Pub Date : 2025-02-01DOI: 10.1016/j.trsl.2024.09.002
Aoran Huang , Jianyun Rao , Xin Feng , Xingru Li , Tianhua Xu , Li Yao
Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3′s interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets.
1.
This study uses single-cell transcriptome to investigate vascular calcification in depth.
2.
This study successfully identifies cellular heterogeneity related to vascular calcification.
3.
This study reveals the crucial role of ID3 in vascular smooth muscle cell osteogenic differentiation.
4.
In vivo and in vitro experiments of this study demonstrate the regulatory role of the USP1/ID3/E12/P21 axis in calcification.
5.
This study provides potential molecular targets for the treatment of calcification-related diseases.
{"title":"Breaking new ground: Unraveling the USP1/ID3/E12/P21 axis in vascular calcification","authors":"Aoran Huang , Jianyun Rao , Xin Feng , Xingru Li , Tianhua Xu , Li Yao","doi":"10.1016/j.trsl.2024.09.002","DOIUrl":"10.1016/j.trsl.2024.09.002","url":null,"abstract":"<div><div>Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3′s interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets.<ul><li><span>1.</span><span><div>This study uses single-cell transcriptome to investigate vascular calcification in depth.</div></span></li><li><span>2.</span><span><div>This study successfully identifies cellular heterogeneity related to vascular calcification.</div></span></li><li><span>3.</span><span><div>This study reveals the crucial role of ID3 in vascular smooth muscle cell osteogenic differentiation.</div></span></li><li><span>4.</span><span><div><em>In vivo</em> and <em>in vitro</em> experiments of this study demonstrate the regulatory role of the USP1/ID3/E12/P21 axis in calcification.</div></span></li><li><span>5.</span><span><div>This study provides potential molecular targets for the treatment of calcification-related diseases.</div></span></li></ul></div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"276 ","pages":"Pages 1-20"},"PeriodicalIF":6.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335633","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 : 2025-01-17DOI: 10.1016/j.trsl.2025.01.002
Jesse A. Davidson , John Iguidbashian , Ludmila Khailova , Tanner Lehmann , Alejandro Suarez-Pierre , Lindsay M. Thomson , Jack Zakrzewski , Eiman Ali , Schuyler Lee , Benjamin S. Frank , Richard J. Ing , Matthew L. Stone , Suzanne Osorio Lujan , Sierra Niemiec , Christopher A. Mancuso
The organ-level molecular response to cardiac surgery with cardiopulmonary bypass (CPB) remains inadequately understood and may be heterogeneous. Here, we measured organ-specific gene expression in a piglet model of CPB with deep hypothermic circulatory arrest (DHCA). Infant piglets underwent peripheral CPB with 75 min of DHCA and 6 h of critical care after separation from CPB. Mechanically ventilated animals served as controls. Tissue was obtained from the lung, kidney, liver, heart, and ileum. RNA sequencing was performed using NovaSeq 6000 and evaluated via differentially expressed gene (DEG) and pathway/network analyses. CPB/DHCA induced significant transcriptomic alterations, with greater changes seen in liver (2,166 DEGs), heart (775 DEGs), and kidney (1,759 DEGs) compared to lung (401 DEGs) and ileum (11 DEGs), and little overlap across organs (<20 % differentially expressed in >1 organ). Key upregulated systems included ribosomal proliferation and mitochondrial assembly in the liver, oxidative stress response and proximal tubular repair in the kidney, myofilament structural genes and pro-hypertrophy pathways in the heart, and solute channels and arginine metabolism in the lung. Downregulation of adaptive immunity genes occurred in multiple organs. Transcriptomics could inform the investigation of targeted therapies and adverse event screening after cardiac surgery.
