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Wang Q, Yang Z, Zhao S, Tian C, Zhang P, Li R. Neuropad Assessment of Sudomotor Function Across Glycemic Levels in Adults. Diabetes Metab Syndr Obes 2025; 18:1047-1060. [PMID: 40226439 PMCID: PMC11992999 DOI: 10.2147/dmso.s507586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 03/11/2025] [Indexed: 04/15/2025] Open
Abstract
Purpose To evaluate the impact of metabolic indicators on plantar sudomotor function and to explore the relationships between metabolic and non-metabolic indicators and sudomotor function in a physical examination cohort using Neuropad. Methods In this cross-sectional study, 481 participants were randomly enrolled. Sudomotor function was evaluated using Neuropad and a handheld color analyzer for both qualitative (visual Neuropad) and quantitative (quantitative Neuropad) analyses. The slope (Slope[1-10]) was used as a quantitative measure of sudomotor function. Additional data included age, BMI (body mass index), FPG (fasting plasma glucose), HbA1c (hemoglobin A1c), blood pressure, lipid levels, and liver and kidney function. Participants were categorized into four blood glucose groups: normoglycemia (FPG <6.1 mmol/L and HbA1c <6%), prediabetes (FPG 6.1-6.9 mmol/L or HbA1c 6.0-6.4%), newly diagnosed diabetes (FPG ≥7.0 mmol/L or HbA1c ≥6.5% with no prior diagnosis, diabetes was diagnosed on the day of the physical examination), and previously diagnosed diabetes. Results (1) The previously diagnosed diabetes group presented a lower slope than the normoglycemia group (6.96 vs 8.73) and a greater rate of incomplete color change (71.11% vs 49.01%). With increasing FPG and HbA1c levels, the 10-minute slope decreased progressively (P =0.003, P=0.006). (2) A multivariable linear mixed-effects model adjusted for confounders indicated that previously diagnosed diabetes was an independent predictor of reduced sudomotor function. (3) Adjusting for the same confounders, previously diagnosed diabetes was associated with a 3.480-fold greater risk of incomplete color change than was normoglycemia (OR = 3.480, 95% CI = 1.506-8.042). (4) Age, BMI, ALB, eGFR, and alcohol consumption history were closely associated with sudomotor function. Conclusion There is a progressive decline in sudomotor function with increasing blood glucose levels in a physical examination cohort, and previously diagnosed diabetes emerges as an independent risk factor for sudomotor dysfunction.
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Affiliation(s)
- Qianzhu Wang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
- Department of Endocrinology, People’s Hospital of Tongliang District, Chongqing, People’s Republic of China
| | - Zheng Yang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Subei Zhao
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Chunyan Tian
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Ping Zhang
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
| | - Rong Li
- Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China
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Li L, Xie S, Deng W. RNA binding proteins: Mechanistic considerations and perspectives in controlling cardiovascular diseases. Eur J Pharmacol 2025; 987:177101. [PMID: 39613174 DOI: 10.1016/j.ejphar.2024.177101] [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: 07/14/2024] [Revised: 11/01/2024] [Accepted: 11/05/2024] [Indexed: 12/01/2024]
Abstract
Cardiovascular diseases (CVDs) are becoming serious disease that endangering human health due to the increasing morbidity and mortality, and many molecular targets are involved in this complex pathologic process. Recently, RNA-binding proteins (RBPs) have received potential attention as a promising targets for preventing CVDs, including myocardial hypertrophy, dilated cardiomyopathy (DCM), myocardial fibrosis, and pulmonary hypertension (PH). As important regulators of RNA metabolism, RBPs play important roles in all steps of the gene expression cascade,and affect the occurrence and development of various diseases. In this review, we discuss the regulatory role of RBPs on various CVDs at the post transcriptional modification level based on current research. We also highlight the existing and potential RNA-based therapeutics that could impact future CVD treatments.
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Affiliation(s)
- Lanlan Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China; Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China
| | - Saiyang Xie
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China; Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China
| | - Wei Deng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China; Hubei Key Laboratory of Metabolic and Chronic Diseases, Wuhan, China; Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan, China; Cardiovascular Research Institute of Wuhan University, Wuhan, 430060, China.
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Abdallah SI, Abubaker NE, Ibrahim MA, Abd Alla A, Humaida RA. Plasma glucose, HbA1c, insulin and lipid profile in Sudanese type 2 diabetic patients with cardiovascular disease: a case control study. F1000Res 2024; 11:472. [PMID: 39450303 PMCID: PMC11499864 DOI: 10.12688/f1000research.110927.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 09/02/2023] Open
Abstract
Background: Type 2 diabetes mellitus (T2DM) and its consequences are a serious global public health issue. By 2030, the number of people with type 2 diabetes is predicted to reach 439 million. The purpose of this study is to evaluate the plasma levels of glucose, HbA1c, insulin, and lipid profile in Sudanese T2DM patients. Methods: This case control study included 165 Sudanese patients with diabetic type 2 and a cardiovascular condition as cases and 165 diabetic type 2 volunteers without a cardiovascular disorder as controls. The concentrations of plasma glucose, HbA1c, and lipid profile were assessed using a Mindray BS-480 auto-chemistry analyzer, and insulin was analyzed using a Cobase 411 auto analyzer. The collected data were analyzed using statistical tools for social science computer programs (SPSS version 21). Results: According to the findings, (59.4%) of patients between the ages of (50-69). Females made up 50.9%. (38.2%) of patients had an illness duration of between (8-15 years). (41.8%) of individuals did not have hypertension. There was a substantial rise in BMI, FBG, HbA1c, HDL-C, and insulin among diabetics with cardiovascular disease compared to diabetics without cardiovascular disease (p-value = 0.001, 0.000, 0.018, and 0.000). Females had significantly higher blood TC, LDL-C, HDL-C, and BMI than males (p-values = 0.000, 0,001, and 0.000, respectively). There were significant positive correlation between FBS, HBA1c, insulin and duration of disease (r=0.155, p, value=0.005) (r=0.160, p, value=0.004)(r=0.103, p. value=0.061)respectively, while there were significant negative correlation between TC, TG,LDL-C, HDL-C and duration of disease (r=-0.152, p, value= 0.006)(r=-0.023, p, value=0.678)(r=-0.113, p, value= 0.040)(r=-0.145, p, value=0.008)respectively. Conclusion: When comparing diabetics with cardiovascular disease to diabetics without cardiovascular disease, there was a substantial rise in BMI, FBG, HbA1c, HDL-C, and insulin. FBS, HBA1c, insulin, and illness duration all had a strong positive connection.
