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Viskupicova J, Michel Espinoza-Fonseca L. Allosteric modulation of SERCA pumps in health and disease: structural dynamics, posttranslational modifications, and therapeutic potential. J Mol Biol 2025:169200. [PMID: 40349954 DOI: 10.1016/j.jmb.2025.169200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2025] [Revised: 04/29/2025] [Accepted: 05/06/2025] [Indexed: 05/14/2025]
Abstract
Sarco/endoplasmic reticulum (SR/ER) Ca2+-ATPase (SERCA) pumps are ubiquitous membrane proteins in all eukaryotic cells, playing a central role in maintaining intracellular calcium homeostasis by re-sequestering Ca2+ ions from the cytosol into the SR/ER at the expense of ATP hydrolysis. SERCA pumps are well-characterized components of the calcium transport machinery in the cell, playing a role in various physiological processes, including muscle contraction, energy metabolism, secretion exocytosis, gene expression, synaptic transmission, cell survival, and fertilization. Allosteric regulation of SERCA pumps plays a key role in health and disease, and modulation of the SERCA pumps has emerged as a therapeutic approach for the treatment of cardiovascular, muscular, metabolic, and neurodegenerative disorders. In this review, we provide a comprehensive overview of the structural dynamics underlying allosteric modulation of SERCA, focusing on the effects of endogenous regulatory proteins, Ca2+ ions, ATP, and small-molecule effectors on the dynamics and function of the pump. We also examine in detail the role of posttranslational modifications as allosteric modulators of SERCA function, focusing on the oxidative modifications S-glutathionylation, S-nitrosylation, tyrosine nitration, and carbonylation, and non-oxidative modifications that include SUMOylation, acetylation, O-GlcNAcylation, phosphorylation, and ubiquitination. Finally, we discuss the therapeutic potential and challenges of allosteric modulation of SERCA pumps, including the design of small-molecule effectors, microRNA-based interventions, and targeted strategies that modulate SERCA posttranslational regulation. Overall, this review aims to bridge the gap between the mechanisms underlying allosteric modulation of SERCA and the translation of basic science discoveries into effective therapies targeting SERCA pumps.
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Affiliation(s)
- Jana Viskupicova
- Centre of Experimental Medicine, Institute of Experimental Pharmacology & Toxicology, Slovak Academy of Sciences, 84104 Bratislava, Slovakia.
| | - L Michel Espinoza-Fonseca
- Center for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
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Xie Y, Li Q, Bian X, Yin Y, Liang Z, Liu X, Zhang T, Liu X, Quan X, Wang Y. Downregulation of SENP1 impairs nuclear condensation of MEF2C and deteriorates ischemic cardiomyopathy. Clin Transl Med 2025; 15:e70318. [PMID: 40341856 PMCID: PMC12059206 DOI: 10.1002/ctm2.70318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 04/08/2025] [Accepted: 04/13/2025] [Indexed: 05/11/2025] Open
Abstract
Ischemic cardiomyopathy (ICM) is characterised by the insufficient capacity of the heart to effectively pump blood, which ultimately contributes to heart failure (HF). In this study, the down regulation of SENP1 is identified in the cardiomyocyte of ICM mouse models and in patients. The depletion of SENP1 exacerbates hypoxia-induced apoptosis of cardiomyocytes in vitro and deteriorated cardiomyocyte injury of ICM mice in vivo. Mechanistically, SENP1 deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 401 for stabilising protein stability. Moreover, the interaction with SENP1 controls the nuclear condensation of MEF2C to promote the expression of genes critical for cardiomyocyte function. When rescuing SENP1 expression using adeno-associated virus serotype 9, the attenuation of cardiomyocyte injury is discerned in the mouse model of ICM. Therefore, these finding elicits a previously unrecognised role and mechanism of SENP1 in safeguarding cardiomyocyte in ICM progression while establishing a basis for the development of SENP1 as a potential marker for ICM diagnosis and treatment. KEY POINTS: SNEP1 is downregulated in the cardiomyocyte of ICM mouse models and in patients. SENP1 deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 401 for protein stability. The interaction with SENP1 controls the nuclear condensation of MEF2C to promote cardiomyocyte function. Cardiac rescue of SENP1 alleviates ischemic heart injury in ICM mouse models by AAV9.
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Affiliation(s)
- Ying Xie
- Shandong Provincial Key Laboratory of Precision OncologyShandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Qiaoyuan Li
- Department of CardiologyBeijing Anzhen Hospital, Capital Medical UniversityBeijingChina
| | - Xiyun Bian
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm InfantsThe Tianjin Fifth Central Hospital, BinhaiTianjinChina
| | - Yan Yin
- Department of CardiologyBeijing Anzhen Hospital, Capital Medical UniversityBeijingChina
| | - Zhuo Liang
- Department of CardiologyBeijing Anzhen Hospital, Capital Medical UniversityBeijingChina
| | - Xu Liu
- Department of CardiologyBeijing Anzhen Hospital, Capital Medical UniversityBeijingChina
| | - Tao Zhang
- Department of CardiologyBeijing Anzhen Hospital, Capital Medical UniversityBeijingChina
| | - Xiaozhi Liu
- Tianjin Key Laboratory of Epigenetics for Organ Development in Preterm InfantsThe Tianjin Fifth Central Hospital, BinhaiTianjinChina
| | - Xin Quan
- Ultrasound Imaging CenterFuwai Hospital, National Center for Cardiovascular DiseaseChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yunlong Wang
- Department of CardiologyBeijing Anzhen Hospital, Capital Medical UniversityBeijingChina
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He Y, Yang Z, Guo D, Luo C, Liu Q, Xian L, Yang F, Huang C, Wei Q. The multifaceted nature of SUMOylation in heart disease and its therapeutic potential. Mol Cell Biochem 2025:10.1007/s11010-025-05286-z. [PMID: 40287894 DOI: 10.1007/s11010-025-05286-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 04/06/2025] [Indexed: 04/29/2025]
Abstract
SUMOylation (SUMO), a crucial post-translational modification, is implicated in the regulation of diverse biological processes and plays a pivotal role in both the maintenance of cardiac function and progression and treatment of heart disease. Here, we reviewed the mechanisms by which SUMO-related various aspects of cardiac function and disease, including cardiac hypertrophy, heart failure, ischemia-reperfusion injury, and myocardial infarction. Furthermore, we highlight its potential as a therapeutic target.
