA NxPs to PC-bearing mice inhibited tumor growth and metastasis and improved survival. Mechanistically, Cas9gRNA-hIL30-PSCA NxPs suppressed ANGPTL 1/2/4, IL1β, CCL2, CXCL1/6, SERPINE1-F1, EFNB2, PLG, PF4, VEGFA, VEGFD, ANG, TGFβ1, EGF and HGF expression in human PC cells while upregulated CDH1, DKK3 and PTEN expression, leading to low proliferation and extensive ischemic necrosis. In the syngeneic PC model, IL30-targeting immunoliposomes downregulated NFKB1 expression and prevented intratumoral influx of CD11b+Gr-1+MDCs, Foxp3+Tregs, and NKp46+RORγt+ILC3, and prolonged host survival by inhibiting tumor progression. This study serves as a proof of principle that immunoliposome-based targeted delivery of Cas9gRNA-IL30 represent a potentially safe and effective strategy for PC treatment. Prostate cancer is an age-related disease and a leading cause of cancer death in men worldwide. Although its incidence has remained stable over the past decade, the proportion of tumors diagnosed in the advanced stages is rising, highlighting the need for improved and personalized treatments, especially for older patients with additional health problems. Di Carlo and coworkers created a NanoLiposome delivery system to transport a gene-editing tool, CRISPR/Cas9, directly to prostate cancer cells, to target and inhibit a particular gene involved in cancer growth. This study tested this approach’s effectiveness and safety on human prostate cancer cells and mouse models.　The findings show the potential of using NanoLiposomes for targeted gene editing in cancer. The researchers conclude that this method could provide a new and effective way to treat prostate cancer, particularly in patients requiring gentler treatment options. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 9","pages":"2033-2051"},"PeriodicalIF":9.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01310-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142134349","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}

{"title":"Activity in the dorsal hippocampus-mPFC circuit modulates stress-coping strategies during inescapable stress","authors":"Sang Ho Yoon, Woo Seok Song, Geehoon Chung, Sang Jeong Kim, Myoung-Hwan Kim","doi":"10.1038/s12276-024-01294-z","DOIUrl":"10.1038/s12276-024-01294-z","url":null,"abstract":"Anatomical connectivity and lesion-deficit studies have shown that the dorsal and ventral hippocampi contribute to cognitive and emotional processes, respectively. However, the role of the dorsal hippocampus (dHP) in emotional or stress-related behaviors remains unclear. Here, we showed that neuronal activity in the dHP affects stress-coping behaviors in mice via excitatory projections to the medial prefrontal cortex (mPFC). The antidepressant ketamine rapidly induced c-Fos expression in both the dorsal and ventral hippocampi. The suppression of GABAergic transmission in the dHP-induced molecular changes similar to those induced by ketamine administration, including eukaryotic elongation factor 2 (eEF2) dephosphorylation, brain-derived neurotrophic factor (BDNF) elevation, and extracellular signal-regulated kinase (ERK) phosphorylation. These synaptic and molecular changes in the dHP induced a reduction in the immobility time of the mice in the tail-suspension and forced swim tests without affecting anxiety-related behavior. Conversely, pharmacological and chemogenetic potentiation of inhibitory neurotransmission in the dHP CA1 region induced passive coping behaviors during the tests. Transneuronal tracing and electrophysiology revealed monosynaptic excitatory connections between dHP CA1 neurons and mPFC neurons. Optogenetic stimulation of dHP CA1 neurons in freely behaving mice produced c-Fos induction and spike firing in the mPFC neurons. Chemogenetic activation of the dHP-recipient mPFC neurons reversed the passive coping behaviors induced by suppression of dHP CA1 neuronal activity. Collectively, these results indicate that neuronal activity in the dHP modulates stress-coping strategies to inescapable stress and contributes to the antidepressant effects of ketamine via the dHP-mPFC circuit. Understanding our brain’s handling of emotions and thought is vital. Recent research indicates that different sections of the hippocampus are responsible for either thought processing or emotional reactions. However, new research by Yoon et al. disputes this, demonstrating that both hippocampus sections can affect behavior via connections with the prefrontal cortex, a brain area involved in decision-making. This study, a mouse experiment, examined how a specific pathway between the dorsal hippocampus and the