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Affiliation(s)
- Salsabbil Idris Abdallah
- Clinical Chemistry Department, Sudan University of Science and Technology,, Khartoum, Khartoum, 11111, Sudan
| | - Nuha Eljailli Abubaker
- Clinical Chemistry Department, Sudan University of Science and Technology,, Khartoum, Khartoum, 11111, Sudan
| | - Mariam Abbas Ibrahim
- Clinical Chemistry Department, Sudan University of Science and Technology,, Khartoum, Khartoum, 11111, Sudan
| | - Ahmed Abd Alla
- Department of Parasitology and Medical Entomology, Sudan University of Science and Technology, Khartoum, Khartoum, 11111, Sudan
| | - Rami Adam Humaida
- Department of lab, Modern medical center, Khartoum, Khartuom, 11111, Sudan
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Varesi A, Campagnoli LIM, Barbieri A, Rossi L, Ricevuti G, Esposito C, Chirumbolo S, Marchesi N, Pascale A. RNA binding proteins in senescence: A potential common linker for age-related diseases? Ageing Res Rev 2023; 88:101958. [PMID: 37211318 DOI: 10.1016/j.arr.2023.101958] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 05/09/2023] [Accepted: 05/18/2023] [Indexed: 05/23/2023]
Abstract
Aging represents the major risk factor for the onset and/or progression of various disorders including neurodegenerative diseases, metabolic disorders, and bone-related defects. As the average age of the population is predicted to exponentially increase in the coming years, understanding the molecular mechanisms underlying the development of aging-related diseases and the discovery of new therapeutic approaches remain pivotal. Well-reported hallmarks of aging are cellular senescence, genome instability, autophagy impairment, mitochondria dysfunction, dysbiosis, telomere attrition, metabolic dysregulation, epigenetic alterations, low-grade chronic inflammation, stem cell exhaustion, altered cell-to-cell communication and impaired proteostasis. With few exceptions, however, many of the molecular players implicated within these processes as well as their role in disease development remain largely unknown. RNA binding proteins (RBPs) are known to regulate gene expression by dictating at post-transcriptional level the fate of nascent transcripts. Their activity ranges from directing primary mRNA maturation and trafficking to modulation of transcript stability and/or translation. Accumulating evidence has shown that RBPs are emerging as key regulators of aging and aging-related diseases, with the potential to become new diagnostic and therapeutic tools to prevent or delay aging processes. In this review, we summarize the role of RBPs in promoting cellular senescence and we highlight their dysregulation in the pathogenesis and progression of the main aging-related diseases, with the aim of encouraging further investigations that will help to better disclose this novel and captivating molecular scenario.
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Affiliation(s)
- Angelica Varesi
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
| | | | - Annalisa Barbieri
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Lorenzo Rossi
- Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland
| | | | - Ciro Esposito
- Department of Internal Medicine and Therapeutics, University of Pavia, Italy; Nephrology and dialysis unit, ICS S. Maugeri SPA SB Hospital, Pavia, Italy; High School in Geriatrics, University of Pavia, Italy
| | | | - Nicoletta Marchesi
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy
| | - Alessia Pascale
- Department of Drug Sciences, Section of Pharmacology, University of Pavia, Pavia, Italy.
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Strollo R, Vinci C, Man YKS, Bruzzaniti S, Piemonte E, Alhamar G, Briganti SI, Malandrucco I, Tramontana F, Fanali C, Garnett J, Buccafusca R, Guyer P, Mamula M, James EA, Pozzilli P, Ludvigsson J, Winyard PG, Galgani M, Nissim A. Autoantibody and T cell responses to oxidative post-translationally modified insulin neoantigenic peptides in type 1 diabetes. Diabetologia 2023; 66:132-146. [PMID: 36207582 PMCID: PMC9729141 DOI: 10.1007/s00125-022-05812-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/28/2022] [Indexed: 12/14/2022]
Abstract
AIMS/HYPOTHESIS Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with type 1 diabetes, even before the clinical onset. However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides. METHODS oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4+ and CD8+ T cell activation by oxPTM-INSPs. RESULTS We observed antibody and T cell responses to three out of six LC-MS/MS-identified insulin peptide candidates: A:12-21 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11-30 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21-30 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (p≤0.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [●OH] and >88% to in silico-oxidised peptide; p≤0.001 vs control participants). Nt-INSP-4 induced the strongest T cell stimulation in type 1 diabetes compared with control participants for both CD4+ (p<0.001) and CD8+ (p=0.049). CD4+ response to oxPTM-INSP-6 was also commoner in type 1 diabetes than in control participants (66.7% vs 27.3%; p=0.039). Among individuals with type 1 diabetes, the CD4+ response to oxPTM-INSP-6 was more frequent than to Nt-INSP-6 (66.7% vs 27.8%; p=0.045). Overall, 44.4% of patients showed a concordant autoimmune response to oxPTM-INSP involving simultaneously CD4+ and CD8+ T cells and autoantibodies. CONCLUSIONS/INTERPRETATION Our findings support the concept that oxidative stress, and neoantigenic epitopes of insulin, may be involved in the immunopathogenesis of type 1 diabetes.