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Affiliation(s)
- Ying He
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhijie Yang
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Dan Guo
- Medical College, Guangxi University, Nanning, Guangxi, China
| | - Cheng Luo
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Qiaoqiao Liu
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China
| | - Lei Xian
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Fan Yang
- The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China.
- Liuzhou Key Laboratory of Primary Cardiomyopathy in Prevention and Treatment, Liuzhou, Guangxi, China.
| | - Chusheng Huang
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
| | - Qingjun Wei
- The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
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Qiu B, Zhang S, Ge S, Yu Z, Wang D, Li K, Yu X, Tang C, Du J, Jin H, Huang Y. Vascular smooth muscle cell-derived SO 2 sulphenylated interferon regulatory factor 1 to inhibit VSMC senescence. Front Pharmacol 2025; 16:1516885. [PMID: 40223932 PMCID: PMC11986361 DOI: 10.3389/fphar.2025.1516885] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Accepted: 03/19/2025] [Indexed: 04/15/2025] Open
Abstract
Background Vascular smooth muscle cell (VSMC) senescence is a critical driver of vascular aging and various age-related cardiovascular diseases. Endogenous sulfur dioxide (SO2), a newly identified key cardiovascular gaseous signaling mediator, accelerates collagen deposition and vascular remodeling in VSMCs when downregulated. However, its effects on VSMC senescence remain unclear. Objective This study focused on exploring the role of endogenous SO2 in VSMC senescence and its associated molecular pathways. Methods Aged mice (24 months old), VSMC-specific aspartate aminotransferase 1 (AAT1) knockout (VSMC-AAT1-KO) mice, D-galactose (D-gal)-treated aorta rings and rat VSMC line A7r5 were used in the experiments. AAT1 expression was detected by Western blot and single-cell RNA sequencing. Senescence markers Tp53, p21Cip/Waf, interleukin 1β (IL-1β) and IL6 expression were detected by Western blot and real-time quantitative PCR. Senescence-associated β-galactosidase (SA-β-gal) activity was detected using SA-β-gal staining kit. Sulphenylation of interferon regulatory factor 1 (IRF1) was detected using a biotin switch assay. The plasmid for mutant IRF1 (mutation of cysteine 83 to serine, C83S) were constructed by site-directed mutagenesis. Results The expression of AAT1, a key enzyme for SO2 production, was reduced in the aortic tissue of aged mice in comparison to young mice. VSMC-AAT1-KO mice exhibited elevated protein expression of senescence markers Tp53, p21Cip/Waf and γ-H2AX in the aortic tissue. AAT1 knockdown in VSMCs elevated expression of Tp53, p21Cip/Waf, IL-1β and IL-6, and enhanced SA-β-gal activity. While SO2 donor supplementation rescued VSMC senescence caused by AAT1 knockdown and blocked aortic ring aging induced by D-gal. Mechanistically, SO2 promoted IRF1 sulphenylation, inhibited IRF1 nuclear translocation, which in turn downregulated the expression of senescence markers and the activity of SA-β-gal. Furthermore, mutation of C83 in IRF1 abolished SO2-mediated IRF1 sulphenylation and blocked the inhibitory effect of SO2 on VSMC senescence. Conclusion Reduction of the endogenous SO2/AAT1 pathway played a crucial role in driving VSMC senescence. Endogenous SO2 counteracted VSMC senescence and vascular aging via the sulphenylation of IRF1 at C83.
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Affiliation(s)
- Bingquan Qiu
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, China
| | - Shangyue Zhang
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, China
| | - Shuang Ge
- Department of Blood Transfusion Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhengyu Yu
- Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
| | - Deqing Wang
- Department of Blood Transfusion Medicine, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Kun Li
- Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China
| | - Xiaoqi Yu
- Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu, China
| | - Chaoshu Tang
- Department of Physiology and Pathophysiology, School of Basic Medical Science, Health Science Center, Peking University, Beijing, China
| | - Junbao Du
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Hongfang Jin
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, China
- State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing, China
| | - Yaqian Huang
- Department of Pediatrics, Children's Medical Center, Peking University First Hospital, Beijing, China
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Stastna M. Post-translational modifications of proteins in cardiovascular diseases examined by proteomic approaches. FEBS J 2025; 292:28-46. [PMID: 38440918 PMCID: PMC11705224 DOI: 10.1111/febs.17108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/22/2024] [Accepted: 02/20/2024] [Indexed: 03/06/2024]
Abstract
Over 400 different types of post-translational modifications (PTMs) have been reported and over 200 various types of PTMs have been discovered using mass spectrometry (MS)-based proteomics. MS-based proteomics has proven to be a powerful method capable of global PTM mapping with the identification of modified proteins/peptides, the localization of PTM sites and PTM quantitation. PTMs play regulatory roles in protein functions, activities and interactions in various heart related diseases, such as ischemia/reperfusion injury, cardiomyopathy and heart failure. The recognition of PTMs that are specific to cardiovascular pathology and the clarification of the mechanisms underlying these PTMs at molecular levels are crucial for discovery of novel biomarkers and application in a clinical setting. With sensitive MS instrumentation and novel biostatistical methods for precise processing of the data, low-abundance PTMs can be successfully detected and the beneficial or unfavorable effects of specific PTMs on cardiac function can be determined. Moreover, computational proteomic strategies that can predict PTM sites based on MS data have gained an increasing interest and can contribute to characterization of PTM profiles in cardiovascular disorders. More recently, machine learning- and deep learning-based methods have been employed to predict the locations of PTMs and explore PTM crosstalk. In this review article, the types of PTMs are briefly overviewed, approaches for PTM identification/quantitation in MS-based proteomics are discussed and recently published proteomic studies on PTMs associated with cardiovascular diseases are included.