medial prefrontal cortex impacts behavior, especially in response to stress and depression-like symptoms. The researchers used various methods, including gene alteration and behavioral tests, to understand how changes in this pathway’s activity affect behavior. This study paves the way for future research to explore how these brain areas interact in the context of emotional and thought processing, potentially leading to more effective depression 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":"56 9","pages":"1921-1935"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01294-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114383","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}

{"title":"STAT3 promotes NLRP3 inflammasome activation by mediating NLRP3 mitochondrial translocation","authors":"Ling Luo, Fupeng Wang, Xueming Xu, Mingliang Ma, Guangyan Kuang, Yening Zhang, Dan Wang, Wei Li, Ningjie Zhang, Kai Zhao","doi":"10.1038/s12276-024-01298-9","DOIUrl":"10.1038/s12276-024-01298-9","url":null,"abstract":"Recognition of the translocation of NLRP3 to various organelles has provided new insights for understanding how the NLRP3 inflammasome is activated by different stimuli. Mitochondria have already been demonstrated to be the site of NLRP3 inflammasome activation, and the latest research suggests that NLRP3 is first recruited to mitochondria, then disassociated, and subsequently recruited to the Golgi network. Although some mitochondrial factors have been found to contribute to the recruitment of NLRP3 to mitochondria, the detailed process of NLRP3 mitochondrial translocation remains unclear. Here, we identify a previously unknown role for Signal transducer and activator of transcription-3 (STAT3) in facilitating the translocation of NLRP3 to mitochondria. STAT3 interacts with NLRP3 and undergoes phosphorylation at Ser727 in response to several NLRP3 agonists, enabling the translocation of STAT3 and thus the bound NLRP3 to mitochondria. Disruption of the interaction between STAT3 and NLRP3 impairs the mitochondrial localization of NLRP3, specifically suppressing NLRP3 inflammasome activation both in vitro and in vivo. In summary, we demonstrate that STAT3 acts as a transporter for mitochondrial translocation of NLRP3 and provide new insight into the spatial regulation of NLRP3. Our bodies have an innate immune system, which is the first line of defense against infections. It uses specific receptors to detect harmful pathogens. This research investigates how a protein, STAT3, affects the activation of a complex, the NLRP3 inflammasome, crucial in our immune response. The study involved experiments with cell cultures and mice, identifying how STAT3 helps move NLRP3 within cells for activation. This was seen in an experimental study. The results show that targeting STAT3 can reduce inflammation caused by the NLRP3 inflammasome. This suggests a new treatment strategy for diseases caused by too much inflammation, like gout, diabetes, and Alzheimer’s disease. The study shows the potential of drugs that stop STAT3 to manage or treat inflammatory conditions, paving the way for future research on such 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":"56 9","pages":"1980-1990"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01298-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114392","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}

{"title":"Blockade of STING activation alleviates microglial dysfunction and a broad spectrum of Alzheimer’s disease pathologies","authors":"Sunwoo Chung, June-Hyun Jeong, Jong-Chan Park, Jong Won Han, Yeajina Lee, Jong-Il Kim, Inhee Mook-Jung","doi":"10.1038/s12276-024-01295-y","DOIUrl":"10.1038/s12276-024-01295-y","url":null,"abstract":"Abnormal glial activation promotes neurodegeneration in Alzheimer’s disease (AD), the most common cause of dementia. Stimulation of the cGAS-STING pathway induces microglial dysfunction and sterile inflammation, which exacerbates AD. We showed that inhibiting STING activation can control microglia and ameliorate a wide spectrum of AD symptoms. The cGAS-STING pathway is required for the detection of ectopic DNA and the subsequent immune response. Amyloid-β (Aβ) and tau induce mitochondrial stress, which causes DNA to be released into the cytoplasm of microglia. cGAS and STING are highly expressed in Aβ plaque-associated microglia, and neuronal STING is upregulated in the brains of AD model animals. The presence of the APOE ε4 allele, an AD risk factor, also upregulated both proteins. STING activation was necessary for microglial NLRP3 activation, proinflammatory