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Bai Y, Wu J, Jian W. Trained immunity in diabetes: emerging targets for cardiovascular complications. Front Endocrinol (Lausanne) 2025; 16:1533620. [PMID: 40438395 PMCID: PMC12116311 DOI: 10.3389/fendo.2025.1533620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Accepted: 04/24/2025] [Indexed: 06/01/2025] Open
Abstract
Diabetes is a metabolic disorder primarily characterized by persistent hyperglycemia. Diabetes-induced inflammation significantly compromises cardiovascular health, greatly increasing the risk of atherosclerosis. The increasing prevalence of harmful lifestyle habits and overconsumption has contributed substantially to the global rise in diabetes-related cardiovascular diseases, creating a significant economic and healthcare burden. Although current therapeutic strategies focus on blood glucose control and metabolic regulation, clinical observations show that diabetic patients still face persistent residual risk of AS even after achieving metabolic stability. Recent studies suggest that this phenomenon is linked to diabetes-induced trained immunity. Diabetes can induce trained immunity in bone marrow progenitor cells and myeloid cells, thus promoting the long-term development of AS. This article first introduces the concept and molecular mechanisms of trained immunity, with particular emphasis on metabolic and epigenetic reprogramming, which plays a crucial role in sustaining chronic inflammation during trained immunity. Next, it summarizes the involvement of trained immunity in diabetes and its contribution to AS, outlining the cell types that can be trained in AS. Finally, it discusses the connection between diabetes-induced trained immunity and AS, as well as the potential of targeting trained immunity as an intervention strategy. Understanding the molecular mechanisms of trained immunity and their impact on disease progression may provide innovative strategies to address the persistent clinical challenges in managing diabetes and its complications.
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Affiliation(s)
- Yanan Bai
- College of Traditional Chinese Medicine, Hunan University of Traditional Chinese Medicine, Changsha, Hunan, China
| | - Jianglan Wu
- College of Traditional Chinese Medicine, Hunan University of Traditional Chinese Medicine, Changsha, Hunan, China
| | - Weixiong Jian
- College of Traditional Chinese Medicine, Hunan University of Traditional Chinese Medicine, Changsha, Hunan, China
- Diagnostics of Traditional Chinese Medicine, National Key Discipline, Hunan University of Traditional Chinese Medicine, Changsha, Hunan, China
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Oniki K, Shigaki T, Kajiwara-Morita A, Shigetome K, Yoshida A, Jinnouchi H, Saruwatari J. Quantitative assessment of metabolic memory and its prediction of renal function decline in patients with type 2 diabetes: A retrospective observational study. Diabetes Metab Syndr 2025; 19:103225. [PMID: 40239378 DOI: 10.1016/j.dsx.2025.103225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 04/07/2025] [Accepted: 04/11/2025] [Indexed: 04/18/2025]
Abstract
AIMS This study quantitatively assesses metabolic memory by modeling the relationship between hyperglycemic exposure and renal function decline in patients with type 2 diabetes (T2D). METHODS This retrospective longitudinal study included 381 Japanese patients with T2D. Hyperglycemic exposure was presented by calculating the area under the curve (AUC) for HbA1c ≥ 6 % (AUCHbA1c ≥ 6 %) during the observation period. A non-linear mixed-effects model was constructed to predict changes in estimated glomerular filtration rate (eGFR) based on AUCHbA1c ≥ 6 %. RESULTS The relationship between AUCHbA1c ≥ 6 % and eGFR changes was shown by a sigmoidal curve, with sex, age, diabetic retinopathy, dyslipidemia, and hypertension incorporated as covariates. The predictive utility of the model was validated using goodness-of-fit plot, visual predictive check, and bootstrap methods. CONCLUSIONS We developed an AUCHbA1c ≥ 6 %-based model to predict renal function decline in patients with T2D, showing that AUCHbA1c ≥ 6 % may serve as a quantitative indicator of metabolic memory.
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Affiliation(s)
- Kentaro Oniki
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Takuro Shigaki
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Ayami Kajiwara-Morita
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; Diabetes Care Center, Jinnouchi Hospital, Kumamoto, Japan
| | - Keiichi Shigetome
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Akira Yoshida
- Diabetes Care Center, Jinnouchi Hospital, Kumamoto, Japan
| | | | - Junji Saruwatari
- Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
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Mimura I, Chen Z, Natarajan R. Epigenetic alterations and memory: key players in the development/progression of chronic kidney disease promoted by acute kidney injury and diabetes. Kidney Int 2025; 107:434-456. [PMID: 39725223 DOI: 10.1016/j.kint.2024.10.031] [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: 02/25/2024] [Revised: 09/20/2024] [Accepted: 10/08/2024] [Indexed: 12/28/2024]
Abstract
Chronic kidney disease (CKD) is a highly prevalent global public health issue and can progress to kidney failure. Survivors of acute kidney injury (AKI) have an increased risk of progressing to CKD by 8.8-fold and kidney failure by 3.1-fold. Further, 20% to 40% of individuals with diabetes will develop CKD, also known as diabetic kidney disease (DKD). Thus, preventing these kidney diseases can positively impact quality-of-life and life-expectancy outcomes for affected individuals. Frequent episodes of hyperglycemia and renal hypoxia are implicated in the pathophysiology of CKD. Prior periods of hyperglycemia/uncontrolled diabetes can result in development/progression of DKD even after achieving normoglycemia, a phenomenon known as metabolic memory or legacy effect. Similarly, in AKI, hypoxic memory is stored in renal cells even after recovery from the initial AKI episode and can transition to CKD. Epigenetic mechanisms involving DNA methylation, chromatin histone post-translational modifications, and noncoding RNAs are implicated in both metabolic and hypoxic memory, collectively known as "epigenetic memory." This epigenetic memory is generally reversible and provides a therapeutic avenue to ameliorate persistent disease progression due to hyperglycemia and hypoxia and prevent/ameliorate CKD progression. Indeed, therapeutic strategies targeting epigenetic memory are effective at preventing CKD development/progression in experimental models of AKI and DKD. Here, we review the latest in-depth evidence for epigenetic features in DKD and AKI, and in epigenetic memories of AKI-to-CKD transition or DKD development and progression, followed by translational and clinical implications of these epigenetic changes for the treatment of these widespread kidney disorders.
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Affiliation(s)
- Imari Mimura
- Division of Nephrology and Endocrinology, the University of Tokyo School of Medicine, Tokyo Japan.
| | - Zhuo Chen
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California, USA.
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Chung JD, Porrello ER, Lynch GS. Muscle regeneration and muscle stem cells in metabolic disease. Free Radic Biol Med 2025; 227:52-63. [PMID: 39581389 DOI: 10.1016/j.freeradbiomed.2024.11.041] [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] [Received: 02/28/2024] [Revised: 11/05/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024]
Abstract
Skeletal muscle has a high regenerative capacity due to its resident adult muscle stem cells (MuSCs), which can repair damaged tissue by forming myofibres de novo. Stem cell dependent regeneration is critical for maintaining skeletal muscle health, and different conditions can draw heavily on MuSC support to preserve muscle function, including metabolic diseases such as diabetes. The global incidence and burden of diabetes is increasing, and skeletal muscle is critical for maintaining systemic metabolic homeostasis and improving outcomes for diabetic patients. Thus, poor muscle health in diabetes, termed diabetic myopathy, is an important complication that must be addressed. The health of MuSCs is also affected by diabetes, responsible for the poor muscle regenerative capacity and contributing to the functional decline in diabetic patients. Here, we review the impact of diabetes and metabolic disease on MuSCs and skeletal muscle, including potential mechanisms for impaired muscle regeneration and MuSC dysfunction, and how these deficits could be addressed.