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Affiliation(s)
- Rocky Strollo
- Department of Science and Technology for Humans and the Environment, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Chiara Vinci
- Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Y K Stella Man
- Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Sara Bruzzaniti
- Institute for Experimental Endocrinology and Oncology 'G. Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy
- Department of Biology, Università degli Studi di Napoli 'Federico II', Naples, Italy
| | - Erica Piemonte
- Department of Molecular Medicine and Medical Biotechnology, Università degli Studi di Napoli 'Federico II', Naples, Italy
| | - Ghadeer Alhamar
- Department of Medicine, Unit of Endocrinology & Diabetes, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Silvia Irina Briganti
- Department of Medicine, Unit of Endocrinology & Diabetes, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Ilaria Malandrucco
- The UOSD of Endocrinology and Metabolic Diseases, Azienda Sanitaria Locale (ASL) Frosinone, Frosinone, Italy
| | - Flavia Tramontana
- Department of Medicine, Unit of Endocrinology & Diabetes, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Chiara Fanali
- Department of Science and Technology for Humans and the Environment, Università Campus Bio-Medico di Roma, Rome, Italy
| | - James Garnett
- Centre for Host-Microbiome Interactions, Dental Institute, King's College London, London, UK
- School of Biological and Chemical Sciences, Queen Mary University of London, London, UK
| | - Roberto Buccafusca
- School of Biological and Chemical Sciences, Queen Mary University of London, London, UK
| | - Perrin Guyer
- Program for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Mark Mamula
- Department of Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Eddie A James
- Program for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA
| | - Paolo Pozzilli
- Department of Medicine, Unit of Endocrinology & Diabetes, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Johnny Ludvigsson
- Division of Pediatrics, Department of Biomedical and Clinical Sciences, Crown Princess Victoria Children's Hospital, Linköping University, Linköping, Sweden
| | - Paul G Winyard
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, St Luke's Campus, Exeter, UK
| | - Mario Galgani
- Institute for Experimental Endocrinology and Oncology 'G. Salvatore', Consiglio Nazionale delle Ricerche, Naples, Italy
- Department of Molecular Medicine and Medical Biotechnology, Università degli Studi di Napoli 'Federico II', Naples, Italy
| | - Ahuva Nissim
- Biochemical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.
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Zhang S, Yang X, Jiang M, Ma L, Hu J, Zhang HH. Post-transcriptional control by RNA-binding proteins in diabetes and its related complications. Front Physiol 2022; 13:953880. [PMID: 36277184 PMCID: PMC9582753 DOI: 10.3389/fphys.2022.953880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 09/20/2022] [Indexed: 11/25/2022] Open
Abstract
Diabetes mellitus (DM) is a fast-growing chronic metabolic disorder that leads to significant health, social, and economic problems worldwide. Chronic hyperglycemia caused by DM leads to multiple devastating complications, including macrovascular complications and microvascular complications, such as diabetic cardiovascular disease, diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy. Numerous studies provide growing evidence that aberrant expression of and mutations in RNA-binding proteins (RBPs) genes are linked to the pathogenesis of diabetes and associated complications. RBPs are involved in RNA processing and metabolism by directing a variety of post-transcriptional events, such as alternative splicing, stability, localization, and translation, all of which have a significant impact on RNA fate, altering their function. Here, we purposed to summarize the current progression and underlying regulatory mechanisms of RBPs in the progression of diabetes and its complications. We expected that this review will open the door for RBPs and their RNA networks as novel therapeutic targets for diabetes and its related complications.
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Affiliation(s)
- Shiyu Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Xiaohua Yang
- The Affiliated Haian Hospital of Nantong University, Nantong, China
| | - Miao Jiang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Lianhua Ma
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
| | - Hong-Hong Zhang
- Department of Endocrinology, The Second Affiliated Hospital, Soochow University, Suzhou, China
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Cui J, Wang P, Yan S, Liang Y, Liu D, Ren S. Perfluorooctane Sulfonate Induces Dysfunction of Human Umbilical Vein Endothelial Cells via Ferroptosis Pathway. TOXICS 2022; 10:503. [PMID: 36136468 PMCID: PMC9500952 DOI: 10.3390/toxics10090503] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 06/16/2023]
Abstract
(1) Background: Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant, and it is receiving increasing attention regarding its human health risks due to its extensive use. Endothelial dysfunction is a mark of cardiovascular disease, but the basic mechanism of PFOS-induced endothelial dysfunction is still not fully understood. Ferroptosis is a newly defined regulatory cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although ferroptosis has been shown to be involved in the pathogenesis of cardiovascular diseases, the involvement of ferroptosis in the pathogenesis of endothelial dysfunction caused by PFOS remains unclear. (2) Purpose: To explore the role of ferroptosis in the dysfunction of endothelial cells and underlying mechanisms. (3) Methods: Human umbilical vein endothelial cells (HUVECs) were exposed to PFOS or PFOS and Fer-1. The viability, morphology change under electronic microscope, lipid-reactive oxygen species (lipid-ROS), and production of nitric oxide (NO) were determined. The expression of glutathione peroxidase 4(GPX4), ferritin heavy chain protein 1 (FTH1), heme oxygenase 1 (HO-1) and Acyl-CoA synthetase long-chain family member 4 (ACSL4) were analyzed via Western blot analysis. (4) Results: PFOS was shown to cause a decrease in viability and morphological changes of mitochondria, and well as an increase in lipid droplets. The expression of GPX4, FTH1 and HO-1 was decreased, and that of ACSL4 was increased after exposure to PFOS. In addition to the above-mentioned ferroptosis-related manifestations, there was also a reduction in NO content. (5) Conclusions: PFOS induces ferroptosis by regulating the GPX4 and ACSL4 pathways, which leads to HUVEC dysfunction.