responses, and type-I-interferon responses. Pharmacological STING inhibition reduced a wide range of AD pathogenic features in AppNL-G-F/hTau double-knock-in mice. An unanticipated transcriptome shift in microglia reduced gliosis and cerebral inflammation. Significant reductions in the Aβ load, tau phosphorylation, and microglial synapse engulfment prevented memory loss. To summarize, our study describes the pathogenic mechanism of STING activation as well as its potential as a therapeutic target in AD. In illnesses like Alzheimer’s that cause brain deterioration, the brain’s defense cells, known as microglia, overreact due to harmful proteins, causing brain damage and memory loss. This research aimed to understand how microglia change in Alzheimer’s and find ways to stop their damaging effects. Using mice with Alzheimer’s, they checked if blocking specific immune pathway could fix microglia dysfunction and Alzheimer’s disease pathologies. They discovered that blocking STING, a crucial part of this pathway, reduced microglia dysfunction brain inflammation, decreased the buildup of Alzheimer’s-related proteins, and improved memory in mice. By blocking the STING activation, the study showed a decrease in damaging brain inflammation and improvements in memory function, suggesting a promising strategy for treating Alzheimer’s. Researchers conclude that targeting the STING could offer a new way to fight Alzheimer’s by reducing inflammation and protecting brain health. 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":"56 9","pages":"1936-1951"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01295-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114385","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}

{"title":"The roles and mechanisms of coding and noncoding RNA variations in cancer","authors":"Sang Yean Kim, Min Jeong Na, Sungpil Yoon, Eunbi Shin, Jin Woong Ha, Soyoung Jeon, Suk Woo Nam","doi":"10.1038/s12276-024-01307-x","DOIUrl":"10.1038/s12276-024-01307-x","url":null,"abstract":"Functional variations in coding and noncoding RNAs are crucial in tumorigenesis, with cancer-specific alterations often resulting from chemical modifications and posttranscriptional processes mediated by enzymes. These RNA variations have been linked to tumor cell proliferation, growth, metastasis, and drug resistance and are valuable for identifying diagnostic or prognostic cancer biomarkers. The diversity of posttranscriptional RNA modifications, such as splicing, polyadenylation, methylation, and editing, is particularly significant due to their prevalence and impact on cancer progression. Additionally, other modifications, including RNA acetylation, circularization, miRNA isomerization, and pseudouridination, are recognized as key contributors to cancer development. Understanding the mechanisms underlying these RNA modifications in cancer can enhance our knowledge of cancer biology and facilitate the development of innovative therapeutic strategies. Targeting these RNA modifications and their regulatory enzymes may pave the way for novel RNA-based therapies, enabling tailored interventions for specific cancer subtypes. This review provides a comprehensive overview of the roles and mechanisms of various coding and noncoding RNA modifications in cancer progression and highlights recent advancements in RNA-based therapeutic applications. In the intricate field of cancer study, researchers investigate how changes in RNA, a molecule that carries genetic instructions, contribute to cancer. Researchers explores these RNA changes, their mechanisms, and their role in cancer development. The authors review various ways RNA can be modified, including methylation, editing, and alternative splicing. The authors underline how these RNA changes can impact cancer development by affecting gene activity, protein creation, and cell behavior. The review’s key findings suggest that RNA changes are deeply involved in cancer’s start, development, and treatment response. By charting the landscape of RNA changes in cancer cells, the authors aim to pave new paths for diagnosis, prognosis, and treatment. They conclude targeting RNA changes offers a promising strategy for developing innovative cancer treatments, marking a significant progress in our approach to fighting this disease. 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":"56 9","pages":"1909-1920"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01307-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114393","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}