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Affiliation(s)
- Jin D Chung
- Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, 3010, VIC, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, 3052, VIC, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, 3052, VIC, Australia
| | - Enzo R Porrello
- Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, 3010, VIC, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, 3052, VIC, Australia; Novo Nordisk Foundation Center for Stem Cell Medicine, Murdoch Children's Research Institute, Melbourne, 3052, VIC, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, 3010, VIC, Australia
| | - Gordon S Lynch
- Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Melbourne, 3010, VIC, Australia.
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5
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Hill C, McKnight AJ, Smyth LJ. Integrated multiomic analyses: An approach to improve understanding of diabetic kidney disease. Diabet Med 2025; 42:e15447. [PMID: 39460977 PMCID: PMC11733670 DOI: 10.1111/dme.15447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024]
Abstract
AIM Diabetes is increasing in prevalence worldwide, with a 20% rise in prevalence predicted between 2021 and 2030, bringing an increased burden of complications, such as diabetic kidney disease (DKD). DKD is a leading cause of end-stage kidney disease, with significant impacts on patients, families and healthcare providers. DKD often goes undetected until later stages, due to asymptomatic disease, non-standard presentation or progression, and sub-optimal screening tools and/or provision. Deeper insights are needed to improve DKD diagnosis, facilitating the identification of higher-risk patients. Improved tools to stratify patients based on disease prognosis would facilitate the optimisation of resources and the individualisation of care. This review aimed to identify how multiomic approaches provide an opportunity to understand the complex underlying biology of DKD. METHODS This review explores how multiomic analyses of DKD are improving our understanding of DKD pathology, and aiding in the identification of novel biomarkers to detect disease earlier or predict trajectories. RESULTS Effective multiomic data integration allows novel interactions to be uncovered and empathises the need for harmonised studies and the incorporation of additional data types, such as co-morbidity, environmental and demographic data to understand DKD complexity. This will facilitate a better understanding of kidney health inequalities, such as social-, ethnicity- and sex-related differences in DKD risk, onset and progression. CONCLUSION Multiomics provides opportunities to uncover how lifetime exposures become molecularly embodied to impact kidney health. Such insights would advance DKD diagnosis and treatment, inform preventative strategies and reduce the global impact of this disease.
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Affiliation(s)
- Claire Hill
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Amy Jayne McKnight
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Laura J. Smyth
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
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6
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Ahmed I, Chakraborty R, Faizy AF, Moin S. Exploring the key role of DNA methylation as an epigenetic modulator in oxidative stress related islet cell injury in patients with type 2 diabetes mellitus: a review. J Diabetes Metab Disord 2024; 23:1699-1718. [PMID: 39610516 PMCID: PMC11599646 DOI: 10.1007/s40200-024-01496-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/21/2024] [Indexed: 11/30/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions.
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Affiliation(s)
- Istiaque Ahmed
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Ritoja Chakraborty
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Abul Faiz Faizy
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Shagufta Moin
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
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Chen Z, Malek V, Natarajan R. Update: the role of epigenetics in the metabolic memory of diabetic complications. Am J Physiol Renal Physiol 2024; 327:F327-F339. [PMID: 38961840 PMCID: PMC11460341 DOI: 10.1152/ajprenal.00115.2024] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/24/2024] [Accepted: 06/27/2024] [Indexed: 07/05/2024] Open
Abstract
Diabetes, a chronic disease characterized by hyperglycemia, is associated with significantly accelerated complications, including diabetic kidney disease (DKD), which increases morbidity and mortality. Hyperglycemia and other diabetes-related environmental factors such as overnutrition, sedentary lifestyles, and hyperlipidemia can induce epigenetic changes. Working alone or with genetic factors, these epigenetic changes that occur without alterations in the underlying DNA sequence, can alter the expression of pathophysiological genes and impair functions of associated target cells/organs, leading to diabetic complications like DKD. Notably, some hyperglycemia-induced epigenetic changes persist in target cells/tissues even after glucose normalization, leading to sustained complications despite glycemic control, so-called metabolic memory. Emerging evidence from in vitro and in vivo animal models and clinical trials with subjects with diabetes identified clear associations between metabolic memory and epigenetic changes including DNA methylation, histone modifications, chromatin structure, and noncoding RNAs at key loci. Targeting such persistent epigenetic changes and/or molecules regulated by them can serve as valuable opportunities to attenuate, or erase metabolic memory, which is crucial to prevent complication progression. Here, we review these cell/tissue-specific epigenetic changes identified to-date as related to diabetic complications, especially DKD, and the current status on targeting epigenetics to tackle metabolic memory. We also discuss limitations in current studies, including the need for more (epi)genome-wide studies, integrative analysis using multiple epigenetic marks and Omics datasets, and mechanistic evaluation of metabolic memory. Considering the tremendous technological advances in epigenomics, genetics, sequencing, and availability of genomic datasets from clinical cohorts, this field is likely to see considerable progress in the upcoming years.
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Affiliation(s)
- Zhuo Chen
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, California
| | - Vajir Malek
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, California
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, California
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Wilson-Verdugo M, Bustos-García B, Adame-Guerrero O, Hersch-González J, Cano-Domínguez N, Soto-Nava M, Acosta CA, Tusie-Luna T, Avila-Rios S, Noriega LG, Valdes VJ. Reversal of high-glucose-induced transcriptional and epigenetic memories through NRF2 pathway activation. Life Sci Alliance 2024; 7:e202302382. [PMID: 38755006 PMCID: PMC11099870 DOI: 10.26508/lsa.202302382] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 04/29/2024] [Accepted: 04/30/2024] [Indexed: 05/18/2024] Open
Abstract
Diabetes complications such as nephropathy, retinopathy, or cardiovascular disease arise from vascular dysfunction. In this context, it has been observed that past hyperglycemic events can induce long-lasting alterations, a phenomenon termed "metabolic memory." In this study, we evaluated the genome-wide gene expression and chromatin accessibility alterations caused by transient high-glucose exposure in human endothelial cells (ECs) in vitro. We found that cells exposed to high glucose exhibited substantial gene expression changes in pathways known to be impaired in diabetes, many of which persist after glucose normalization. Chromatin accessibility analysis also revealed that transient hyperglycemia induces persistent alterations, mainly in non-promoter regions identified as enhancers with neighboring genes showing lasting alterations. Notably, activation of the NRF2 pathway through NRF2 overexpression or supplementation with the plant-derived compound sulforaphane, effectively reverses the glucose-induced transcriptional and chromatin accessibility memories in ECs. These findings underscore the enduring impact of transient hyperglycemia on ECs' transcriptomic and chromatin accessibility profiles, emphasizing the potential utility of pharmacological NRF2 pathway activation in mitigating and reversing the high-glucose-induced transcriptional and epigenetic alterations.