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Wang P, Kuang Y, Liu Y, Zhang Y, Gao H, Ma Q. Levels of plasma Quaking and cyclooxygenase-2 predict in-stent restenosis in patients with coronary artery disease after percutaneous coronary intervention. ZHONG NAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF CENTRAL SOUTH UNIVERSITY. MEDICAL SCIENCES 2022; 47:739-747. [PMID: 35837773 PMCID: PMC10930024 DOI: 10.11817/j.issn.1672-7347.2022.210716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Indexed: 06/15/2023]
Abstract
OBJECTIVES Percutaneous coronary intervention (PCI) is one of the important methods for the treatment of coronary artery disease (CAD). In-sent restenosis (ISR) after PCI for patients suffered from CAD is considered to be an essential factor affecting long-term outcomes and prognosis of this disease. This study aims to investigate the correlation between plasma Quaking (QKI) and cyclooxygenase-2 (COX-2) levels and ISR in patients with CAD. METHODS A total of 218 consecutive CAD patients who underwent coronary angiography and coronary arterial stenting from September 2019 to September 2020 in the Department of Cardiology of Xiangya Hospital of Central South University were enrolled in this study, and 35 matched individuals from the physical examination center were served as a control group. After admission, clinical data of these 2 groups were collected. Plasma QKI and COX-2 levels were measured by enzyme linked immunosorbent assay (ELISA). Follow-up angiography was performed 12 months after PCI. CAD patients were divided into a NISR group (n=160) and an ISR group (n=58) according to the occurrence of ISR based on the coronary angiography. The clinical data, coronary angiography, and stent features between the NISR group and the ISR group were compared, and multivariate logistic regression was used to explore the factors influencing ISR. The occurrence of major adverse cardiovascular events (MACE) 1 year after operation was recorded. Fifty-eight patients with ISR were divided into an MACE group (n=24) and a non-MACE group (n=34), classified according to the occurrence of MACE, and the plasma levels of QKI and COX-2 were compared between the 2 groups. Receiver operating characteristic (ROC) curves were utilized to analyze the diagnostic value of plamsa levels of QKI and COX-2 for ISR and MACE occurrences in patients after PCI. RESULTS Compared with control group, plasma levels of QKI and COX-2 in the CAD group decreased significantly (all P<0.001). Compared with the NISR group, the plasma levels of QKI and COX-2 also decreased obviously in the ISR group (all P<0.001), while the levels of high sensitivity C-reactive protein (hs-CRP) and glycosylated hemoglobin (HbAlc) significantly increased (all P<0.001). The level of COX-2 was negatively correlated with hs-CRP (r=-0.385, P=0.003). Multivariate logistic regression analysis showed that high level of plasma QKI and COX-2 were protective factors for in-stent restenosis after PCI, while hs-CRP was a risk factor. ROC curve analysis showed that the sensitivity and specificity of plasma QKI for evaluating the predictive value of ISR were 77.5% and 66.5%, respectively, and the sensitivity and specificity of plasma COX-2 for evaluating the predictive value of ISR were 80.0% and 70.7%, respectively. The sensitivity and specificity of plasma QKI combined with COX-2 for evaluating the predictive value of ISR were 81.3% and 74.1%, respectively. The sensitivity and specificity of plasma QKI for evaluating the prognosis of ISR were 75.0% and 64.7%, respectively. The sensitivity and specificity of plasma COX-2 for evaluating the prognosis of ISR were 75.0% and 70.6%, respectively. The sensitivity and specificity of plasma QKI combined with COX-2 for prognostic evaluation of ISR were 81.7% and 79.4%, respectively. The sensitivity and specificity of plasma COX-2 combined with QKI for evaluating ISR and MACE occurrences in patients after PCI were better than those of COX-2 or QKI alone (P<0.001). CONCLUSIONS High level of plasma QKI and COX-2 might be a protective factor for ISR, which can also predict ISR patient's prognosis.
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Affiliation(s)
- Ping Wang
- Department of Cardiology, Xiangya Hospital, Central South University; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha 410008.
| | - Yuanyuan Kuang
- Department of Cardiology, Xiangya Hospital, Central South University; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha 410008
| | - Yubo Liu
- Department of Cardiology, Xiangya Hospital, Central South University; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha 410008
| | - Yinzhuang Zhang
- Department of Cardiology, First Hospital of Changsha, Changsha 410005, China
| | - Haodong Gao
- Department of Cardiology, Xiangya Hospital, Central South University; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha 410008
| | - Qilin Ma
- Department of Cardiology, Xiangya Hospital, Central South University; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha 410008.
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Malhi NK, Allen CL, Stewart E, Horton KL, Riu F, Batson J, Amoaku W, Morris JC, Arkill KP, Bates DO. Serine-arginine-rich protein kinase-1 inhibition for the treatment of diabetic retinopathy. Am J Physiol Heart Circ Physiol 2022; 322:H1014-H1027. [PMID: 35302878 PMCID: PMC9109797 DOI: 10.1152/ajpheart.00001.2022] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Angiogenic VEGF isoforms are upregulated in diabetic retinopathy (DR), driving pathological growth and fluid leakage. Serine-arginine-rich protein kinase-1 (SRPK1) regulates VEGF splicing, and its inhibition blocks angiogenesis. We tested the hypothesis that SRPK1 is activated in diabetes, and an SRPK1 inhibitor (SPHINX31) switches VEGF splicing in DR and prevents increased vascular permeability into the retina. SRPK1 was activated by high glucose (HG), in a PKC-dependent manner, and was blocked by SPHINX31. HG induced release of SRSF1 from the nuclear speckles, which was also SRPK1 dependent, and increased retinal pigment epithelial (RPE) monolayer admittance, which was reversed by SRPK1 inhibition (P < 0.05). Diabetes increased retinal permeability and thickness after 14 days which was blocked by treatment with SPHINX31 eye drops (P < 0.0001). These results show that SRPK1 inhibition, administered as an eye drop, protected the retinal barrier from hyperglycemia-associated loss of integrity in RPE cells in vitro and in diabetic rats in vivo. A clinical trial of another SRPK1 inhibitor has now been initiated in patients with diabetic macular edema.NEW & NOTEWORTHY VEGF-A165b splicing is induced by hyperglycemia through PKC-mediated activation of SRPK1 in RPE cells, increasing their permeability and angiogenic capability. SRPK1 inhibitors can be given as eye drops to reduce retinal permeability and edema in diabetic retinopathy.