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Affiliation(s)
- Miroslava Stastna
- Institute of Analytical Chemistry of the Czech Academy of SciencesBrnoCzech Republic
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Min Z, Guo Y, Ning L. Paromomycin targets HDAC1-mediated SUMOylation and IGF1R translocation in glioblastoma. Front Pharmacol 2024; 15:1490878. [PMID: 39723246 PMCID: PMC11668589 DOI: 10.3389/fphar.2024.1490878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Accepted: 11/08/2024] [Indexed: 12/28/2024] Open
Abstract
Objective This study investigates the effects of Paromomycin on SUMOylation-related pathways in glioblastoma (GBM), specifically targeting HDAC1 inhibition. Methods Using TCGA and GTEx datasets, we identified SUMOylation-related genes associated with GBM prognosis. Molecular docking analysis suggested Paromomycin as a potential HDAC1 inhibitor. In vitro assays on U-251MG GBM cells were performed to assess Paromomycin's effects on cell viability, SUMOylation gene expression, and IGF1R translocation using CCK8 assays, qRT-PCR, and immunofluorescence. Results Paromomycin treatment led to a dose-dependent reduction in GBM cell viability, colony formation, and migration. It modulated SUMO1 expression and decreased IGF1R nuclear translocation, an effect reversible by the HDAC1 inhibitor Trochostatin A (TSA), suggesting Paromomycin's involvement in SUMO1-regulated pathways. Conclusion This study highlights Paromomycin's potential as a therapeutic agent for GBM by targeting HDAC1-mediated SUMOylation pathways and influencing IGF1R translocation, warranting further investigation for its clinical application.
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Li L, Gao PP, Chen TT, Li N, Zhang HJ, Li MQ, Chen YN, Wei W, Wang H, Sun WY. SUMO: A new perspective to decipher fibrosis. Acta Physiol (Oxf) 2024; 240:e14240. [PMID: 39404508 DOI: 10.1111/apha.14240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 09/13/2024] [Accepted: 09/25/2024] [Indexed: 11/10/2024]
Abstract
Fibrosis is characterized by excessive extracellular matrix (ECM) deposition resulting from dysregulated wound healing and connective tissue repair mechanisms. Excessive accumulation of ECM leads to fibrous tissue formation, impairing organ function and driving the progression of various fibrotic diseases. Recently, the role of small ubiquitin-like modifiers (SUMO) in fibrotic diseases has attracted significant attention. SUMO-mediated SUMOylation, a highly conserved posttranslational modification, participates in a variety of biological processes, including nuclear-cytosolic transport, cell cycle progression, DNA damage repair, and cellular metabolism. Conversely, SUMO-specific proteases cleave the isopeptide bond of SUMO conjugates, thereby regulating the deSUMOylation process. Mounting evidence indicates that SUMOylation and deSUMOylation regulate the functions of several proteins, such as Smad3, NF-κB, and promyelocytic leukemia protein, which are implicated in fibrotic diseases like liver fibrosis, myocardial fibrosis, and pulmonary fibrosis. This review summarizes the role of SUMO in fibrosis-related pathways and explores its pathological relevance in various fibrotic diseases. All evidence suggest that the SUMO pathway is important targets for the development of treatments for fibrotic diseases.
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Affiliation(s)
- Ling Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
| | - Ping-Ping Gao
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
| | - Ting-Ting Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
| | - Nan Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
| | - Hui-Juan Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
| | - Meng-Qi Li
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
| | - Ya-Ning Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
| | - Hua Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Wu-Yi Sun
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, 230032, Anhui, China
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Ho JSY, Jou E, Khong PL, Foo RSY, Sia CH. Epigenetics in Heart Failure. Int J Mol Sci 2024; 25:12010. [PMID: 39596076 PMCID: PMC11593553 DOI: 10.3390/ijms252212010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 10/31/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
Heart failure is a clinical syndrome with rising global incidence and poor prognosis despite improvements in medical therapy. There is increasing research interest in epigenetic therapies for heart failure. Pathological cardiac remodelling may be driven by stress-activated cardiac signalling cascades, and emerging research has shown the involvement of epigenetic signals that regulate transcriptional changes leading to heart failure. In this review, we appraise the current evidence for the role of epigenetic modifications in heart failure. These include DNA methylation and histone modifications by methylation, acetylation, phosphorylation, ubiquitination and sumoylation, which are critical processes that establish an epigenetic pattern and translate environmental stress into genetic expression, leading to cardiac remodeling. We summarize the potential epigenetic therapies currently in development, including the limited clinical trials of epigenetic therapies in heart failure. The dynamic changes in the epigenome in the disease process require further elucidation, and so does the impact of this process on the development of therapeutics. Understanding the role of epigenetics in heart failure may pave the way for the identification of novel biomarkers and molecular targets, and facilitate the development of personalized therapies for this important condition.