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Affiliation(s)
- Martí Wilson-Verdugo
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Brandon Bustos-García
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Olga Adame-Guerrero
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Jaqueline Hersch-González
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Nallely Cano-Domínguez
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
| | - Maribel Soto-Nava
- Centre for Research in Infectious Diseases of the National Institute of Respiratory Diseases (CIENI/INER), Mexico City, Mexico
| | | | - Teresa Tusie-Luna
- Unidad de Biología Molecular y Medicina Genómica Instituto de Investigaciones Biomédicas UNAM/Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubiran, Ciudad de México, Mexico
| | - Santiago Avila-Rios
- Centre for Research in Infectious Diseases of the National Institute of Respiratory Diseases (CIENI/INER), Mexico City, Mexico
| | - Lilia G Noriega
- Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Ciudad de México, Mexico
| | - Victor J Valdes
- Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, México
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Behnoush AH, Maleki S, Arzhangzadeh A, Khalaji A, Pezeshki PS, Vaziri Z, Esmaeili Z, Ebrahimi P, Ashraf H, Masoudkabir F, Vasheghani‐Farahani A, Hosseini K, Mehrani M, Hernandez AV. Prediabetes and major adverse cardiac events after acute coronary syndrome: An overestimated concept. Clin Cardiol 2024; 47:e24262. [PMID: 38558072 PMCID: PMC10983809 DOI: 10.1002/clc.24262] [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] [Received: 12/19/2023] [Revised: 03/08/2024] [Accepted: 03/18/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Unlike diabetes, the effect of prediabetes on outcomes in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI) is not much investigated. We investigated the association between fasting glycemic status and major adverse cardiovascular and cerebrovascular events (MACCE) in patients with ACS undergoing PCI and had mid to long-term follow-up after coronary stenting. METHODS Registry-based retrospective cohort study included ACS patients who underwent PCI at the Tehran Heart Center from 2015 to 2021 with a median follow-up of 378 days. Patients were allocated into normoglycemic, prediabetic, and diabetic groups. The primary and secondary outcomes were MACCE and its components, respectively. Unadjusted and adjusted Cox models were used to evaluate the association between glycemic status and outcomes. RESULTS Among 13 682 patients, 3151 (23%) were prediabetic, and 5834 (42.6%) were diabetic. MACCE risk was significantly higher for diabetic versus normoglycemic (adjusted hazard ratio [aHR]: 1.22, 95% confidence interval [CI]: 1.06-1.41), but nonsignificantly higher for prediabetic versus normoglycemic (aHR: 0.95, 95% CI: 0.78-1.10). All-cause mortality risk was significantly higher in diabetic versus normoglycemic (aHR: 1.42, 95% CI: 1.08-1.86), but nonsignificantly higher for prediabetic versus normoglycemic (aHR: 1.15, 95% CI: 0.84-1.59). Among other components of MACCE, only coronary artery bypass grafting was significantly higher in diabetic patients, and not prediabetic, compared with normoglycemic. CONCLUSIONS Prediabetic ACS patients undergoing PCI, unlike diabetics, are not at increased risk of MACCE and all-cause mortality. While prediabetic patients could be regarded as having the same risk as nondiabetics, careful consideration to provide more intensive pre- and post-PCI care in diabetic patients is mandatory.
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Affiliation(s)
- Amir Hossein Behnoush
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- School of MedicineTehran University of Medical SciencesTehranIran
- Non‐Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences InstituteTehran University of Medical SciencesTehranIran
| | - Saba Maleki
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- School of MedicineGuilan University of Medical Sciences (GUMS)RashtGuilan ProvinceIran
| | - Alireza Arzhangzadeh
- Department of Cardiology, School of MedicineShiraz University of Medical SciencesShirazIran
| | - Amirmohammad Khalaji
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- School of MedicineTehran University of Medical SciencesTehranIran
- Non‐Communicable Diseases Research Center, Endocrinology and Metabolism Population Sciences InstituteTehran University of Medical SciencesTehranIran
| | - Parmida Sadat Pezeshki
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- School of MedicineTehran University of Medical SciencesTehranIran
| | - Zahra Vaziri
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Student Research CommitteeBabol University of Medical SciencesBabolIran
| | - Zahra Esmaeili
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- School of MedicineTehran University of Medical SciencesTehranIran
| | - Pouya Ebrahimi
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Jundishapur University of Medical SciencesAhvazIran
| | - Haleh Ashraf
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
| | - Farzad Masoudkabir
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
| | - Ali Vasheghani‐Farahani
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
| | - Kaveh Hosseini
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
| | - Mehdi Mehrani
- Cardiac Primary Prevention Research Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
- Tehran Heart Center, Cardiovascular Diseases Research InstituteTehran University of Medical SciencesTehranIran
| | - Adrian V. Hernandez
- Health Outcomes, Policy, and Evidence Synthesis (HOPES) GroupUniversity of Connecticut School of PharmacyStorrsConnecticutUSA
- Unidad de Revisiones Sistemáticas y Meta‐análisis (URSIGET), Vicerrectorado de InvestigaciónUniversidad San Ignacio de LoyolaLimaPeru
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10
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Wang N, Zhang C. Recent Advances in the Management of Diabetic Kidney Disease: Slowing Progression. Int J Mol Sci 2024; 25:3086. [PMID: 38542060 PMCID: PMC10970506 DOI: 10.3390/ijms25063086] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/28/2024] [Accepted: 03/05/2024] [Indexed: 01/03/2025] Open
Abstract
Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future.
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Affiliation(s)
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China;
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11
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Yu G, Tam HCH, Huang C, Shi M, Lim CKP, Chan JCN, Ma RCW. Lessons and Applications of Omics Research in Diabetes Epidemiology. Curr Diab Rep 2024; 24:27-44. [PMID: 38294727 PMCID: PMC10874344 DOI: 10.1007/s11892-024-01533-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/04/2024] [Indexed: 02/01/2024]
Abstract
PURPOSE OF REVIEW Recent advances in genomic technology and molecular techniques have greatly facilitated the identification of disease biomarkers, advanced understanding of pathogenesis of different common diseases, and heralded the dawn of precision medicine. Much of these advances in the area of diabetes have been made possible through deep phenotyping of epidemiological cohorts, and analysis of the different omics data in relation to detailed clinical information. In this review, we aim to provide an overview on how omics research could be incorporated into the design of current and future epidemiological studies. RECENT FINDINGS We provide an up-to-date review of the current understanding in the area of genetic, epigenetic, proteomic and metabolomic markers for diabetes and related outcomes, including polygenic risk scores. We have drawn on key examples from the literature, as well as our own experience of conducting omics research using the Hong Kong Diabetes Register and Hong Kong Diabetes Biobank, as well as other cohorts, to illustrate the potential of omics research in diabetes. Recent studies highlight the opportunity, as well as potential benefit, to incorporate molecular profiling in the design and set-up of diabetes epidemiology studies, which can also advance understanding on the heterogeneity of diabetes. Learnings from these examples should facilitate other researchers to consider incorporating research on omics technologies into their work to advance the field and our understanding of diabetes and its related co-morbidities. Insights from these studies would be important for future development of precision medicine in diabetes.
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Affiliation(s)
- Gechang Yu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Henry C H Tam
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Chuiguo Huang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Mai Shi
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Cadmon K P Lim
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China
| | - Ronald C W Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, HKSAR, China.
- Chinese University of Hong Kong- Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, HKSAR, China.
- Laboratory for Molecular Epidemiology in Diabetes, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, HKSAR, China.
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12
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Riksen NP, Bekkering S, Mulder WJM, Netea MG. Trained immunity in atherosclerotic cardiovascular disease. Nat Rev Cardiol 2023; 20:799-811. [PMID: 37322182 DOI: 10.1038/s41569-023-00894-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/19/2023] [Indexed: 06/17/2023]
Abstract
Trained immunity, also known as innate immune memory, is a persistent hyper-responsive functional state of innate immune cells. Accumulating evidence implicates trained immunity as an underlying mechanism of chronic inflammation in atherosclerotic cardiovascular disease. In this context, trained immunity is induced by endogenous atherosclerosis-promoting factors, such as modified lipoproteins or hyperglycaemia, causing broad metabolic and epigenetic reprogramming of the myeloid cell compartment. In addition to traditional cardiovascular risk factors, lifestyle factors, including unhealthy diets, sedentary lifestyle, sleep deprivation and psychosocial stress, as well as inflammatory comorbidities, have been shown to activate trained immunity-like mechanisms in bone marrow haematopoietic stem cells. In this Review, we discuss the molecular and cellular mechanisms of trained immunity, its systemic regulation through haematopoietic progenitor cells in the bone marrow, and the activation of these mechanisms by cardiovascular disease risk factors. We also highlight other trained immunity features that are relevant for atherosclerotic cardiovascular disease, including the diverse cell types that show memory characteristics and transgenerational inheritance of trained immunity traits. Finally, we propose potential strategies for the therapeutic modulation of trained immunity to manage atherosclerotic cardiovascular disease.