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Affiliation(s)
- Naseeb K Malhi
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Claire L Allen
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | | | - Katherine L Horton
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - Federica Riu
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | | | - Winfried Amoaku
- Division of Clinical Neuroscience, Department of Ophthalmology, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Jonathan C Morris
- School of Chemistry, University of New South Wales, Sydney, New South Wales, Australia
| | - Kenton P Arkill
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom
| | - David O Bates
- Tumour and Vascular Biology Laboratories, Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.,Exonate Limited, Duxford, United Kingdom.,COMPARE, University of Birmingham and University of Nottingham Midlands, Nottingham, United Kingdom
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10
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Chen X, Wu J, Li Z, Han J, Xia P, Shen Y, Ma J, Liu X, Zhang J, Yu P. Advances in The Study of RNA-binding Proteins in Diabetic Complications. Mol Metab 2022; 62:101515. [PMID: 35597446 PMCID: PMC9168169 DOI: 10.1016/j.molmet.2022.101515] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/21/2022] [Accepted: 05/12/2022] [Indexed: 12/18/2022] Open
Abstract
Background It has been reported that diabetes mellitus affects 435 million people globally as a primary health care problem. Despite many therapies available, many diabetes remains uncontrolled, giving rise to irreversible diabetic complications that pose significant risks to patients’ wellbeing and survival. Scope of Review In recent years, as much effort is put into elucidating the posttranscriptional gene regulation network of diabetes and diabetic complications; RNA binding proteins (RBPs) are found to be vital. RBPs regulate gene expression through various post-transcriptional mechanisms, including alternative splicing, RNA export, messenger RNA translation, RNA degradation, and RNA stabilization. Major Conclusions Here, we summarized recent studies on the roles and mechanisms of RBPs in mediating abnormal gene expression in diabetes and its complications. Moreover, we discussed the potential and theoretical basis of RBPs to treat diabetes and its complications.
• Mechanisms of action of RBPs involved in diabetic complications are summarized and elucidated. • We discuss the theoretical basis and potential of RBPs for the treatment of diabetes and its complications. • We summarize the possible effective drugs for diabetes based on RBPs promoting the development of future therapeutic drugs.
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Affiliation(s)
- Xinyue Chen
- The Second Clinical Medical College of Nanchang University, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiaqiang Wu
- The Second Clinical Medical College of Nanchang University, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhangwang Li
- The Second Clinical Medical College of Nanchang University, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiashu Han
- Department of Thoracic Surgery, Peking Union Medical College Hospital, Beijing 100730, China
| | - Panpan Xia
- Department of Metabolism and Endocrinology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yunfeng Shen
- Department of Metabolism and Endocrinology, the Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianyong Ma
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, USA
| | - Xiao Liu
- Department of Cardiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing Zhang
- The Second Clinical Medical College of Nanchang University, the Second Affiliated Hospital of Nanchang University, Nanchang, China; Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Jiangxi, Nanchang 330006, China.
| | - Peng Yu
- The Second Clinical Medical College of Nanchang University, the Second Affiliated Hospital of Nanchang University, Nanchang, China; Department of Metabolism and Endocrinology, the Second Affiliated Hospital of Nanchang University, Nanchang, China.
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11
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Identification of the Relationship between Hub Genes and Immune Cell Infiltration in Vascular Endothelial Cells of Proliferative Diabetic Retinopathy Using Bioinformatics Methods. DISEASE MARKERS 2022; 2022:7231046. [PMID: 35154512 PMCID: PMC8831064 DOI: 10.1155/2022/7231046] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/19/2021] [Accepted: 01/03/2022] [Indexed: 12/13/2022]
Abstract
Background Diabetic retinopathy (DR) is a serious ophthalmopathy that causes blindness, especially in the proliferative stage. However, the pathogenesis of its effect on endothelial cells, especially its relationship with immune cell infiltration, remains unclear. Methods The dataset GSE94019 was downloaded from the Gene Expression Omnibus (GEO) database to obtain DEGs. Through aggregate analyses such as Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis, a protein-protein interaction (PPI) network was constructed to analyze the potential function of DEGs. Weighted gene coexpression network analysis (WGCNA) and Cytoscape software including molecular complex detection (MCODE) and cytoHubba plug-ins were used to comprehensively analyze and determine the hub genes. ImmuCellAI analysis was performed to further study the relationship between samples, hub genes, and 24 types of immune cell infiltration. Finally, gene-set enrichment analysis (GSEA) was employed to identify the enrichment of immune cell infiltration and endothelial cell phenotype modifications in GO biological processes (BP) based on the expression level of hub genes. Results 2393 DEGs were identified, of which 800 genes were downregulated, and 1593 genes were upregulated. The results of functional enrichment revealed that 1398 BP terms were significantly enriched in DEGs. Three hub genes, EEF1A1, RPL11, and RPS27A, which were identified by conjoint analysis using WGCNA and Cytoscape software, were positively correlated with the number of CD4 naive T cells and negatively correlated with the numbers of B cells. The number of CD4 naive T cells, T helper 2 (Th2) cells, and effector memory T (Tem) cells were significantly higher while CD8 naive T cells and B cells significantly were lower in the diabetic group than in the nondiabetic group. Conclusions We unearthed the DEGs and Hub genes of endothelial cells related to the pathogenesis of PDR: EEF1A1, RPL11, and RPS27A, which are highly related to each other and participate in the specific biological process of inflammation-related immune cell infiltration and endothelial cell development, chemotaxis, and proliferation, thus providing new perspectives into the diagnosis of and potential “killing two birds with one stone” targeted therapy for PDR.