{"title":"Cardiopulmonary bypass with deep hypothermic circulatory arrest results in organ-specific transcriptomic responses in pediatric swine","authors":"Jesse A. Davidson , John Iguidbashian , Ludmila Khailova , Tanner Lehmann , Alejandro Suarez-Pierre , Lindsay M. Thomson , Jack Zakrzewski , Eiman Ali , Schuyler Lee , Benjamin S. Frank , Richard J. Ing , Matthew L. Stone , Suzanne Osorio Lujan , Sierra Niemiec , Christopher A. Mancuso","doi":"10.1016/j.trsl.2025.01.002","DOIUrl":"10.1016/j.trsl.2025.01.002","url":null,"abstract":"<div><div>The organ-level molecular response to cardiac surgery with cardiopulmonary bypass (CPB) remains inadequately understood and may be heterogeneous. Here, we measured organ-specific gene expression in a piglet model of CPB with deep hypothermic circulatory arrest (DHCA). Infant piglets underwent peripheral CPB with 75 min of DHCA and 6 h of critical care after separation from CPB. Mechanically ventilated animals served as controls. Tissue was obtained from the lung, kidney, liver, heart, and ileum. RNA sequencing was performed using NovaSeq 6000 and evaluated via differentially expressed gene (DEG) and pathway/network analyses. CPB/DHCA induced significant transcriptomic alterations, with greater changes seen in liver (2,166 DEGs), heart (775 DEGs), and kidney (1,759 DEGs) compared to lung (401 DEGs) and ileum (11 DEGs), and little overlap across organs (<20 % differentially expressed in >1 organ). Key upregulated systems included ribosomal proliferation and mitochondrial assembly in the liver, oxidative stress response and proximal tubular repair in the kidney, myofilament structural genes and pro-hypertrophy pathways in the heart, and solute channels and arginine metabolism in the lung. Downregulation of adaptive immunity genes occurred in multiple organs. Transcriptomics could inform the investigation of targeted therapies and adverse event screening after cardiac surgery.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"277 ","pages":"Pages 64-74"},"PeriodicalIF":6.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143019236","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}
The use of e-cigarettes has grown rapidly in recent years, raising concerns about their impact on human health, particularly on critical physiological barriers such as the blood-brain barrier (BBB), alveolar-capillary barrier, and vascular systems. This systematic review evaluates the current literature on the effects of e-cigarette exposure on these barrier systems. E-cigarettes, regardless of nicotine content, have been shown to induce oxidative stress, inflammation, and disruption of tight junction proteins, leading to impaired barrier function. Key findings include compromised pulmonary function, increased vascular stiffness, and neuroinflammation. The review highlights potential long-term health risks associated with e-cigarette use, such as cardiovascular disease, neurodevelopmental disorders, and multi-organ fibrosis, and emphasizes the need for public health interventions to regulate e-cigarette use, especially in vulnerable populations like pregnant women and adolescents.
{"title":"Assessing the impact of e-cigarettes on human barrier systems: A systematic review","authors":"Gabriella Lupo , Carmelina Daniela Anfuso , Giuseppe Smecca , Alessia Cosentino , Aleksandra Agafonova , Chiara Prinzi , Rosario Junior Ferrauto , Stefano Turzo , Venerando Rapisarda , Caterina Ledda","doi":"10.1016/j.trsl.2025.01.001","DOIUrl":"10.1016/j.trsl.2025.01.001","url":null,"abstract":"<div><div>The use of e-cigarettes has grown rapidly in recent years, raising concerns about their impact on human health, particularly on critical physiological barriers such as the blood-brain barrier (BBB), alveolar-capillary barrier, and vascular systems. This systematic review evaluates the current literature on the effects of e-cigarette exposure on these barrier systems. E-cigarettes, regardless of nicotine content, have been shown to induce oxidative stress, inflammation, and disruption of tight junction proteins, leading to impaired barrier function. Key findings include compromised pulmonary function, increased vascular stiffness, and neuroinflammation. The review highlights potential long-term health risks associated with e-cigarette use, such as cardiovascular disease, neurodevelopmental disorders, and multi-organ fibrosis, and emphasizes the need for public health interventions to regulate e-cigarette use, especially in vulnerable populations like pregnant women and adolescents.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"277 ","pages":"Pages 39-63"},"PeriodicalIF":6.4,"publicationDate":"2025-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143019308","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 : 2025-01-04DOI: 10.1016/j.trsl.2024.12.006