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Affiliation(s)
- Niels P Riksen
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Siroon Bekkering
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Willem J M Mulder
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Mihai G Netea
- Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
- Department for Genomics and Immunoregulation, University of Bonn, Bonn, Germany
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13
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Dwivedi S, Chavan A, Paul AT. SET7, a lysine-specific methyl transferase: An intriguing epigenetic target to combat diabetic nephropathy. Drug Discov Today 2023; 28:103754. [PMID: 37648018 DOI: 10.1016/j.drudis.2023.103754] [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: 04/24/2023] [Revised: 07/14/2023] [Accepted: 08/24/2023] [Indexed: 09/01/2023]
Abstract
Diabetic nephropathy (DN) is a dreadful complication of diabetes that affects ∼50% of diabetics and is a leading cause of end-stage renal disease (ESRD). Studies have linked aberrant expression of lysine methyltransferases (KMTs) to the onset and progression of DN. SET7 is a KMT that methylates specific lysine residues of the histone and nonhistone proteins. It plays an important role in the transforming growth factor-β (TGF-β)-induced upregulation of extracellular matrix (ECM)-associated genes that are responsible for the inflammatory cascade observed in DN. Inhibiting SET7 has potential to attenuate renal disorders in animal studies. This review will focus on the role of SET7 in DN and its potential as a therapeutic target to combat DN.
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Affiliation(s)
- Samarth Dwivedi
- Natural Product Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science (Pilani Campus), Pilani 333031, Rajasthan, India
| | - Atharva Chavan
- Natural Product Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science (Pilani Campus), Pilani 333031, Rajasthan, India
| | - Atish T Paul
- Natural Product Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science (Pilani Campus), Pilani 333031, Rajasthan, India.
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14
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Janssen AWM, van Heck JIP, Stienstra R, Aarntzen EHJG, van Diepen JA, Riksen NP, Tack CJ. Arterial wall inflammation assessed by 18F-FDG-PET/CT is higher in individuals with Type 1 diabetes and associated with circulating inflammatory proteins. Cardiovasc Res 2023; 119:1942-1951. [PMID: 37079728 PMCID: PMC10439710 DOI: 10.1093/cvr/cvad058] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 11/24/2022] [Accepted: 12/20/2022] [Indexed: 04/22/2023] Open
Abstract
AIMS The article investigates whether chronic hyperglycaemia in Type 1 diabetes (T1D) is associated with a proinflammatory immune signature and with arterial wall inflammation, driving the development of atherosclerosis. METHODS AND RESULTS Patients with T1D (n = 41), and healthy age-, sex-, and body mass index-matched controls (n = 20) were recruited. Arterial wall inflammation and haematopoietic activity were measured with 2'-deoxy-2'-(18F)-fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography. In addition, flow cytometry of circulating leucocytes was performed as well as targeted proteomics to measure circulating inflammatory markers. 18F-FDG uptake in the wall of the abdominal aorta, carotid arteries, and iliac arteries was higher in T1D compared with that in the healthy controls. Also, 18F-FDG uptake in the bone marrow and spleen was higher in patients with T1D. CCR2 and CD36 expressions on circulating monocytes were higher in patients with T1D, as well as several circulating inflammatory proteins. In addition, several circulating inflammatory markers (osteoprotegerin, transforming growth factor-alpha, CX3CL1, and colony-stimulating factor-1) displayed a positive correlation with FDG uptake. Within T1D, no differences were found between people with a high and low HbA1c. CONCLUSION These findings strengthen the concept that chronic hyperglycaemia in T1D induces inflammatory changes that fuel arterial wall inflammation leading to atherosclerosis. The degree of hyperglycaemia appears to play a minor role in driving this inflammatory response in patients with T1D.
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Affiliation(s)
- Anna W M Janssen
- Department of Internal Medicine (463), Radboud University Medical Center, PO Box 9101, Geert Grooteplein 8, Nijmegen 6500 HB, The Netherlands
| | - Julia I P van Heck
- Department of Internal Medicine (463), Radboud University Medical Center, PO Box 9101, Geert Grooteplein 8, Nijmegen 6500 HB, The Netherlands
| | - Rinke Stienstra
- Department of Internal Medicine (463), Radboud University Medical Center, PO Box 9101, Geert Grooteplein 8, Nijmegen 6500 HB, The Netherlands
- Division of Human Nutrition and Health, Wageningen University and Research Division of Human Nutrition and Health (Bode 62), P.O. Box 176700 AA, Wageningen, The Netherlands
| | - Erik H J G Aarntzen
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Janna A van Diepen
- Department of Internal Medicine (463), Radboud University Medical Center, PO Box 9101, Geert Grooteplein 8, Nijmegen 6500 HB, The Netherlands
| | - Niels P Riksen
- Department of Internal Medicine (463), Radboud University Medical Center, PO Box 9101, Geert Grooteplein 8, Nijmegen 6500 HB, The Netherlands
| | - Cees J Tack
- Department of Internal Medicine (463), Radboud University Medical Center, PO Box 9101, Geert Grooteplein 8, Nijmegen 6500 HB, The Netherlands
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15
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Liu Z, Liu J, Wang W, An X, Luo L, Yu D, Sun W. Epigenetic modification in diabetic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1133970. [PMID: 37455912 PMCID: PMC10348754 DOI: 10.3389/fendo.2023.1133970] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 05/30/2023] [Indexed: 07/18/2023] Open
Abstract
Diabetic kidney disease (DKD) is a common microangiopathy in diabetic patients and the main cause of death in diabetic patients. The main manifestations of DKD are proteinuria and decreased renal filtration capacity. The glomerular filtration rate and urinary albumin level are two of the most important hallmarks of the progression of DKD. The classical treatment of DKD is controlling blood glucose and blood pressure. However, the commonly used clinical therapeutic strategies and the existing biomarkers only partially slow the progression of DKD and roughly predict disease progression. Therefore, novel therapeutic methods, targets and biomarkers are urgently needed to meet clinical requirements. In recent years, increasing attention has been given to the role of epigenetic modification in the pathogenesis of DKD. Epigenetic variation mainly includes DNA methylation, histone modification and changes in the noncoding RNA expression profile, which are deeply involved in DKD-related inflammation, oxidative stress, hemodynamics, and the activation of abnormal signaling pathways. Since DKD is reversible at certain disease stages, it is valuable to identify abnormal epigenetic modifications as early diagnosis and treatment targets to prevent the progression of end-stage renal disease (ESRD). Because the current understanding of the epigenetic mechanism of DKD is not comprehensive, the purpose of this review is to summarize the role of epigenetic modification in the occurrence and development of DKD and evaluate the value of epigenetic therapies in DKD.
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Affiliation(s)
- Zhe Liu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
- College of Basic Medical Sciences, Jilin University, Changchun, Jilin, China
| | - Jiahui Liu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Wanning Wang
- Department of Nephrology, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xingna An
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ling Luo
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Dehai Yu
- Public Research Platform, First Hospital of Jilin University, Changchun, Jilin, China
| | - Weixia Sun
- Department of Nephrology, First Hospital of Jilin University, Changchun, Jilin, China
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16
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Sandholm N, Dahlström EH, Groop PH. Genetic and epigenetic background of diabetic kidney disease. Front Endocrinol (Lausanne) 2023; 14:1163001. [PMID: 37324271 PMCID: PMC10262849 DOI: 10.3389/fendo.2023.1163001] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 05/10/2023] [Indexed: 06/17/2023] Open
Abstract
Diabetic kidney disease (DKD) is a severe diabetic complication that affects up to half of the individuals with diabetes. Elevated blood glucose levels are a key underlying cause of DKD, but DKD is a complex multifactorial disease, which takes years to develop. Family studies have shown that inherited factors also contribute to the risk of the disease. During the last decade, genome-wide association studies (GWASs) have emerged as a powerful tool to identify genetic risk factors for DKD. In recent years, the GWASs have acquired larger number of participants, leading to increased statistical power to detect more genetic risk factors. In addition, whole-exome and whole-genome sequencing studies are emerging, aiming to identify rare genetic risk factors for DKD, as well as epigenome-wide association studies, investigating DNA methylation in relation to DKD. This article aims to review the identified genetic and epigenetic risk factors for DKD.