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12
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Louis JM, Agarwal A, Mondal S, Talukdar I. A global analysis on the differential regulation of RNA binding proteins (RBPs) by TNF–α as potential modulators of metabolic syndromes. BBA ADVANCES 2022; 2:100037. [PMID: 37082594 PMCID: PMC10074950 DOI: 10.1016/j.bbadva.2021.100037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 12/12/2021] [Accepted: 12/15/2021] [Indexed: 11/25/2022] Open
Abstract
Metabolic syndrome (MetS) is associated with a group of conditions, which enhances the risk of diabetes, heart diseases and stroke in the affected individuals. Earlier reports from our lab have shown that Tumor necrosis factor-α (TNF-α) significantly modulates the expression of 56 genes at the alternative splicing level which are involved in various signaling and metabolic pathways (MetS genes) connected to MetS. These MetS genes were predicted to interact with various RNA-binding proteins (RBPs) when exposed to TNF-α, resulting changes in their alternative splicing patterns. Here we are presenting data of an RNA-Seq analysis, which identified 1218 unique, and significantly regulated genes by TNF-α, 15% of which are RBPs . Among the 1218 genes, 204 genes have been identified as MetS genes by the ingenuity pathway analysis, and 10% of the MetS genes are found as RBPs. Our results also show that TNF-α changes the phosphorylation status of certain RBPs such as SR proteins, crucial players in alternative splicing, possibly via changing the activation status of certain upstream signaling molecules which also act as upstream kinases for these proteins. Taken together, these findings suggest that TNF-α influences the regulation of the RBPs at the various levels for their expression, which may lead to the alteration of the splicing pattern of the MetS genes. MetS genes acting as RBPs and are modulated by TNF-α, predict the existence of highly interconnected mechanisms which require further analysis to understand their dual roles on the onset of these diseases.
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13
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Kelaini S, Chan C, Cornelius VA, Margariti A. RNA-Binding Proteins Hold Key Roles in Function, Dysfunction, and Disease. BIOLOGY 2021; 10:biology10050366. [PMID: 33923168 PMCID: PMC8146904 DOI: 10.3390/biology10050366] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/21/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023]
Abstract
RNA-binding proteins (RBPs) are multi-faceted proteins in the regulation of RNA or its RNA splicing, localisation, stability, and translation. Amassing proof from many recent and dedicated studies reinforces the perception of RBPs exerting control through differing expression levels, cellular localization and post-transcriptional alterations. However, since the regulation of RBPs is reliant on the micro-environment and events like stress response and metabolism, their binding affinities and the resulting RNA-RBP networks may be affected. Therefore, any misregulation and disruption in the features of RNA and its related homeostasis can lead to a number of diseases that include diabetes, cardiovascular disease, and other disorders such as cancer and neurodegenerative diseases. As such, correct regulation of RNA and RBPs is crucial to good health as the effect RBPs exert through loss of function can cause pathogenesis. In this review, we will discuss the significance of RBPs and their typical function and how this can be disrupted in disease.
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14
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Integrated analysis of RNA-binding proteins in thyroid cancer. PLoS One 2021; 16:e0247836. [PMID: 33711033 PMCID: PMC7954316 DOI: 10.1371/journal.pone.0247836] [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: 09/26/2020] [Accepted: 02/14/2021] [Indexed: 12/23/2022] Open
Abstract
Recently, the incidence of thyroid cancer (THCA) has been on the rise. RNA binding proteins (RBPs) and their abnormal expression are closely related to the emergence and pathogenesis of tumor diseases. In this study, we obtained gene expression data and corresponding clinical information from the TCGA database. A total of 162 aberrantly expressed RBPs were obtained, comprising 92 up-regulated and 70 down-regulated RBPs. Then, we performed a functional enrichment analysis and constructed a PPI network. Through univariate Cox regression analysis of key genes and found that NOLC1 (p = 0.036), RPS27L (p = 0.011), TDRD9 (p = 0.016), TDRD6 (p = 0.002), IFIT2 (p = 0.037), and IFIT3 (p = 0.02) were significantly related to the prognosis. Through the online website Kaplan-Meier plotter and multivariate Cox analysis, we identified 2 RBP-coding genes (RPS27L and IFIT3) to construct a predictive model in the entire TCGA dataset and then validate in two subsets. In-depth analysis revealed that the data gave by this model, the patient's high-risk score is very closely related to the overall survival rate difference (p = 0.038). Further, we investigated the correlation between the model and the clinic, and the results indicated that the high-risk was in the male group (p = 0.011) and the T3-4 group (p = 0.046) was associated with a poor prognosis. On the whole, the conclusions of our research this time can make it possible to find more insights into the research on the pathogenesis of THCA, this could be beneficial for individualized treatment and medical decision making.
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15
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Luo EF, Li HX, Qin YH, Qiao Y, Yan GL, Yao YY, Li LQ, Hou JT, Tang CC, Wang D. Role of ferroptosis in the process of diabetes-induced endothelial dysfunction. World J Diabetes 2021; 12:124-137. [PMID: 33594332 PMCID: PMC7839168 DOI: 10.4239/wjd.v12.i2.124] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 11/30/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Endothelial dysfunction, a hallmark of diabetes, is a critical and initiating contributor to the pathogenesis of diabetic cardiovascular complications. However, the underlying mechanisms are still not fully understood. Ferroptosis is a newly defined regulated cell death driven by cellular metabolism and iron-dependent lipid peroxidation. Although the involvement of ferroptosis in disease pathogenesis has been shown in cancers and degenerative diseases, the participation of ferroptosis in the pathogenesis of diabetic endothelial dysfunction remains unclear.
AIM To examine the role of ferroptosis in diabetes-induced endothelial dysfunction and the underlying mechanisms.
METHODS Human umbilical vein endothelial cells (HUVECs) were treated with high glucose (HG), interleukin-1β (IL-1β), and ferroptosis inhibitor, and then the cell viability, reactive oxygen species (ROS), and ferroptosis-related marker protein were tested. To further determine whether the p53-xCT (the substrate-specific subunit of system Xc-)-glutathione (GSH) axis is involved in HG and IL-1β induced ferroptosis, HUVECs were transiently transfected with p53 small interfering ribonucleic acid or NC small interfering ribonucleic acid and then treated with HG and IL-1β. Cell viability, ROS, and ferroptosis-related marker protein were then assessed. In addition, we detected the xCT and p53 expression in the aorta of db/db mice.