Mengmeng Liu , Yuanqing Yao , Fangyan Tan , Jing Wang , Rong Hu , Jianlin Du , Yonghong Jiang , Xin Yuan
Renal ischemia-reperfusion injury (IRI) is a common clinical condition that currently lacks effective treatment options. Inhibitors targeting the sodium-glucose co-transporter-2 (SGLT-2), recognized for their role in managing hyperglycemia, have demonstrated efficacy in enhancing the health outcomes for diabetic patients grappling with chronic kidney disease. Nevertheless, the precise impact of SGLT-2 inhibitors on renal ischemia-reperfusion injury (IRI) and the corresponding transcriptomic alterations remain to be elucidated. In our research, we developed a model of IRI using male C57BL/6 mice by clamping the unilateral renal artery and administering empagliflozin Transcriptomic alterations were analyzed using RNA sequencing (RNA-Seq), complemented by proteomic analysis to investigate the effects of empagliflozin. Histological assessments revealed increased renal inflammatory cell infiltration, widespread renal tubular injury, and elevated autophagosomes formation in the IRI group compared to controls. These pathological changes were significantly attenuated following empagliflozin treatment. Besides, renal function impairment can be alleviated in empagliflozin-treated group. RNA-Seq analysis identified lysosomal autophagy as a key biological process in IRI mice. Empagliflozin exerted a renoprotective effect by downregulating lysosome-associated membrane proteins, primarily LAMP1, LAMP2, and LAMP4 (CD68), through the PI3K-Akt, MAPK, and mTOR signaling pathways, thereby inhibiting autophagic processes. In conclusion, this study highlights enhanced inflammation and disrupted metabolism as hallmark transcriptomic signatures of renal. Furthermore, it demonstrates the renoprotective effects of empagliflozin in alleviating renal IRI by modulating autophagic processes.
{"title":"Sodium-glucose co-transporter 2 (SGLT-2) inhibitors ameliorate renal ischemia-reperfusion injury (IRI) by modulating autophagic processes","authors":"Mengmeng Liu , Yuanqing Yao , Fangyan Tan , Jing Wang , Rong Hu , Jianlin Du , Yonghong Jiang , Xin Yuan","doi":"10.1016/j.trsl.2024.12.006","DOIUrl":"10.1016/j.trsl.2024.12.006","url":null,"abstract":"<div><div>Renal ischemia-reperfusion injury (IRI) is a common clinical condition that currently lacks effective treatment options. Inhibitors targeting the sodium-glucose co-transporter-2 (SGLT-2), recognized for their role in managing hyperglycemia, have demonstrated efficacy in enhancing the health outcomes for diabetic patients grappling with chronic kidney disease. Nevertheless, the precise impact of SGLT-2 inhibitors on renal ischemia-reperfusion injury (IRI) and the corresponding transcriptomic alterations remain to be elucidated. In our research, we developed a model of IRI using male C57BL/6 mice by clamping the unilateral renal artery and administering empagliflozin Transcriptomic alterations were analyzed using RNA sequencing (RNA-Seq), complemented by proteomic analysis to investigate the effects of empagliflozin. Histological assessments revealed increased renal inflammatory cell infiltration, widespread renal tubular injury, and elevated autophagosomes formation in the IRI group compared to controls. These pathological changes were significantly attenuated following empagliflozin treatment. Besides, renal function impairment can be alleviated in empagliflozin-treated group. RNA-Seq analysis identified lysosomal autophagy as a key biological process in IRI mice. Empagliflozin exerted a renoprotective effect by downregulating lysosome-associated membrane proteins, primarily LAMP1, LAMP2, and LAMP4 (CD68), through the PI3K-Akt, MAPK, and mTOR signaling pathways, thereby inhibiting autophagic processes. In conclusion, this study highlights enhanced inflammation and disrupted metabolism as hallmark transcriptomic signatures of renal. Furthermore, it demonstrates the renoprotective effects of empagliflozin in alleviating renal IRI by modulating autophagic processes.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"277 ","pages":"Pages 27-38"},"PeriodicalIF":6.4,"publicationDate":"2025-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985940","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 : 2025-01-03DOI: 10.1016/j.trsl.2024.12.005
