Pub Date : 2024-09-04DOI: 10.1038/s12276-024-01305-z
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
{"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":"https://doi.org/10.1038/s12276-024-01305-z","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1038/s12276-024-01310-2
Cristiano Fieni, Carlo Sorrentino, Stefania Livia Ciummo, Antonella Fontana, Lavinia Vittoria Lotti, Sofia Scialis, Darien Calvo Garcia, Massimo Caulo, Emma Di Carlo
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.
{"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":"https://doi.org/10.1038/s12276-024-01310-2","url":null,"abstract":"<p><p>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<sup>+</sup>Gr-1<sup>+</sup>MDCs, Foxp3<sup>+</sup>Tregs, and NKp46<sup>+</sup>RORγt<sup>+</sup>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01294-z
Sang Ho Yoon, Woo Seok Song, Geehoon Chung, Sang Jeong Kim, Myoung-Hwan Kim
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.
{"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":"https://doi.org/10.1038/s12276-024-01294-z","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01298-9
Ling Luo, Fupeng Wang, Xueming Xu, Mingliang Ma, Guangyan Kuang, Yening Zhang, Dan Wang, Wei Li, Ningjie Zhang, Kai Zhao
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.
{"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":"https://doi.org/10.1038/s12276-024-01298-9","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01295-y
Sunwoo Chung, June-Hyun Jeong, Jong-Chan Park, Jong Won Han, Yeajina Lee, Jong-Il Kim, Inhee Mook-Jung
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.
神经胶质的异常激活会促进阿尔茨海默病(AD)的神经变性,而阿尔茨海默病是导致痴呆症的最常见原因。cGAS-STING 通路的刺激会诱发小胶质细胞功能障碍和无菌性炎症,从而加剧阿尔茨海默病。我们的研究表明,抑制 STING 的激活可以控制小胶质细胞,并改善多种 AD 症状。cGAS-STING 通路是检测异位 DNA 和随后的免疫反应所必需的。淀粉样蛋白-β(Aβ)和tau诱导线粒体应激,导致DNA释放到小胶质细胞的胞浆中。作为AD风险因子的APOE ε4等位基因的存在也会上调这两种蛋白。STING 激活是小胶质细胞 NLRP3 激活、促炎反应和 I 型干扰素反应的必要条件。药理 STING 抑制可减少 AppNL-G-F/hTau 双基因敲入小鼠的多种 AD 致病特征。小胶质细胞的转录组发生了意想不到的变化,从而减少了胶质细胞增生和脑部炎症。Aβ负荷、tau磷酸化和小胶质细胞突触吞噬的显著减少防止了记忆丧失。总之,我们的研究描述了 STING 激活的致病机制及其作为 AD 治疗靶点的潜力。
{"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":"https://doi.org/10.1038/s12276-024-01295-y","url":null,"abstract":"<p><p>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 App<sup>NL-G-F</sup>/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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01307-x
Sang Yean Kim, Min Jeong Na, Sungpil Yoon, Eunbi Shin, Jin Woong Ha, Soyoung Jeon, Suk Woo Nam
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.
{"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":"https://doi.org/10.1038/s12276-024-01307-x","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01297-w
Jin Young Sung, Seul Gi Kim, So-Young Park, Jae-Ryong Kim, Hyoung Chul Choi
Telomere dysfunction is a well-known molecular trigger of senescence and has been associated with various age-related diseases, including atherosclerosis. However, the mechanisms involved have not yet been elucidated, and the extent to which telomeres contribute to atherosclerosis is unknown. Therefore, we investigated the mechanism of metformin-induced telomere stabilization and the ability of metformin to inhibit vascular smooth muscle cell (VSMC) senescence caused by advanced atherosclerosis. The present study revealed that metformin inhibited the phenotypes of atherosclerosis and senescence in VSMCs. Metformin increased the phosphorylation of AMPK-dependent PGC-1α and thus increased telomerase activity and the protein level of TERT in OA-treated VSMCs. Mechanistically, the phosphorylation of AMPK and PGC-1α by metformin not only enhanced telomere function but also increased the protein level of TERT, whereas TERT knockdown accelerated the development of atherosclerosis and senescent phenotypes in OA-treated VSMCs regardless of metformin treatment. Furthermore, the in vivo results showed that metformin attenuated the formation of atherosclerotic plaque markers in the aortas of HFD-fed ApoE KO mice. Although metformin did not reduce plaque size, it inhibited the phosphorylation of the AMPK/PGC-1α/TERT signaling cascade, which is associated with the maintenance and progression of plaque formation, in HFD-fed ApoE KO mice. Accordingly, metformin inhibited atherosclerosis-associated phenotypes in vitro and in vivo. These observations show that the enhancement of telomere function by metformin is involved in specific signaling pathways during the progression of atherosclerosis. These findings suggest that telomere stabilization by metformin via the AMPK/p-PGC-1α pathway might provide a strategy for developing therapeutics against vascular diseases such as atherosclerosis.