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Affiliation(s)
- Jamie Sin Ying Ho
- Department of Cardiology, National University Heart Centre, Singapore 119228, Singapore; (J.S.Y.H.); (R.S.Y.F.)
| | - Eric Jou
- Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK;
- Kellogg College, University of Oxford, Oxford OX2 6PN, UK
| | - Pek-Lan Khong
- Department of Diagnostic Imaging, National University Hospital, National University Health System, Singapore 119074, Singapore;
- Department of Diagnostic Radiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
| | - Roger S. Y. Foo
- Department of Cardiology, National University Heart Centre, Singapore 119228, Singapore; (J.S.Y.H.); (R.S.Y.F.)
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Ching-Hui Sia
- Department of Cardiology, National University Heart Centre, Singapore 119228, Singapore; (J.S.Y.H.); (R.S.Y.F.)
- Cardiovascular Research Institute, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
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Sun X, Zhou Q, Xiao C, Mao C, Liu Y, Chen G, Song Y. Role of post-translational modifications of Sp1 in cardiovascular diseases. Front Cell Dev Biol 2024; 12:1453901. [PMID: 39252788 PMCID: PMC11381397 DOI: 10.3389/fcell.2024.1453901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 08/14/2024] [Indexed: 09/11/2024] Open
Abstract
Specific protein 1 (Sp1) is pivotal in sustaining baseline transcription as well as modulating cell signaling pathways and transcription factors activity. Through interactions with various proteins, especially transcription factors, Sp1 controls the expression of target genes, influencing numerous biological processes. Numerous studies have confirmed Sp1's significant regulatory role in the pathogenesis of cardiovascular disorders. Post-translational modifications (PTMs) of Sp1, such as phosphorylation, ubiquitination, acetylation, glycosylation, SUMOylation, and S-sulfhydration, can enhance or modify its transcriptional activity and DNA-binding stability. These modifications also regulate Sp1 expression across different cell types. Sp1 is crucial in regulating non-coding gene expression and the activity of proteins in response to pathophysiological stimuli. Understanding Sp1 PTMs advances our knowledge of cell signaling pathways in controlling Sp1 stability during cardiovascular disease onset and progression. It also aids in identifying novel pharmaceutical targets and biomarkers essential for preventing and managing cardiovascular diseases.
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Affiliation(s)
- Xutao Sun
- Department of Synopsis of the Golden Chamber, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Qi Zhou
- Department of Pharmacology, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Chengpu Xiao
- Department of Typhoid, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Caiyun Mao
- Department of Pharmacology, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Ying Liu
- The Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, Hunan, China
| | - Guozhen Chen
- Department of Pediatrics, Yantai Yuhuangding Hospital, Shandong, China
| | - Yunjia Song
- Department of Pharmacology, Heilongjiang University of Chinese Medicine, Harbin, China
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Amin N, Abbasi IN, Wu F, Shi Z, Sundus J, Badry A, Yuan X, Zhao BX, Pan J, Mi XD, Luo Y, Geng Y, Fang M. The Janus face of HIF-1α in ischemic stroke and the possible associated pathways. Neurochem Int 2024; 177:105747. [PMID: 38657682 DOI: 10.1016/j.neuint.2024.105747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/01/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024]
Abstract
Stroke is the most devastating disease, causing paralysis and eventually death. Many clinical and experimental trials have been done in search of a new safe and efficient medicine; nevertheless, scientists have yet to discover successful remedies that are also free of adverse effects. This is owing to the variability in intensity, localization, medication routes, and each patient's immune system reaction. HIF-1α represents the modern tool employed to treat stroke diseases due to its functions: downstream genes such as glucose metabolism, angiogenesis, erythropoiesis, and cell survival. Its role can be achieved via two downstream EPO and VEGF strongly related to apoptosis and antioxidant processes. Recently, scientists paid more attention to drugs dealing with the HIF-1 pathway. This review focuses on medicines used for ischemia treatment and their potential HIF-1α pathways. Furthermore, we discussed the interaction between HIF-1α and other biological pathways such as oxidative stress; however, a spotlight has been focused on certain potential signalling contributed to the HIF-1α pathway. HIF-1α is an essential regulator of oxygen balance within cells which affects and controls the expression of thousands of genes related to sustaining homeostasis as oxygen levels fluctuate. HIF-1α's role in ischemic stroke strongly depends on the duration and severity of brain damage after onset. HIF-1α remains difficult to investigate, particularly in ischemic stroke, due to alterations in the acute and chronic phases of the disease, as well as discrepancies between the penumbra and ischemic core. This review emphasizes these contrasts and analyzes the future of this intriguing and demanding field.