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Affiliation(s)
- Niina Sandholm
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Emma H. Dahlström
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
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17
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Kim T, Nosella M, Bolik-Coulon N, Harkness R, Huang S, Kay L. Correlating histone acetylation with nucleosome core particle dynamics and function. Proc Natl Acad Sci U S A 2023; 120:e2301063120. [PMID: 37011222 PMCID: PMC10104578 DOI: 10.1073/pnas.2301063120] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/06/2023] [Indexed: 04/05/2023] Open
Abstract
Epigenetic modifications of chromatin play a critical role in regulating the fidelity of the genetic code and in controlling the translation of genetic information into the protein components of the cell. One key posttranslational modification is acetylation of histone lysine residues. Molecular dynamics simulations, and to a smaller extent experiment, have established that lysine acetylation increases the dynamics of histone tails. However, a systematic, atomic resolution experimental investigation of how this epigenetic mark, focusing on one histone at a time, influences the structural dynamics of the nucleosome beyond the tails, and how this translates into accessibility of protein factors such as ligases and nucleases, has yet to be performed. Herein, using NMR spectroscopy of nucleosome core particles (NCPs), we evaluate the effects of acetylation of each histone on tail and core dynamics. We show that for histones H2B, H3, and H4, the histone core particle dynamics are little changed, even though the tails have increased amplitude motions. In contrast, significant increases to H2A dynamics are observed upon acetylation of this histone, with the docking domain and L1 loop particularly affected, correlating with increased susceptibility of NCPs to nuclease digestion and more robust ligation of nicked DNA. Dynamic light scattering experiments establish that acetylation decreases inter-NCP interactions in a histone-dependent manner and facilitates the development of a thermodynamic model for NCP stacking. Our data show that different acetylation patterns result in nuanced changes to NCP dynamics, modulating interactions with other protein factors, and ultimately controlling biological output.
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Affiliation(s)
- Tae Hun Kim
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Chemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
| | - Michael L. Nosella
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
| | - Nicolas Bolik-Coulon
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Chemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
| | - Robert W. Harkness
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Chemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
| | - Shuya Kate Huang
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Chemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
| | - Lewis E. Kay
- Department of Molecular Genetics, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Biochemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Department of Chemistry, University of Toronto, Toronto, ONM5S 1A8, Canada
- Program in Molecular Medicine, Hospital for Sick Children, Toronto, ONM5G 1X8, Canada
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18
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Mohandes S, Doke T, Hu H, Mukhi D, Dhillon P, Susztak K. Molecular pathways that drive diabetic kidney disease. J Clin Invest 2023; 133:165654. [PMID: 36787250 PMCID: PMC9927939 DOI: 10.1172/jci165654] [Citation(s) in RCA: 164] [Impact Index Per Article: 82.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Kidney disease is a major driver of mortality among patients with diabetes and diabetic kidney disease (DKD) is responsible for close to half of all chronic kidney disease cases. DKD usually develops in a genetically susceptible individual as a result of poor metabolic (glycemic) control. Molecular and genetic studies indicate the key role of podocytes and endothelial cells in driving albuminuria and early kidney disease in diabetes. Proximal tubule changes show a strong association with the glomerular filtration rate. Hyperglycemia represents a key cellular stress in the kidney by altering cellular metabolism in endothelial cells and podocytes and by imposing an excess workload requiring energy and oxygen for proximal tubule cells. Changes in metabolism induce early adaptive cellular hypertrophy and reorganization of the actin cytoskeleton. Later, mitochondrial defects contribute to increased oxidative stress and activation of inflammatory pathways, causing progressive kidney function decline and fibrosis. Blockade of the renin-angiotensin system or the sodium-glucose cotransporter is associated with cellular protection and slowing kidney function decline. Newly identified molecular pathways could provide the basis for the development of much-needed novel therapeutics.
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Affiliation(s)
- Samer Mohandes
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Tomohito Doke
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hailong Hu
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Poonam Dhillon
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Katalin Susztak
- Renal, Electrolyte, and Hypertension Division, Department of Medicine;,Institute for Diabetes, Obesity, and Metabolism;,Department of Genetics; and,Kidney Innovation Center; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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19
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Liao Y, Chu C, Ma Q, Yan Y, Wang D, Sun Y, Wang Y, Hu J, Chen C, Mu J. Transient high salt intake causes epigenetic changes and leads to persistent inflammatory activation to produce "salt memory". J Nutr Biochem 2023; 115:109281. [PMID: 36758838 DOI: 10.1016/j.jnutbio.2023.109281] [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: 06/29/2022] [Revised: 11/21/2022] [Accepted: 02/03/2023] [Indexed: 02/10/2023]
Abstract
Transient high salt intake causes a sustained increase in blood pressure (BP) even after returning to a normal-salt diet, a phenomenon known as "salt memory." However, the molecular mechanisms of this phenomenon remain to be elucidated. Dahl salt-sensitive (SS) rats were fed a high-salt (8% NaCl) or high-salt diet and treated with drugs for 8 to 16 weeks and then returned to a normal-salt diet for 3 months. This study investigated the molecular mechanisms of salt memory and its mediation of SS hypertension and renal damage. We show that transient high salt intake caused persistent elevation of BP and exacerbation of kidney damage in Dahl SS rats even after returning to a normal-salt diet. Both epigenetic changes and inflammatory activation also persisted after resumption of a normal diet. Arterial BP, renal injury and the inflammatory response returned to normal levels in rats administered mycophenolate mofetil (MMF) during the 8-week period of high salt intake, resulting in the disappearance of salt memory. However, the vasodilator hydralazine did not ameliorate kidney damage or inflammatory activation, although it decreased BP to control levels. Transient high salt intake increased histone 3 lysine 4 monomethylation (H3K4me1) levels at the nuclear factor κB (NF-κB) subunit p65 promoter in SS rats, promoting p65 gene transcription and NF-κB activation and further leading to a series of inflammatory responses. Our findings demonstrate that transient high salt-induced epigenetic changes and persistent inflammatory activation play important roles in salt memory and its mediation of SS hypertension and renal damage.
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Affiliation(s)
- Yueyuan Liao
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Chao Chu
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Qiong Ma
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Yu Yan
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Dan Wang
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Yue Sun
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Yang Wang
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Jiawen Hu
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Chen Chen
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China
| | - Jianjun Mu
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China; Key Laboratory of Molecular Cardiology of Shaanxi Province, Xi'an Jiaotong University, Xi'an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, China.
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20
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Olivieri F, Prattichizzo F, Lattanzio F, Bonfigli AR, Spazzafumo L. Antifragility and antiinflammaging: Can they play a role for a healthy longevity? Ageing Res Rev 2023; 84:101836. [PMID: 36574863 DOI: 10.1016/j.arr.2022.101836] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 12/14/2022] [Accepted: 12/21/2022] [Indexed: 12/25/2022]
Abstract
One of the most exciting challenges of the research on aging is to explain how the environmental factors interact with the genetic background to modulate the chances to reach the extreme limit of human life in healthy conditions. The complex epigenetic mechanisms can explain both the interaction between DNA and environmental factors, and the long-distance persistence of lifestyle effects, due to the so called "epigenetic memory". One of the most extensively investigated theories on aging focuses on the inflammatory responses, suggesting that the age-related progression of low-grade and therefore for long time subclinical, chronic, systemic, inflammatory process, named "inflammaging", could be the most relevant risk factor for the development and progression of the most common age-related diseases and ultimately of death. The results of many studies on long-lived people, especially on centenarians, suggested that healthy old people can cope with inflammaging upregulating the antiinflammaging responses. Overall, a genetic make-up coding for a strong antiinflammaging response and an age-related ability to remodel key metabolic pathways to cope with a plethora of antigens and stressors seem to be the best ways for reach the extreme limit of human lifespan in health status. In this scenario, we wondered if the antifragility concept, recently developed in the framework of business and risk analysis, could add some information to disentangle the heterogeneous nature of the aging process in human. The antifragility is the property of the complex systems to increase their performances because of high stress. Based on this theory we were wondering if some subjects could be able to modulate faster than others their epigenome to cope with a plethora of stressors during life, probably modulating the inflammatory and anti-inflammatory responses. In this framework, antifragility could share some common mechanisms with anti-inflammaging, modulating the ability to restrain the inflammatory responses, so that antifragility and antiinflammaging could be viewed as different pieces of the same puzzle, both impinging upon the chances to travel along the healthy aging trajectory.