RESULTS It was found that HG and IL-1β induced ferroptosis in HUVECs, as evidenced by the protective effect of the ferroptosis inhibitors, Deferoxamine and ferrostatin-1, resulting in increased lipid ROS and decreased cell viability. Mechanistically, activation of the p53-xCT-GSH axis induced by HG and IL-1β enhanced ferroptosis in HUVECs. In addition, a decrease in xCT and the presence of de-endothelialized areas were observed in the aortic endothelium of db/db mice.
CONCLUSION Ferroptosis is involved in endothelial dysfunction and p53-xCT-GSH axis activation plays a crucial role in endothelial cell ferroptosis and endothelial dysfunction.
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Affiliation(s)
- Er-Fei Luo
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Hong-Xia Li
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Yu-Han Qin
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Yong Qiao
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Gao-Liang Yan
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Yu-Yu Yao
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Lin-Qing Li
- School of Medicine, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Jian-Tong Hou
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Cheng-Chun Tang
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Dong Wang
- Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
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16
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Cornelius VA, Yacoub A, Kelaini S, Margariti A. Diabetic endotheliopathy: RNA-binding proteins as new therapeutic targets. Int J Biochem Cell Biol 2020; 131:105907. [PMID: 33359016 DOI: 10.1016/j.biocel.2020.105907] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/06/2020] [Accepted: 12/07/2020] [Indexed: 12/31/2022]
Abstract
Diabetic Endotheliopathy is widely regarded as a principal contributor to cardiovascular disease pathogenesis in individuals with Diabetes mellitus. The endothelium, the innermost lining of blood vessels, consists of an extensive monolayer of endothelial cells. Previously regarded as an interface, the endothelium is now accepted as an organ system with critical roles in vascular health; its dysfunction therefore is detrimental. Endothelial dysfunction induces blood vessel damage resulting in a restriction of blood and oxygen supply to tissues, the central pathology of cardiovascular disease. Hyperglycemic conditions have repeatedly been isolated as a pivotal inducer of endothelial cell dysfunction. Numerous studies have since proven hyperglycemic conditions to significantly alter the gene expression profile of endothelial cells, with this being largely attributable to the post-transcriptional regulation of RNA-binding proteins. In particular, the RBP Quaking-7 has recently emerged as a crucial mediator of diabetic endotheliopathy, with great potential to become a therapeutic target.
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Affiliation(s)
- Victoria A Cornelius
- The Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, BT9 7BL, UK
| | - Andrew Yacoub
- The Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, BT9 7BL, UK
| | - Sophia Kelaini
- The Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, BT9 7BL, UK
| | - Andriana Margariti
- The Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, BT9 7BL, UK.
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17
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Filippova N, Nabors LB. ELAVL1 Role in Cell Fusion and Tunneling Membrane Nanotube Formations with Implication to Treat Glioma Heterogeneity. Cancers (Basel) 2020; 12:E3069. [PMID: 33096700 PMCID: PMC7590168 DOI: 10.3390/cancers12103069] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/15/2020] [Accepted: 10/18/2020] [Indexed: 12/16/2022] Open
Abstract
Homotypic and heterotypic cell fusions via permanent membrane fusions and temporal tunneling nanotube formations in the glioma microenvironment were recently documented in vitro and in vivo and mediate glioma survival, plasticity, and recurrence. Chronic inflammation, a hypoxic environment, aberrant mitochondrial function, and ER stress due to unfolded protein accumulation upregulate cell fusion events, which leads to tumor heterogeneity and represents an adaptive mechanism to promote tumor cell survival and plasticity in cytotoxic, nutrient-deprived, mechanically stressed, and inflammatory microenvironments. Cell fusion is a multistep process, which consists of the activation of the cellular stress response, autophagy formation, rearrangement of cytoskeletal architecture in the areas of cell-to-cell contacts, and the expression of proinflammatory cytokines and fusogenic proteins. The mRNA-binding protein of ELAV-family HuR is a critical node, which orchestrates the stress response, autophagy formation, cytoskeletal architecture, and the expression of proinflammatory cytokines and fusogenic proteins. HuR is overexpressed in gliomas and is associated with poor prognosis and treatment resistance. Our review provides a link between the HuR role in the regulation of cell fusion and tunneling nanotube formations in the glioma microenvironment and the potential suppression of these processes by different classes of HuR inhibitors.
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Affiliation(s)
- Natalia Filippova
- Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Louis B. Nabors
- Department of Neurology, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
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18
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Yang C, Eleftheriadou M, Kelaini S, Morrison T, González MV, Caines R, Edwards N, Yacoub A, Edgar K, Moez A, Ivetic A, Zampetaki A, Zeng L, Wilkinson FL, Lois N, Stitt AW, Grieve DJ, Margariti A. Targeting QKI-7 in vivo restores endothelial cell function in diabetes. Nat Commun 2020; 11:3812. [PMID: 32732889 PMCID: PMC7393072 DOI: 10.1038/s41467-020-17468-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 07/02/2020] [Indexed: 11/24/2022] Open
Abstract
Vascular endothelial cell (EC) dysfunction plays a key role in diabetic complications. This study discovers significant upregulation of Quaking-7 (QKI-7) in iPS cell-derived ECs when exposed to hyperglycemia, and in human iPS-ECs from diabetic patients. QKI-7 is also highly expressed in human coronary arterial ECs from diabetic donors, and on blood vessels from diabetic critical limb ischemia patients undergoing a lower-limb amputation. QKI-7 expression is tightly controlled by RNA splicing factors CUG-BP and hnRNPM through direct binding. QKI-7 upregulation is correlated with disrupted cell barrier, compromised angiogenesis and enhanced monocyte adhesion. RNA immunoprecipitation (RIP) and mRNA-decay assays reveal that QKI-7 binds and promotes mRNA degradation of downstream targets CD144, Neuroligin 1 (NLGN1), and TNF-α-stimulated gene/protein 6 (TSG-6). When hindlimb ischemia is induced in diabetic mice and QKI-7 is knocked-down in vivo in ECs, reperfusion and blood flow recovery are markedly promoted. Manipulation of QKI-7 represents a promising strategy for the treatment of diabetic vascular complications.