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Affiliation(s)
- Nashwa Amin
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China; Department of Zoology, Faculty of Science, Aswan University, Egypt; Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Irum Naz Abbasi
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Fei Wu
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zongjie Shi
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Javaria Sundus
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Azhar Badry
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Xia Yuan
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Bing-Xin Zhao
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Jie Pan
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Xiao-Dan Mi
- Center for Rehabilitation Medicine, Rehabilitation & Sports Medicine Research Institute of Zhejiang Province, Department of Rehabilitation Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yuhuan Luo
- Department of Pediatrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Geng
- Center for Rehabilitation Medicine, Department of Neurology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, China
| | - Marong Fang
- Institute of Systemic Medicine, Zhejiang University School of Medicine, Hangzhou, China; Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
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Wang Z, Pan B, Su L, Yu H, Wu X, Yao Y, Zhang X, Qiu J, Tang N. SUMOylation inhibitors activate anti-tumor immunity by reshaping the immune microenvironment in a preclinical model of hepatocellular carcinoma. Cell Oncol (Dordr) 2024; 47:513-532. [PMID: 38055116 DOI: 10.1007/s13402-023-00880-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/18/2023] [Indexed: 12/07/2023] Open
Abstract
PURPOSE High levels of heterogeneity and immunosuppression characterize the HCC immune microenvironment (TME). Unfortunately, the majority of hepatocellular carcinoma (HCC) patients do not benefit from immune checkpoint inhibitors (ICIs) therapy. New small molecule therapies for the treatment of HCC are the goal of our research. METHODS SUMOylation inhibitors (TAK-981 and ML-792) were evaluated for the treatment of preclinical mouse HCC models (including subcutaneous and orthotopic HCC models). We profile immune cell subsets from tumor samples after SUMOylation inhibitors treatment using single-cell RNA sequencing (scRNA-seq), mass cytometry (CyTOF), flow cytometry, and multiple immunofluorescences (mIF). RESULTS We discover that SUMOylation is higher in HCC patient samples compared to normal liver tissue. TAK-981 and ML-792 decrease SUMOylation at nanomolar levels in HCC cells and also successfully reduced the tumor burden. Analysis combining scRNA-seq and CyTOF demonstrate that treatment with SUMOylation inhibitors reduces the exhausted CD8+T (Tex) cells while enhancing the cytotoxic NK cells, M1 macrophages and cytotoxic T lymphocytes (CTL) in preclinical mouse HCC model. Furthermore, SUMOylation inhibitors have the potential to activate innate immune signals from CD8+T, NK and macrophages while promoting TNFα and IL-17 secretion. Most notably, SUMOylation inhibitors can directly alter the TME by adjusting the abundance of intestinal microbiota, thereby restoring anti-tumor immunity in HCC models. CONCLUSIONS This preclinical study suggests that SUMO signaling inhibitors may be beneficial for the treatment of HCC.
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Affiliation(s)
- Zengbin Wang
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Banglun Pan
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
| | - Lili Su
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Huahui Yu
- Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Xiaoxuan Wu
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
| | - Yuxin Yao
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
| | - Xiaoxia Zhang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
| | - Jiacheng Qiu
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China
| | - Nanhong Tang
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, 29 Xinquan Road, Fuzhou, 350001, China.
- Cancer Center of Fujian Medical University, Fujian Medical University Union Hospital, Fuzhou, China.
- Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
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12
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Huang CH, Yang TT, Lin KI. Mechanisms and functions of SUMOylation in health and disease: a review focusing on immune cells. J Biomed Sci 2024; 31:16. [PMID: 38280996 PMCID: PMC10821541 DOI: 10.1186/s12929-024-01003-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 01/05/2024] [Indexed: 01/29/2024] Open
Abstract
SUMOylation, which is a type of post-translational modification that involves covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to target substrates, regulates various important molecular and cellular processes, including transcription, the cell cycle, cell signaling, and DNA synthesis and repair. Newly synthesized SUMO is immature and cleaved by the SUMO-specific protease family, resulting in exposure of the C-terminal Gly-Gly motif to become the mature form. In the presence of ATP, mature SUMO is conjugated with the activating enzyme E1 through the cysteine residue of E1, followed by transfer to the cysteine residue of E2-conjugating enzyme Ubc9 in humans that recognizes and modifies the lysine residue of a substrate protein. E3 SUMO ligases promote SUMOylation. SUMOylation is a reversible modification and mediated by SUMO-specific proteases. Cumulative studies have indicated that SUMOylation affects the functions of protein substrates in various manners, including cellular localization and protein stability. Gene knockout studies in mice have revealed that several SUMO cycling machinery proteins are crucial for the development and differentiation of various cell lineages, including immune cells. Aberrant SUMOylation has been implicated in several types of diseases, including cancers, cardiovascular diseases, and autoimmune diseases. This review summarizes the biochemistry of SUMO modification and the general biological functions of proteins involved in SUMOylation. In particular, this review focuses on the molecular mechanisms by which SUMOylation regulates the development, maturation, and functions of immune cells, including T, B, dendritic, and myeloid cells. This review also discusses the underlying relevance of disruption of SUMO cycling and site-specific interruption of SUMOylation on target proteins in immune cells in diseases, including cancers and infectious diseases.
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Affiliation(s)
- Chien-Hsin Huang
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 110, Taiwan
| | - Tsan-Tzu Yang
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 110, Taiwan
| | - Kuo-I Lin
- Genomics Research Center, Academia Sinica, 128 Academia Road, Sec. 2, Nankang District, Taipei, 115, Taiwan.
- Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 110, Taiwan.
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Li W, Han Q, Zhu Y, Zhou Y, Zhang J, Wu W, Li Y, Liu L, Qiu Y, Hu K, Yin D. SUMOylation of RNF146 results in Axin degradation and activation of Wnt/β-catenin signaling to promote the progression of hepatocellular carcinoma. Oncogene 2023; 42:1728-1740. [PMID: 37029301 DOI: 10.1038/s41388-023-02689-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 03/26/2023] [Accepted: 03/28/2023] [Indexed: 04/09/2023]
Abstract
Aberrant SUMOylation contributes to the progression of hepatocellular carcinoma (HCC), yet the molecular mechanisms have not been well elucidated. RING-type E3 ubiquitin ligase RNF146 is a key regulator of the Wnt/β-catenin signaling pathway, which is frequently hyperactivated in HCC. Here, it is identified that RNF146 can be modified by SUMO3. By mutating all lysines in RNF146, we found that K19, K61, K174 and K175 are the major sites for SUMOylation. UBC9/PIAS3/MMS21 and SENP1/2/6 mediated the conjugation and deconjugation of SUMO3, respectively. Furthermore, SUMOylation of RNF146 promoted its nuclear localization, while deSUMOylation induced its cytoplasmic localization. Importantly, SUMOylation promotes the association of RNF146 with Axin to accelerate the ubiquitination and degradation of Axin. Intriguingly, only UBC9/PIAS3 and SENP1 can act at K19/K175 in RNF146 and affect its role in regulating the stability of Axin. In addition, inhibiting RNF146 SUMOylation suppressed the progression of HCC both in vitro and in vivo. And, patients with higher expression of RNF146 and UBC9 have the worst prognosis. Taken together, we conclude that RNF146 SUMOylation at K19/K175 promotes its association with Axin and accelerates Axin degradation, thereby enhancing β-catenin signaling and contributing to cancer progression. Our findings reveal that RNF146 SUMOylation is a potential therapeutic target in HCC.