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Affiliation(s)
- Fabiola Olivieri
- Department of Clinical and Molecular Sciences, DISCLIMO, Università Politecnica Delle Marche, Ancona, Italy; Clinica di Medicina di Laboratorio e di Precisione, IRCCS INRCA, Ancona, Italy.
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21
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Di Pietrantonio N, Di Tomo P, Mandatori D, Formoso G, Pandolfi A. Diabetes and Its Cardiovascular Complications: Potential Role of the Acetyltransferase p300. Cells 2023; 12:431. [PMID: 36766773 PMCID: PMC9914144 DOI: 10.3390/cells12030431] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/17/2023] [Accepted: 01/24/2023] [Indexed: 01/31/2023] Open
Abstract
Diabetes has been shown to accelerate vascular senescence, which is associated with chronic inflammation and oxidative stress, both implicated in the development of endothelial dysfunction. This condition represents the initial alteration linking diabetes to related cardiovascular (CV) complications. Recently, it has been hypothesised that the acetyltransferase, p300, may contribute to establishing an early vascular senescent phenotype, playing a relevant role in diabetes-associated inflammation and oxidative stress, which drive endothelial dysfunction. Specifically, p300 can modulate vascular inflammation through epigenetic mechanisms and transcription factors acetylation. Indeed, it regulates the inflammatory pathway by interacting with nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit (NF-κB p65) or by inducing its acetylation, suggesting a crucial role of p300 as a bridge between NF-κB p65 and the transcriptional machinery. Additionally, p300-mediated epigenetic modifications could be upstream of the activation of inflammatory cytokines, and they may induce oxidative stress by affecting the production of reactive oxygen species (ROS). Because several in vitro and in vivo studies shed light on the potential use of acetyltransferase inhibitors, a better understanding of the mechanisms underlying the role of p300 in diabetic vascular dysfunction could help in finding new strategies for the clinical management of CV diseases related to diabetes.
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Affiliation(s)
- Nadia Di Pietrantonio
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Pamela Di Tomo
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Domitilla Mandatori
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Gloria Formoso
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
| | - Assunta Pandolfi
- Department of Medical, Oral and Biotechnological Sciences, Center for Advanced Studies and Technology-CAST, University G. D’Annunzio of Chieti-Pescara, 66100 Chieti, Italy
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22
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Omar M, Alexiou M, Rekhi UR, Lehmann K, Bhardwaj A, Delyea C, Elahi S, Febbraio M. DNA methylation changes underlie the long-term association between periodontitis and atherosclerotic cardiovascular disease. Front Cardiovasc Med 2023; 10:1164499. [PMID: 37153468 PMCID: PMC10160482 DOI: 10.3389/fcvm.2023.1164499] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 03/22/2023] [Indexed: 05/09/2023] Open
Abstract
Periodontitis, the leading cause of adult tooth loss, has been identified as an independent risk factor for cardiovascular disease (CVD). Studies suggest that periodontitis, like other CVD risk factors, shows the persistence of increased CVD risk even after mitigation. We hypothesized that periodontitis induces epigenetic changes in hematopoietic stem cells in the bone marrow (BM), and such changes persist after the clinical elimination of the disease and underlie the increased CVD risk. We used a BM transplant approach to simulate the clinical elimination of periodontitis and the persistence of the hypothesized epigenetic reprogramming. Using the low-density lipoprotein receptor knockout (LDLRo ) atherosclerosis mouse model, BM donor mice were fed a high-fat diet to induce atherosclerosis and orally inoculated with Porphyromonas gingivalis (Pg), a keystone periodontal pathogen; the second group was sham-inoculated. Naïve LDLR o mice were irradiated and transplanted with BM from one of the two donor groups. Recipients of BM from Pg-inoculated donors developed significantly more atherosclerosis, accompanied by cytokine/chemokines that suggested BM progenitor cell mobilization and were associated with atherosclerosis and/or PD. Using whole-genome bisulfite sequencing, 375 differentially methylated regions (DMRs) and global hypomethylation in recipients of BM from Pg-inoculated donors were observed. Some DMRs pointed to the involvement of enzymes with major roles in DNA methylation and demethylation. In validation assays, we found a significant increase in the activity of ten-eleven translocase-2 and a decrease in the activity of DNA methyltransferases. Plasma S-adenosylhomocysteine levels were significantly higher, and the S-adenosylmethionine to S-adenosylhomocysteine ratio was decreased, both of which have been associated with CVD. These changes may be related to increased oxidative stress as a result of Pg infection. These data suggest a novel and paradigm-shifting mechanism in the long-term association between periodontitis and atherosclerotic CVD.
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23
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Iron: Not Just a Passive Bystander in AITD. Nutrients 2022; 14:nu14214682. [PMID: 36364944 PMCID: PMC9658435 DOI: 10.3390/nu14214682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/27/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Autoimmune thyroid disease (AITD) is the most prevalent autoimmune disease all over the world and the most frequent cause of hypothyroidism in areas of iodine sufficiency. The pathogenesis of AITD is multifactorial and depends on complex interactions between genetic and environmental factors, with epigenetics being the crucial link. Iron deficiency (ID) can reduce the activities of thyroid peroxidase and 5′-deiodinase, inhibit binding of triiodothyronine to its nuclear receptor, and cause slower utilization of T3 from the serum pool. Moreover, ID can disturb the functioning of the immune system, increasing the risk of autoimmune disorders. ID can be responsible for residual symptoms that may persist in patients with AITD, even if their thyrometabolic status has been controlled. The human lifestyle in the 21st century is inevitably associated with exposure to chemical compounds, pathogens, and stress, which implies an increased risk of autoimmune disorders and thyroid dysfunction. To summarize, in our paper we discuss how iron deficiency can impair the functions of the immune system, cause epigenetic changes in human DNA, and potentiate tissue damage by chemicals acting as thyroid disruptors.
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24
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Tanemoto F, Nangaku M, Mimura I. Epigenetic memory contributing to the pathogenesis of AKI-to-CKD transition. Front Mol Biosci 2022; 9:1003227. [PMID: 36213117 PMCID: PMC9532834 DOI: 10.3389/fmolb.2022.1003227] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 08/24/2022] [Indexed: 11/18/2022] Open
Abstract
Epigenetic memory, which refers to the ability of cells to retain and transmit epigenetic marks to their daughter cells, maintains unique gene expression patterns. Establishing programmed epigenetic memory at each stage of development is required for cell differentiation. Moreover, accumulating evidence shows that epigenetic memory acquired in response to environmental stimuli may be associated with diverse diseases. In the field of kidney diseases, the “memory” of acute kidney injury (AKI) leads to progression to chronic kidney disease (CKD); epidemiological studies show that patients who recover from AKI are at high risk of developing CKD. The underlying pathological processes include nephron loss, maladaptive epithelial repair, inflammation, and endothelial injury with vascular rarefaction. Further, epigenetic alterations may contribute as well to the pathophysiology of this AKI-to-CKD transition. Epigenetic changes induced by AKI, which can be recorded in cells, exert long-term effects as epigenetic memory. Considering the latest findings on the molecular basis of epigenetic memory and the pathophysiology of AKI-to-CKD transition, we propose here that epigenetic memory contributing to AKI-to-CKD transition can be classified according to the presence or absence of persistent changes in the associated regulation of gene expression, which we designate “driving” memory and “priming” memory, respectively. “Driving” memory, which persistently alters the regulation of gene expression, may contribute to disease progression by activating fibrogenic genes or inhibiting renoprotective genes. This process may be involved in generating the proinflammatory and profibrotic phenotypes of maladaptively repaired tubular cells after kidney injury. “Priming” memory is stored in seemingly successfully repaired tubular cells in the absence of detectable persistent phenotypic changes, which may enhance a subsequent transcriptional response to the second stimulus. This type of memory may contribute to AKI-to-CKD transition through the cumulative effects of enhanced expression of profibrotic genes required for wound repair after recurrent AKI. Further understanding of epigenetic memory will identify therapeutic targets of future epigenetic intervention to prevent AKI-to-CKD transition.