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Affiliation(s)
- Chunbo Yang
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | | | - Sophia Kelaini
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Thomas Morrison
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Marta Vilà González
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Rachel Caines
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Nicola Edwards
- Centre for Bioscience in the Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, M15GD, UK
| | - Andrew Yacoub
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Kevin Edgar
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Arya Moez
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Aleksandar Ivetic
- School of Cardiovascular Medicine and Sciences, BHF Centre of Research Excellence, King's College London, The James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Anna Zampetaki
- School of Cardiovascular Medicine and Sciences, BHF Centre of Research Excellence, King's College London, The James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Lingfang Zeng
- School of Cardiovascular Medicine and Sciences, BHF Centre of Research Excellence, King's College London, The James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Fiona L Wilkinson
- Centre for Bioscience in the Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, M15GD, UK
| | - Noemi Lois
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Alan W Stitt
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - David J Grieve
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK
| | - Andriana Margariti
- The Wellcome-Wolfson Institute of Experimental Medicine, Belfast, BT9 7BL, UK.
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19
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Shen Z, Chen Q, Ying H, Ma Z, Bi X, Li X, Wang M, Jin C, Lai D, Zhao Y, Fu G. Identification of differentially expressed genes in the endothelial precursor cells of patients with type 2 diabetes mellitus by bioinformatics analysis. Exp Ther Med 2019; 19:499-510. [PMID: 31897097 PMCID: PMC6923743 DOI: 10.3892/etm.2019.8239] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 10/18/2019] [Indexed: 12/21/2022] Open
Abstract
Type 2 diabetes mellitus (DM) is a metabolic disease with worldwide prevalence that is associated with a decrease in the number and function of endothelial progenitor cells (EPCs). The aim of the present study was to explore the potential hub genes of EPCs in patients with type 2 DM. Differentially expressed genes (DEGs) were screened from a public microarray dataset (accession no. GSE43950). Pathway and functional enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery. The protein-protein interaction (PPI) network was visualized. The most significantly clustered modules and hub genes were identified using Cytoscape. Furthermore, hub genes were validated by quantitative PCR analysis of EPCs isolated from diabetic and normal subjects. Subsequently, weighted gene co-expression network analysis (WGCNA) was performed to identify the modules incorporating the genes exhibiting the most significant variance. A total of 970 DEGs were obtained and they were mainly accumulated in inflammation-associated pathways. A total of 9 hub genes were extracted from the PPI network and the highest differential expression was determined for the interleukin 8 (IL8) and CXC chemokine ligand 1 (CXCL1) genes. In the WGCNA performed to determine the modules associated with type 2 DM, one module incorporated IL8 and CXCL1. Finally, pathway enrichment of 10% genes in the pink module ordered by intramodular connectivity (IC) was associated with the IL17 and the chemokine signaling pathways. The present results revealed that the expression of IL8 and CXCL1 may serve important roles in the pathophysiology of EPCs during type 2 DM and inflammatory response may be critical for the reduced number and hypofunction of EPCs isolated from patients with diabetes.
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Affiliation(s)
- Zhida Shen
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Qi Chen
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Hangying Ying
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Zetao Ma
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Xukun Bi
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Xiaoting Li
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Meihui Wang
- Biomedical Research Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Chongying Jin
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Dongwu Lai
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Yanbo Zhao
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
| | - Guosheng Fu
- Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, P.R. China
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20
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Caines R, Cochrane A, Kelaini S, Vila-Gonzalez M, Yang C, Eleftheriadou M, Moez A, Stitt AW, Zeng L, Grieve DJ, Margariti A. The RNA-binding protein QKI controls alternative splicing in vascular cells, producing an effective model for therapy. J Cell Sci 2019; 132:jcs.230276. [PMID: 31331967 DOI: 10.1242/jcs.230276] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 07/10/2019] [Indexed: 12/31/2022] Open
Abstract
Dysfunction of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) leads to ischaemia, the central pathology of cardiovascular disease. Stem cell technology will revolutionise regenerative medicine, but a need remains to understand key mechanisms of vascular differentiation. RNA-binding proteins have emerged as novel post-transcriptional regulators of alternative splicing and we have previously shown that the RNA-binding protein Quaking (QKI) plays roles in EC differentiation. In this study, we decipher the role of the alternative splicing isoform Quaking 6 (QKI-6) to induce VSMC differentiation from induced pluripotent stem cells (iPSCs). PDGF-BB stimulation induced QKI-6, which bound to HDAC7 intron 1 via the QKI-binding motif, promoting HDAC7 splicing and iPS-VSMC differentiation. Overexpression of QKI-6 transcriptionally activated SM22 (also known as TAGLN), while QKI-6 knockdown diminished differentiation capability. VSMCs overexpressing QKI-6 demonstrated greater contractile ability, and upon combination with iPS-ECs-overexpressing the alternative splicing isoform Quaking 5 (QKI-5), exhibited higher angiogenic potential in vivo than control cells alone. This study demonstrates that QKI-6 is critical for modulation of HDAC7 splicing, regulating phenotypically and functionally robust iPS-VSMCs. These findings also highlight that the QKI isoforms hold key roles in alternative splicing, giving rise to cells which can be used in vascular therapy or for disease modelling.This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Rachel Caines
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Amy Cochrane
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Sophia Kelaini
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Marta Vila-Gonzalez
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Chunbo Yang
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Magdalini Eleftheriadou
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Arya Moez
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Alan W Stitt
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Lingfang Zeng
- Cardiovascular Division, King's College London, London SE5 9NU, UK
| | - David J Grieve
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
| | - Andriana Margariti
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL
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