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Affiliation(s)
- Wenjia Li
- Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Pathology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China
| | - Qingfang Han
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Henan Research Centre for Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuanxin Zhu
- Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Orthopedics, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China
| | - Yingshi Zhou
- Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
- Department of Ultrasound Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Jingyuan Zhang
- Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Weijun Wu
- Department of Oncology Radiotherapy, the First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421000, China
| | - Yu Li
- Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
- Henan Research Centre for Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Yuntan Qiu
- Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China
| | - Kaishun Hu
- Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
| | - Dong Yin
- Guangdong Provincial Key Laboratory of Malignant Tumour Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
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Karandikar P, Gerstl JVE, Kappel AD, Won SY, Dubinski D, Garcia-Segura ME, Gessler FA, See AP, Peruzzotti-Jametti L, Bernstock JD. SUMOtherapeutics for Ischemic Stroke. Pharmaceuticals (Basel) 2023; 16:ph16050673. [PMID: 37242456 DOI: 10.3390/ph16050673] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/25/2023] [Accepted: 04/27/2023] [Indexed: 05/28/2023] Open
Abstract
The small, ubiquitin-like modifier (SUMO) is a post-translational modifier with a profound influence on several key biological processes, including the mammalian stress response. Of particular interest are its neuroprotective effects, first recognized in the 13-lined ground squirrel (Ictidomys tridecemlineatus), in the context of hibernation torpor. Although the full scope of the SUMO pathway is yet to be elucidated, observations of its importance in managing neuronal responses to ischemia, maintaining ion gradients, and the preconditioning of neural stem cells make it a promising therapeutic target for acute cerebral ischemia. Recent advances in high-throughput screening have enabled the identification of small molecules that can upregulate SUMOylation, some of which have been validated in pertinent preclinical models of cerebral ischemia. Accordingly, the present review aims to summarize current knowledge and highlight the translational potential of the SUMOylation pathway in brain ischemia.
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Affiliation(s)
- Paramesh Karandikar
- T. H. Chan School of Medicine, University of Massachusetts, Worcester, MA 01655, USA
| | - Jakob V E Gerstl
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Ari D Kappel
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02215, USA
| | - Sae-Yeon Won
- Department of Neurosurgery, University Medicine Rostock, 18057 Rostock, Germany
| | - Daniel Dubinski
- Department of Neurosurgery, University Medicine Rostock, 18057 Rostock, Germany
| | - Monica Emili Garcia-Segura
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
- NIHR Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Florian A Gessler
- Department of Neurosurgery, University Medicine Rostock, 18057 Rostock, Germany
| | - Alfred Pokmeng See
- Department of Neurosurgery, Boston Children's Hospital, Boston, MA 02215, USA
| | - Luca Peruzzotti-Jametti
- Department of Clinical Neurosciences, University of Cambridge, Cambridge CB2 0QQ, UK
- NIHR Biomedical Research Centre, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Joshua D Bernstock
- Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA
- Department of Neurosurgery, University Medicine Rostock, 18057 Rostock, Germany
- Koch Institute for Integrated Cancer Research, MIT, Cambridge, MA 02142, USA
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15
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Ramos JTGDS, Pereira AG, Ferrari FS, Andrade MF, de Melo CS, Boas PJFV, Felix TF, de Carvalho M, Dorna MS, Azevedo PS, Phillips BE, Polegato BF, Okoshi K, Bazan SGZ, Paiva SAR, Zornoff LAM, Reis PP, Minicucci MF. Circulating miRNAs are associated with frailty and ST-elevation myocardial infarction pathways. Arch Gerontol Geriatr 2023; 106:104870. [PMID: 36442406 DOI: 10.1016/j.archger.2022.104870] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Revised: 11/10/2022] [Accepted: 11/16/2022] [Indexed: 11/21/2022]
Abstract
BACKGROUND Frailty and ST-Elevation Myocardial Infarction (STEMI) share similar molecular pathways. Specific biomarkers, such as microRNAs (miRNAs), may provide insights into the molecular mechanisms that cause the relationship between frailty and STEMI. OBJECTIVE Our aim was to identify and compare circulating miRNA levels between frail and non-frail older adults following STEMI and comprehend the regulatory miRNA-gene networks and pathways involved in this condition. METHODS This exploratory study is a subanalysis of a larger observational study. In this study, we selected patients ≥ 65 years old, following STEMI, with pre-frail/frail (n=5) and non-frail (n=4) phenotype evaluated using the Clinical Frailty Scale and serum circulating miRNA levels were analyzed. RESULTS Pre-frail/frail patients had greater serum levels of 53 miRNAs, compared with non-frail patients. Notably, miR-103a-3p, miR-598-3p, and miR-130a-3p were the top three significantly deregulated miRNAs predicted to modulate gene expression associated with aging. Additional computational analyses showed 7,420 predicted miRNA gene targets, which were regulated by at least two of the 53 identified miRNAs. Pathway enrichment analysis showed that axon guidance and MAPK signaling were among pathways regulated by miRNA target genes. CONCLUSIONS These novel findings suggest a correlation between the identified miRNAs, target genes, and pathways in pre-frail and frail patients with myocardial infarction.