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Karamanakos G, Kokkinos A, Dalamaga M, Liatis S. Highlighting the Role of Obesity and Insulin Resistance in Type 1 Diabetes and Its Associated Cardiometabolic Complications. Curr Obes Rep 2022; 11:180-202. [PMID: 35931912 DOI: 10.1007/s13679-022-00477-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/29/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW This narrative review appraises research data on the potentially harmful effect of obesity and insulin resistance (IR) co-existence with type 1 diabetes mellitus (T1DM)-related cardiovascular (CVD) complications and evaluates possible therapeutic options. RECENT FINDINGS Obesity and IR have increasingly been emerging in patients with T1DM. Genetic, epigenetic factors, and subcutaneous insulin administration are implicated in the pathogenesis of this coexistence. Accumulating evidence implies that the concomitant presence of obesity and IR is an independent predictor of worse CVD outcomes. The prevalence of obesity and IR has increased in patients with T1DM. This increase can be partly attributed to general population trends but, additionally, to iatrogenic weight gain caused by insulin treatment. This association might be the missing link explaining the excess CVD burden observed in patients with T1DM despite optimal glycemic control. Data on newer agents for type 2 diabetes mellitus (T2DM) treatment are unraveling novel ways to challenge this aggravating coexistence.
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Affiliation(s)
- Georgios Karamanakos
- First Department of Propaedeutic Internal Medicine, Medical School, National Kapodistrian University of Athens, Laiko General Hospital, 17 Agiou Thoma Street, Athens, 11527, Greece.
| | - Alexander Kokkinos
- First Department of Propaedeutic Internal Medicine, Medical School, National Kapodistrian University of Athens, Laiko General Hospital, 17 Agiou Thoma Street, Athens, 11527, Greece
| | - Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Stavros Liatis
- First Department of Propaedeutic Internal Medicine, Medical School, National Kapodistrian University of Athens, Laiko General Hospital, 17 Agiou Thoma Street, Athens, 11527, Greece
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Kushwaha K, Garg SS, Gupta J. Targeting epigenetic regulators for treating diabetic nephropathy. Biochimie 2022; 202:146-158. [PMID: 35985560 DOI: 10.1016/j.biochi.2022.08.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/01/2022] [Accepted: 08/02/2022] [Indexed: 11/25/2022]
Abstract
Diabetes is accompanied by the worsening of kidney functions. The reasons for kidney dysfunction mainly include high blood pressure (BP), high blood sugar levels, and genetic makeup. Vascular complications are the leading cause of the end-stage renal disorder (ESRD) and death of diabetic patients. Epigenetics has emerged as a new area to explain the inheritance of non-mendelian conditions like diabetic kidney diseases. Aberrant post-translational histone modifications (PTHMs), DNA methylation (DNAme), and miRNA constitute major epigenetic mechanisms that progress diabetic nephropathy (DN). Increased blood sugar levels alter PTHMs, DNAme, and miRNA in kidney cells results in aberrant gene expression that causes fibrosis, accumulation of extracellular matrix (ECM), increase in reactive oxygen species (ROS), and renal injuries. Histone acetylation (HAc) and histone deacetylation (HDAC) are the most studied epigenetic modifications with implications in the occurrence of kidney disorders. miRNAs induced by hyperglycemia in renal cells are also responsible for ECM accumulation and dysfunction of the glomerulus. In this review, we highlight the role of epigenetic modifications in DN progression and current strategies employed to ameliorate DN.
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Affiliation(s)
- Kriti Kushwaha
- Department of Biotechnology, School of Bioengineering and Bioscience, Lovely Professional University, Phagwara, Punjab, India
| | - Sourbh Suren Garg
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India
| | - Jeena Gupta
- Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India.
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27
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Chen Z, Natarajan R. Epigenetic modifications in metabolic memory: What are the memories, and can we erase them? Am J Physiol Cell Physiol 2022; 323:C570-C582. [PMID: 35785987 PMCID: PMC9359656 DOI: 10.1152/ajpcell.00201.2022] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/29/2022] [Accepted: 06/29/2022] [Indexed: 11/22/2022]
Abstract
Inherent and acquired abnormalities in gene regulation due to the influence of genetics and epigenetics (traits related to environment rather than genetic factors) underlie many diseases including diabetes. Diabetes could lead to multiple complications including retinopathy, nephropathy, and cardiovascular disease that greatly increase morbidity and mortality. Epigenetic changes have also been linked to diabetes-related complications. Genes associated with many pathophysiological features of these vascular complications (e.g., inflammation, fibrosis, and oxidative stress) can be regulated by epigenetic mechanisms involving histone posttranslational modifications, DNA methylation, changes in chromatin structure/remodeling, and noncoding RNAs. Intriguingly, these epigenetic changes triggered during early periods of hyperglycemic exposure and uncontrolled diabetes are not immediately corrected even after restoration of normoglycemia and metabolic balance. This latency in effect across time and conditions is associated with persistent development of complications in diabetes with prior history of poor glycemic control, termed as metabolic memory or legacy effect. Epigenetic modifications are generally reversible and provide a window of therapeutic opportunity to ameliorate cellular dysfunction and mitigate or "erase" metabolic memory. Notably, trained immunity and related epigenetic changes transmitted from hematopoietic stem cells to innate immune cells have also been implicated in metabolic memory. Hence, identification of epigenetic variations at candidate genes, or epigenetic signatures genome-wide by epigenome-wide association studies can aid in prompt diagnosis to prevent progression of complications and identification of much-needed new therapeutic targets. Herein, we provide a review of epigenetics and epigenomics in metabolic memory of diabetic complications covering the current basic research, clinical data, and translational implications.
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Affiliation(s)
- Zhuo Chen
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of City of Hope, Duarte, California
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28
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Liu N, Liu Y, Dong D, Yu J, Yuan H. Effects of Inflammatory Factor Expression Regulated by 12/15 Lipoxygenase on Obesity-Related Nephropathy. Nutrients 2022; 14:nu14132743. [PMID: 35807921 PMCID: PMC9268756 DOI: 10.3390/nu14132743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 06/15/2022] [Accepted: 06/25/2022] [Indexed: 02/01/2023] Open
Abstract
Background: It has been demonstrated that 12/15-lipoxygenase (LO) contributes to insulin resistance by promoting beta cells’ exposure to inflammation. We investigate the mechanism by which 12/15-LO regulates the expression of inflammatory factors in obesity-related glomerular disease (ORG). Methods: Glomerular mesangial cells were treated with metabolite of 12/15-LO, and the expression of inflammatory factors was measured. Cell histones methylation in 12/15-LO related metabolic memory process were evaluated by chromatin immunoprecipitation (ChIP) assays. Wild-type (WT) and 12/15-LO knockout mice were fed a high-fat diet (HFD) to induce ORG. Results: 12(S)-HETE increased TNF-α, MCP-1, and IL-6 mRNA expression. Inhibition of 12/15-LO reduced the expression of inflammatory factors stimulated by PA or TNF-α. ChIP assays showed that 12(S)-HETE increased H3K4me modification in the TNF-α, IL-6, and MCP-1 gene promoters, and decreased H3K9me3 modification in the MCP-1 and IL-6 gene promoter. Urinary albumin excretion was greater in HFD-fed than in standard fat diet-fed mice, but both urinary protein and microalbumin amounts were lower in HFD-fed 12/15-LO knockout than in WT mice. The levels of TNF-α, IL-6, and MCP-1 in serum and renal cortex were higher in WT than in 12/15-LO knockout mice. Conclusions: 12/15-LO may regulate the expression of inflammatory factors in ORG by methylation of histones in the promoter regions of genes encoding inflammatory factors, sustaining the inflammatory phenotype of ORG.