{"title":"Telomere stabilization by metformin mitigates the progression of atherosclerosis via the AMPK-dependent p-PGC-1α pathway.","authors":"Jin Young Sung, Seul Gi Kim, So-Young Park, Jae-Ryong Kim, Hyoung Chul Choi","doi":"10.1038/s12276-024-01297-w","DOIUrl":"https://doi.org/10.1038/s12276-024-01297-w","url":null,"abstract":"<p><p>Telomere dysfunction is a well-known molecular trigger of senescence and has been associated with various age-related diseases, including atherosclerosis. However, the mechanisms involved have not yet been elucidated, and the extent to which telomeres contribute to atherosclerosis is unknown. Therefore, we investigated the mechanism of metformin-induced telomere stabilization and the ability of metformin to inhibit vascular smooth muscle cell (VSMC) senescence caused by advanced atherosclerosis. The present study revealed that metformin inhibited the phenotypes of atherosclerosis and senescence in VSMCs. Metformin increased the phosphorylation of AMPK-dependent PGC-1α and thus increased telomerase activity and the protein level of TERT in OA-treated VSMCs. Mechanistically, the phosphorylation of AMPK and PGC-1α by metformin not only enhanced telomere function but also increased the protein level of TERT, whereas TERT knockdown accelerated the development of atherosclerosis and senescent phenotypes in OA-treated VSMCs regardless of metformin treatment. Furthermore, the in vivo results showed that metformin attenuated the formation of atherosclerotic plaque markers in the aortas of HFD-fed ApoE KO mice. Although metformin did not reduce plaque size, it inhibited the phosphorylation of the AMPK/PGC-1α/TERT signaling cascade, which is associated with the maintenance and progression of plaque formation, in HFD-fed ApoE KO mice. Accordingly, metformin inhibited atherosclerosis-associated phenotypes in vitro and in vivo. These observations show that the enhancement of telomere function by metformin is involved in specific signaling pathways during the progression of atherosclerosis. These findings suggest that telomere stabilization by metformin via the AMPK/p-PGC-1α pathway might provide a strategy for developing therapeutics against vascular diseases such as atherosclerosis.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01308-w
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
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.
{"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":"https://doi.org/10.1038/s12276-024-01308-w","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01301-3
Se Jin Im, Kyungmin Lee, Sang-Jun Ha
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.
IL-2 疗法可增强 CD8 + T 细胞的功能,最初被用作抗癌免疫疗法的基石。然而,这种疗法的影响超出了 CD8 + T 细胞,扩大到表达 IL-2R 的细胞,如内皮细胞和调节性 T 细胞(Tregs),从而导致各种副作用。因此,IL-2疗法从治疗的前沿退了一步。免疫检查点抑制剂(ICIs),如抗PD-1/PD-L1抗体和CTLA-4抗体,因其治疗反应持久、副作用少而被广泛使用。然而,只有一小部分癌症患者对 ICIs 有反应,目前正在研究将 IL-2 作为一种联合疗法,以提高这些 ICIs 的疗效。为了减轻副作用,人们致力于开发 IL-2 的变体,这些变体不会与表达 IL-2Rα 的细胞强烈结合,而是通过 IL-2Rβγ 发出信号。然而,最近的研究表明,在持续性抗原刺激模型中,结合 PD-1 抑制剂有效刺激抗原特异性衰竭的 CD8 + T 细胞需要 1)与 IL-2Rα 结合或 2)通过与 PD-1 融合传递。本综述探讨了 IL-2 作为免疫治疗药物的历史背景,并讨论了其在癌症免疫疗法中的未来应用方向。
{"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":"https://doi.org/10.1038/s12276-024-01301-3","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-02DOI: 10.1038/s12276-024-01302-2
Jung Ha Kim, Kabsun Kim, Inyoung Kim, Semun Seong, Jeong-Tae Koh, Nacksung Kim
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.
{"title":"Stanniocalcin 1 and 1,25-dihydroxyvitamin D<sub>3</sub> 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":"https://doi.org/10.1038/s12276-024-01302-2","url":null,"abstract":"<p><p>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 D<sub>3</sub> [1,25(OH)<sub>2</sub>D<sub>3</sub>] 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)<sub>2</sub>D<sub>3</sub> 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)<sub>2</sub>D<sub>3</sub> increased STC1 expression through direct binding to the Stc1 promoter of the vitamin D receptor (VDR). STC1 activated the 1,25(OH)<sub>2</sub>D<sub>3</sub>-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)<sub>2</sub>D<sub>3</sub> on receptor activator of nuclear factor-κB ligand (RANKL) secretion and inhibited osteoblast differentiation by exhibiting a positive correlation with 1,25(OH)<sub>2</sub>D<sub>3</sub>. 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)<sub>2</sub>D<sub>3</sub> 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)<sub>2</sub>D<sub>3</sub> through 1,25(OH)<sub>2</sub>D<sub>3</sub> administration may reduce bone mass by inhibiting osteoblast differentiation.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}