{"title":"Emerin mislocalization during chromatin bridge resolution can drive prostate cancer cell invasiveness in a collagen-rich microenvironment","authors":"Marta Popęda, Kamil Kowalski, Tomasz Wenta, Galina V. Beznoussenko, Michał Rychłowski, Alexander Mironov, Zeno Lavagnino, Sara Barozzi, Julia Richert, Rebecca Bertolio, Kamil Myszczyński, Jolanta Szade, Michał Bieńkowski, Kevin Miszewski, Marcin Matuszewski, Anna J. Żaczek, Luca Braga, Giannino Del Sal, Natalia Bednarz-Knoll, Paolo Maiuri, Paulina Nastały","doi":"10.1038/s12276-024-01308-w","DOIUrl":"10.1038/s12276-024-01308-w","url":null,"abstract":"Micronuclei (MN) can form through many mechanisms, including the breakage of aberrant cytokinetic chromatin bridges. The frequent observation of MN in tumors suggests that they might not merely be passive elements but could instead play active roles in tumor progression. Here, we propose a mechanism through which the presence of micronuclei could induce specific phenotypic and functional changes in cells and increase the invasive potential of cancer cells. Through the integration of diverse in vitro imaging and molecular techniques supported by clinical samples from patients with prostate cancer (PCa) defined as high-risk by the D’Amico classification, we demonstrate that the resolution of chromosome bridges can result in the accumulation of Emerin and the formation of Emerin-rich MN. These structures are negative for Lamin A/C and positive for the Lamin-B receptor and Sec61β. MN can act as a protein sinks and result in the pauperization of Emerin from the nuclear envelope. The Emerin mislocalization phenotype is associated with a molecular signature that is correlated with a poor prognosis in PCa patients and is enriched in metastatic samples. Emerin mislocalization corresponds with increases in the migratory and invasive potential of tumor cells, especially in a collagen-rich microenvironment. Our study demonstrates that the mislocalization of Emerin to MN results in increased cell invasiveness, thereby worsening patient prognosis. Micronuclei, small nuclei formed during incorrect cell division, can signal genomic instability, often found in cancer. This research investigates how micronuclei may contribute to cancer progression, in the context of prostate cancer, by focusing on the nuclear envelope protein, Emerin. The team conducted experiments using different cell lines and patient samples to understand how Emerin’s misplacement from nuclear envelope to micronuclei can impact cancer cell behavior. The study involved analyzing cells for Emerin distribution, observing the effects of Emerin misplacement on cell movement and invasiveness, and examining prostate cancer tissue to see how these findings relate to the disease in patients. It was observed that the presence of Emerin-rich micronuclei correlates to more aggressive cancer behavior and could predict worse outcomes. Targeting the pathways leading to Emerin misplacement could offer novel strategies for treating aggressive prostate cancer. 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":"56 9","pages":"2016-2032"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01308-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114388","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}

{"title":"Harnessing IL-2 for immunotherapy against cancer and chronic infection: a historical perspective and emerging trends","authors":"Se Jin Im, Kyungmin Lee, Sang-Jun Ha","doi":"10.1038/s12276-024-01301-3","DOIUrl":"10.1038/s12276-024-01301-3","url":null,"abstract":"IL-2 therapy, which enhances the function of CD8 + T cells, was initially employed as the cornerstone of immunotherapy against cancer. However, the impact of this therapy extends beyond CD8 + T cells to cells expressing IL-2R, such as endothelial cells and regulatory T cells (Tregs), resulting in various side effects. Consequently, IL-2 therapy has taken a step back from the forefront of treatment. Immune checkpoint inhibitors (ICIs), such as anti-PD-1/PD-L1 antibodies and CTLA-4 antibodies, are used because of their durable therapeutic responses and the reduced incidence of side effects. Nevertheless, only a small fraction of cancer patients respond to ICIs, and research on IL-2 as a combination treatment to improve the efficacy of these ICIs is ongoing. To mitigate side effects, efforts have focused on developing IL-2 variants that do not strongly bind to cells expressing IL-2Rα and favor signaling through IL-2Rβγ. However, recent studies have suggested that, in the context of persistent antigen stimulation models, effective stimulation of antigen-specific exhausted CD8 + T cells in combination with PD-1 