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Affiliation(s)
| | - Amanda Gomes Pereira
- São Paulo State University (Unesp), Medical School, Internal Medicine Department, Botucatu, Brazil.
| | - Felipe Sanches Ferrari
- São Paulo State University (Unesp), Medical School, Internal Medicine Department, Botucatu, Brazil
| | - Morganna Freitas Andrade
- São Paulo State University (Unesp), Medical School, Internal Medicine Department, Botucatu, Brazil
| | - Caroline Souto de Melo
- Department of Anesthesiology, Complexo Hospitalar Santa Genoveva de Uberlândia, Minas Gerais, Brazil
| | | | - Tainara F Felix
- São Paulo State University (Unesp), Medical School, Experimental Research Unit (UNIPEX), Botucatu, Brazil
| | - Marcio de Carvalho
- São Paulo State University (Unesp), Medical School, Experimental Research Unit (UNIPEX), Botucatu, Brazil
| | - Mariana Souza Dorna
- São Paulo State University (Unesp), Medical School, Internal Medicine Department, Botucatu, Brazil
| | - Paula Schmidt Azevedo
- São Paulo State University (Unesp), Medical School, Internal Medicine Department, Botucatu, Brazil
| | - Bethan E Phillips
- Medical Research Council-Versus Arthritis Centre for Musculoskeletal Ageing Research and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, University of Nottingham, Derby, UK
| | - Bertha Furlan Polegato
- São Paulo State University (Unesp), Medical School, Internal Medicine Department, Botucatu, Brazil
| | - Katashi Okoshi
- São Paulo State University (Unesp), Medical School, Internal Medicine Department, Botucatu, Brazil
| | | | | | | | - Patricia P Reis
- São Paulo State University (Unesp), Medical School, Experimental Research Unit (UNIPEX), Botucatu, Brazil; São Paulo State University (Unesp), Medical School, Department of Surgery and Orthopedics, Botucatu, Brazil
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16
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Wei Q, Hao X, Lau BWM, Wang S, Li Y. Baicalin regulates stem cells as a creative point in the treatment of climacteric syndrome. Front Pharmacol 2022; 13:986436. [DOI: 10.3389/fphar.2022.986436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/17/2022] [Indexed: 11/05/2022] Open
Abstract
Graphical AbstractThis review summarizes the regulatory role of Baicalin on the diverse behaviors of distinct stem cell populations and emphasizes the potential applications of Baicalin and stem cell therapy in climacteric syndrome.
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17
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Hleșcu AA, Grigoraș A, Covatariu G, Moscalu M, Amalinei C. The Value of Myocardium and Kidney Histopathological and Immunohistochemical Findings in Accidental Hypothermia-Related Fatalities. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:1507. [PMID: 36363464 PMCID: PMC9694447 DOI: 10.3390/medicina58111507] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/12/2022] [Accepted: 10/20/2022] [Indexed: 08/30/2023]
Abstract
Background and Objectives: The post-mortem diagnosis of hypothermia is challenging in forensics. The aim of our study was to detect the kidney and heart histopathological changes that occurred in a group of hypothermia-related fatalities. Materials and Methods: The cohort included 107 cases identified in the database of our department between 2007 and 2021, which have been associated with extreme cold stress. Demographic and clinicopathological data were collected from the medico-legal reports. Archived tissue samples were evaluated to identify the histopathological features, in routine haematoxylin-eosin (H&E), Periodic acid-Schiff (PAS), and Masson's trichrome stainings, while cardiac sirtuin1 (SIRT1) and renal ubiquitin (Ub) immunostaining have been performed. Results: The majority of cases exposed to low temperatures were males (76%) from rural regions (68.2%) during the cold season. Paradoxical undressing was documented in 9.3% of cases. The common comorbidities included alcoholism (50.5%), neuropsychiatric diseases (10.3%), diabetes mellitus (3.7%), and lung tuberculosis (4.7%). The microscopic heart exam revealed areas of myocardial degeneration (100%), contraction bands (95.3%), fatty change (13.1%) and focal wavy contractile myocardial cells. Basal vacuolisation of renal tubular epithelial cells (Armanni-Ebstein lesions) (21.5%), focal tubular necrosis (7.5%), tubular renal cysts (7.5%), interstitial haemorrhages (5.6%), diabetic kidney disease (3.7%), background benign nephroangiosclerosis (42.1%), variable thickening of tubules and corpuscles basement membranes, capsular space amorphous material, and intratubular casts were identified in kidney tissue samples. Myocardial cells displayed SIRT1 weak expression, with a loss of immunopositivity correlated with areas with contraction bands, while a variable Ub expression was observed in renal corpuscles capsules, proximal, distal, and collecting renal tubules, Henle's loops, urothelium, and intratubular casts. Conclusions: In the context of the current concept that death associated with hypothermia is still a diagnosis of exclusion, our findings suggest that the microscopic exam provides relevant data that support the diagnosis of hypothermia-related fatalities in appropriate circumstances of death. A deeper insight into the histopathologic findings in hypothermic patients may lead to new therapeutic approaches in these cases.