Shiao-Ying Chang , Min-Chun Liao , Kana N. Miyata , Yuchao Pang , Xin-Ping Zhao , Junzheng Peng , Alain Rivard , Julie R. Ingelfinger , John S.D. Chan , Shao-Ling Zhang
Renal hedgehog interacting protein (Hhip) activates sodium-glucose cotransporter 2 (Sglt2) expression and promotes tubular senescence in murine diabetic kidney disease (DKD), yet its underlying mechanism(s) are poorly understood. Here we study the effect of the SGLT2 inhibitor, canagliflozin on tubulopathy (fibrosis and apoptosis) in Akita/HhipRPTC-transgenic (Tg) mice with overexpression of Hhip in their renal proximal tubular cells (RPTCs) and its relevant mechanisms. The DKD-tubulopathy with pronounced Sglt2 expression was aggravated in the kidney of Akita/HhipRPTC-Tg cf. Akita/non-Tg mice. A strong association was observed between Hhip and tubular senescence in Nephroseq from the Nakagawa chronic kidney disease study. Both in vivo and in vitro, excessive Hhip in RPTCs triggered RPTC senescence (polyploidization and cytoskeleton destabilization) and released extracellular vesicles (EVs) carrying Hhip (EVsHhip), most of which were apoptotic bodies (ABsHhip) or microvesicles (MVsHhip) and little exosomes (EXOsHhip). Further, Hhip stimulated β2-microglobulin, which further interacts with EVsHhip, together facilitating RPTC turn-over from cellular senescence to fibrosis and/or apoptosis, ultimately leading to advanced tubulopathy. In contrast, canagliflozin administration offset the action of Hhip in RPTCs, thereby preventing DKD progression. In conclusion, canagliflozin prevented excessive Hhip-mediated tubulopathy, possibly via the inhibition of excessive Hhip carried by extracellular vehicles in DKD.
{"title":"Canagliflozin inhibits hedgehog interacting protein (Hhip) induction of tubulopathy in diabetic Akita mice","authors":"Shiao-Ying Chang , Min-Chun Liao , Kana N. Miyata , Yuchao Pang , Xin-Ping Zhao , Junzheng Peng , Alain Rivard , Julie R. Ingelfinger , John S.D. Chan , Shao-Ling Zhang","doi":"10.1016/j.trsl.2024.12.005","DOIUrl":"10.1016/j.trsl.2024.12.005","url":null,"abstract":"<div><div>Renal hedgehog interacting protein (Hhip) activates sodium-glucose cotransporter 2 (Sglt2) expression and promotes tubular senescence in murine diabetic kidney disease (DKD), yet its underlying mechanism(s) are poorly understood. Here we study the effect of the SGLT2 inhibitor, canagliflozin on tubulopathy (fibrosis and apoptosis) in Akita/<em>Hhip</em><sup>RPTC</sup>-transgenic (Tg) mice with overexpression of Hhip in their renal proximal tubular cells (RPTCs) and its relevant mechanisms. The DKD-tubulopathy with pronounced Sglt2 expression was aggravated in the kidney of Akita/<em>Hhip</em><sup>RPTC</sup>-Tg cf. Akita/non-Tg mice. A strong association was observed between Hhip and tubular senescence in Nephroseq from the Nakagawa chronic kidney disease study. Both <em>in vivo</em> and <em>in vitro</em>, excessive Hhip in RPTCs triggered RPTC senescence (polyploidization and cytoskeleton destabilization) and released extracellular vesicles (EVs) carrying Hhip (EVs<sup>Hhip</sup>), most of which were apoptotic bodies (ABs<sup>Hhip</sup>) or microvesicles (MVs<sup>Hhip</sup>) and little exosomes (EXOs<sup>Hhip</sup>). Further, Hhip stimulated β2-microglobulin, which further interacts with EVs<sup>Hhip</sup>, together facilitating RPTC turn-over from cellular senescence to fibrosis and/or apoptosis, ultimately leading to advanced tubulopathy. In contrast, canagliflozin administration offset the action of Hhip in RPTCs, thereby preventing DKD progression. In conclusion, canagliflozin prevented excessive Hhip-mediated tubulopathy, possibly via the inhibition of excessive Hhip carried by extracellular vehicles in DKD.</div></div>","PeriodicalId":23226,"journal":{"name":"Translational Research","volume":"277 ","pages":"Pages 13-26"},"PeriodicalIF":6.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142934207","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}
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