inhibitors requires either 1) binding to IL-2Rα or 2) delivery via a fusion with PD-1. This review explores the historical context of IL-2 as an immunotherapeutic agent and discusses future directions for its use in cancer immunotherapy. Interleukin-2 is crucial for combating cancer, but its use is restricted due to severe side effects. This article reviews the development of IL-2 therapy and how it affects CD8 T cells—important immune cells that can become dysfunctional or “exhausted.” To reduce the unwanted effects, researchers have been trying to create a safer version of IL-2 that avoids targeting certain immune and body cells that contribute to these side effects. Recent studies, however, indicate that using the original form of IL-2 or specifically targeting exhausted CD8 T cells with a marker called PD-1 could be more effective in fighting tumors. Additionally, combining IL-2 therapy with PD-1 blockade can enhance T cells response to cancer. These findings suggest a promising future for personalized and effective cancer 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":"56 9","pages":"1900-1908"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01301-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114389","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}

{"title":"Stanniocalcin 1 and 1,25-dihydroxyvitamin D3 cooperatively regulate bone mineralization by osteoblasts","authors":"Jung Ha Kim, Kabsun Kim, Inyoung Kim, Semun Seong, Jeong-Tae Koh, Nacksung Kim","doi":"10.1038/s12276-024-01302-2","DOIUrl":"10.1038/s12276-024-01302-2","url":null,"abstract":"Stanniocalcin 1 (STC1) is a calcium- and phosphate-regulating hormone that is expressed in all tissues, including bone tissues, and is involved in calcium and phosphate homeostasis. Previously, STC1 expression was found to be increased by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] administration in renal proximal tubular cells. In this study, we investigated whether STC1 directly regulates osteoblast differentiation or reciprocally controls the effects of 1,25(OH)2D3 on osteoblasts to contribute to bone homeostasis. We found that STC1 inhibited osteoblast differentiation in vitro and bone morphogenetic protein 2 (BMP2)-induced ectopic bone formation in vivo. Moreover, 1,25(OH)2D3 increased STC1 expression through direct binding to the Stc1 promoter of the vitamin D receptor (VDR). STC1 activated the 1,25(OH)2D3–VDR signaling pathway through the upregulation of VDR expression mediated by the inhibition of Akt phosphorylation in osteoblasts. STC1 further increased the effects of 1,25(OH)2D3 on receptor activator of nuclear factor-κB ligand (RANKL) secretion and inhibited osteoblast differentiation by exhibiting a positive correlation with 1,25(OH)2D3. The long-bone phenotype of transgenic mice overexpressing STC1 specifically in osteoblasts was not significantly different from that of wild-type mice. However, compared with that in the wild-type mice, 1,25(OH)2D3 administration significantly decreased bone mass in the STC1 transgenic mice. Collectively, these results suggest that STC1 negatively regulates osteoblast differentiation and bone formation; however, the inhibitory effect of STC1 on osteoblasts is transient and can be reversed under normal conditions. Nevertheless, the synergistic effect of STC1 and 1,25(OH)2D3 through 1,25(OH)2D3 administration may reduce bone mass by inhibiting osteoblast differentiation. In the field of bone health, it’s important to understand how our bodies control bone creation. This research investigates how Stanniocalcin 1 and 1,25-dihydroxyvitamin D3 work together to affect bone mineralization by osteoblasts. The team used mouse models and cell cultures in their experiment. They found that STC1 alone can slow down osteoblast differentiation and bone creation, but this effect is stronger when 1,25-dihydroxyvitamin D3 is also present. This suggests a complex relationship that could affect bone health. They conclude that the combined regulation by STC1 and 1,25-dihydroxyvitamin D3 is a key factor in bone mineralization, providing new insights into managing bone health. This knowledge could lead to treatments for bone diseases by targeting these pathways. Future research may show how to adjust these interactions for treatment benefits, potentially improving results for those with bone health problems. 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":"56 9","pages":"1991-2001"},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01302-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114391","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}