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Affiliation(s)
- Andreea Alexandra Hleșcu
- Legal Medicine Department, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Adriana Grigoraș
- Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Department of Histopathology, Institute of Legal Medicine, 700455 Iasi, Romania
| | - Gabriela Covatariu
- Faculty of Civil Engineering and Building Services, “Gheorghe Asachi” Technical University, 700050 Iasi, Romania
| | - Mihaela Moscalu
- Department of Preventive Medicine and Interdisciplinarity, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Cornelia Amalinei
- Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Department of Histopathology, Institute of Legal Medicine, 700455 Iasi, Romania
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Zhao W, Zhang X, Zhao J, Fan N, Rong J. SUMOylation of Nuclear γ-Actin by SUMO2 supports DNA Damage Repair against Myocardial Ischemia-Reperfusion Injury. Int J Biol Sci 2022; 18:4595-4609. [PMID: 35864967 PMCID: PMC9295056 DOI: 10.7150/ijbs.74407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/21/2022] [Indexed: 02/07/2023] Open
Abstract
Myocardial infarction triggers oxidative DNA damage, apoptosis and adverse cardiac remodeling in the heart. Small ubiquitin-like modifier (SUMO) proteins mediate post-translational SUMOylation of the cardiac proteins in response to oxidative stress signals. Upregulation of isoform SUMO2 could attenuate myocardial injury via increasing protein SUMOylation. The present study aimed to discover the identity and cardioprotective activities of SUMOylated proteins. A plasmid vector for expressing N-Strep-SUMO2 protein was generated and introduced into H9c2 rat cardiomyocytes. The SUMOylated proteins were isolated with Strep-Tactin® agarose beads and identified by MALDI-TOF-MS technology. As a result, γ-actin was identified from a predominant protein band of ~42 kDa and verified by Western blotting. The roles of SUMO2 and γ-actin SUMOylation were subsequently determined in a mouse model of myocardial infarction induced by ligating left anterior descending coronary artery and H9c2 cells challenged by hypoxia-reoxygenation. In vitro lentiviral-mediated SUMO2 expression in H9c2 cells were used to explore the role of SUMOylation of γ-actin. SUMOylation of γ-actin by SUMO2 was proven to be a new cardioprotective mechanism from the following aspects: 1) SUMO2 overexpression reduced the number of TUNEL positive cells, the levels of 8-OHdG and p-γ-H2ax while promoted the nuclear deposition of γ-actin in mouse model and H9c2 cell model of myocardial infarction; 2) SUMO-2 silencing decreased the levels of nuclear γ-actin and SUMOylation while exacerbated DNA damage; 3) Mutated γ-actin (K68R/K284R) void of SUMOylation sites failed to protect cardiomyocytes against hypoxia-reoxygenation challenge. The present study suggested that SUMO2 upregulation promoted DNA damage repair and attenuated myocardial injury via increasing SUMOylation of γ-actin in the cell nucleus.
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Affiliation(s)
- Wei Zhao
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China.,Zhujiang Hospital, Southern Medical University, 253 Industrial Road, Guangzhou 51000, Guangdong Province, China
| | - Xiuying Zhang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China
| | - Jia Zhao
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China
| | - Ni Fan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China
| | - Jianhui Rong
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong 999077, China.,Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen 518000, China
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19
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Ubiquitin and Ubiquitin-like Proteins in Cancer, Neurodegenerative Disorders, and Heart Diseases. Int J Mol Sci 2022; 23:ijms23095053. [PMID: 35563444 PMCID: PMC9105348 DOI: 10.3390/ijms23095053] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 01/14/2023] Open
Abstract
Post-translational modification (PTM) is an essential mechanism for enhancing the functional diversity of proteins and adjusting their signaling networks. The reversible conjugation of ubiquitin (Ub) and ubiquitin-like proteins (Ubls) to cellular proteins is among the most prevalent PTM, which modulates various cellular and physiological processes by altering the activity, stability, localization, trafficking, or interaction networks of its target molecules. The Ub/Ubl modification is tightly regulated as a multi-step enzymatic process by enzymes specific to this family. There is growing evidence that the dysregulation of Ub/Ubl modifications is associated with various diseases, providing new targets for drug development. In this review, we summarize the recent progress in understanding the roles and therapeutic targets of the Ub and Ubl systems in the onset and progression of human diseases, including cancer, neurodegenerative disorders, and heart diseases.
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20
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Liu P, Zhang J, Wang Y, Wang C, Qiu X, Chen DQ. Natural Products Against Renal Fibrosis via Modulation of SUMOylation. Front Pharmacol 2022; 13:800810. [PMID: 35308200 PMCID: PMC8931477 DOI: 10.3389/fphar.2022.800810] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 02/08/2022] [Indexed: 12/29/2022] Open
Abstract
Renal fibrosis is the common and final pathological process of kidney diseases. As a dynamic and reversible post-translational modification, SUMOylation and deSUMOylation of transcriptional factors and key mediators significantly affect the development of renal fibrosis. Recent advances suggest that SUMOylation functions as the promising intervening target against renal fibrosis, and natural products prevent renal fibrosis via modulating SUMOylation. Here, we introduce the mechanism of SUMOylation in renal fibrosis and therapeutic effects of natural products. This process starts by summarizing the key mediators and enzymes during SUMOylation and deSUMOylation and its regulation role in transcriptional factors and key mediators in renal fibrosis, then linking the mechanism findings of SUMOylation and natural products to develop novel therapeutic candidates for treating renal fibrosis, and concludes by commenting on promising therapeutic targets and candidate natural products in renal fibrosis via modulating SUMOylation, which highlights modulating SUMOylation as a promising strategy for natural products against renal fibrosis.
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Affiliation(s)
- Peng Liu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Jing Zhang
- Institute of Plant Resources, Yunnan University, Kunming, China
| | - Yun Wang
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Chen Wang
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Xinping Qiu
- Shunyi Hospital, Beijing Hospital of Traditional Chinese Medicine, Beijing, China
| | - Dan-Qian Chen
- Department of Emergency, China-Japan Friendship Hospital, Beijing, China
- *Correspondence: Dan-Qian Chen,
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