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Affiliation(s)
- Nian Liu
- Department of Urology, First Hospital of Jilin University, Xin Min Street 1, Changchun 130021, China;
| | - Yang Liu
- Department of Nephrology, First Hospital of Jilin University, Xin Min Street 1, Changchun 130021, China; (Y.L.); (D.D.); (J.Y.)
| | - Dan Dong
- Department of Nephrology, First Hospital of Jilin University, Xin Min Street 1, Changchun 130021, China; (Y.L.); (D.D.); (J.Y.)
| | - Jinyu Yu
- Department of Nephrology, First Hospital of Jilin University, Xin Min Street 1, Changchun 130021, China; (Y.L.); (D.D.); (J.Y.)
| | - Hang Yuan
- Department of Nephrology, First Hospital of Jilin University, Xin Min Street 1, Changchun 130021, China; (Y.L.); (D.D.); (J.Y.)
- Correspondence: ; Tel.: +86-17604307906
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29
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Liao Y, Chu C, Yan Y, Wang D, Ma Q, Gao K, Sun Y, Hu J, Zheng W, Mu J. High Dietary Salt Intake Is Associated With Histone Methylation in Salt-Sensitive Individuals. Front Nutr 2022; 9:857562. [PMID: 35571911 PMCID: PMC9097549 DOI: 10.3389/fnut.2022.857562] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/14/2022] [Indexed: 11/13/2022] Open
Abstract
Background High salt diet is one of the important risk factors of hypertension and cardiovascular diseases. Increasingly strong evidence supports epigenetic mechanisms' significant role in hypertension. We aimed to explore associations of epigenetics with high salt diet, salt sensitivity (SS), and SS hypertension. Methods We conducted a dietary intervention study of chronic salt loading in 339 subjects from northern China in 2004 and divided the subjects into different salt sensitivity phenotypes. A total of 152 participants were randomly selected from the same cohort for follow-up in 2018 to explore the effect of a high-salt diet on serum monomethylation of H3K4 (H3K4me1), histone methyltransferase Set7, and lysine-specific demethylase 1 (LSD-1). Results Among SS individuals, the blood pressure (SBP: 140.8 vs. 132.9 mmHg; MAP: 104.2 vs. 98.7 mmHg) and prevalence of hypertension (58.8 vs. 32.8%) were significantly higher in high salt (HS) diet group than in normal salt (NS) diet group, but not in the salt-resistant (SR) individuals (P > 0.05). Serum H3K4me1 level (287.3 vs. 179.7 pg/ml, P < 0.05) significantly increased in HS group of SS individuals, but not in SR individuals. We found daily salt intake in SS individuals was positively correlated with serum H3K4me1 (r = 0.322, P = 0.005) and Set7 (r = 0.340, P = 0.005) levels after adjusting for age and gender, but not with LSD-1 (r = -0.137, P = 0.251). In addition, positive correlation between the serum H3K4me1 level and Set7 level (r = 0.326, P = 0.007) was also found in SS individuals. These correlations were not evident in SR individuals. Conclusion Our study indicates that high salt diet increases the serum H3K4me1 and Set7 levels in SS individuals.
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Affiliation(s)
- Yueyuan Liao
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Chao Chu
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Yu Yan
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Dan Wang
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Qiong Ma
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Ke Gao
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Yue Sun
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Jiawen Hu
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Wenling Zheng
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
| | - Jianjun Mu
- Department of Cardiology, First Affiliated Hospital of Medical School, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Molecular Cardiology, Xi'an Jiaotong University, Xi'an, China.,Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, China
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30
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Fiorello ML, Treweeke AT, Macfarlane DP, Megson IL. Intermittent exposure of cultured endothelial cells to physiologically relevant fructose concentrations has a profound impact on nitric oxide production and bioenergetics. PLoS One 2022; 17:e0267675. [PMID: 35560114 PMCID: PMC9106152 DOI: 10.1371/journal.pone.0267675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/12/2022] [Indexed: 11/18/2022] Open
Abstract
Hyperglycaemia is known to induce endothelial dysfunction and changes in metabolic function, which could be implicated in diabetes-induced cardiovascular disease. To date, however, little is known about the impact of physiologically relevant concentrations of fructose on endothelial cells. A novel in vitro model was devised to establish the impact of substitution of a small proportion of glucose with an equal concentration (0.1 mM or 1 mM) of fructose on EA.hy926 endothelial cells during periodic carbohydrate “meals” superimposed on a normoglycaemic (5.5 mM) background. Parallel experiments were conducted using meals consisting of normoglycaemic glucose, intermediate glucose (12.5 mM) or profound hyperglycaemia (25 mM), each delivered for 2 h, with and without substituted fructose over 50 h. Outcome measures included nitrite as a surrogate marker of the mediator of healthy endothelial function, nitric oxide (NO), and a range of bioenergetic parameters using a metabolic analyser. Despite its relatively low proportion of carbohydrate load, intermittent fructose induced a substantial reduction (approximately 90%) in NO generation in cells treated with either concentration of fructose. Cell markers of oxidative stress were not altered by this treatment regimen. However, the cells experienced a marked increase in metabolic activity induced by fructose, irrespective of the glucose concentration delivered simultaneously in the “meals”. Indeed, glucose alone failed to induce any metabolic impact in this model. Key metabolic findings were a 2-fold increase in basal oxygen consumption rate and a similar change in extracellular acidification rate–a marker of glycolysis. Non-metabolic oxygen consumption also increased substantially in cells exposed to fructose. There was no difference between results with 0.1 mM fructose and those with 1 mM fructose. Low, physiologically relevant concentrations of fructose, delivered in a pattern that mimics mealtime consumption, had a profound impact on endothelial function and bioenergetics in an in vitro cell model. The results suggest that endothelial cells are exquisitely sensitive to circulating fructose; the potential ensuing dysfunction could have major implications for development of atherosclerotic disease associated with high fructose consumption.
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Affiliation(s)
- Maria Luisa Fiorello
- Division of Biomedical Sciences, University of the Highlands & Islands, Inverness, United Kingdom
| | - Andrew T. Treweeke
- Division of Biomedical Sciences, University of the Highlands & Islands, Inverness, United Kingdom
| | - David P. Macfarlane
- Department of Diabetes, NHS Highland, Raigmore Hospital, Inverness, United Kingdom
| | - Ian L. Megson
- Division of Biomedical Sciences, University of the Highlands & Islands, Inverness, United Kingdom
- * E-mail:
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The Role of Epigenetic Modifications in Late Complications in Type 1 Diabetes. Genes (Basel) 2022; 13:genes13040705. [PMID: 35456511 PMCID: PMC9029845 DOI: 10.3390/genes13040705] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 11/29/2022] Open
Abstract
Type 1 diabetes is a chronic autoimmune disease in which the destruction of pancreatic β cells leads to hyperglycemia. The prevention of hyperglycemia is very important to avoid or at least postpone the development of micro- and macrovascular complications, also known as late complications. These include diabetic retinopathy, chronic renal failure, diabetic neuropathy, and cardiovascular diseases. The impact of long-term hyperglycemia has been shown to persist long after the normalization of blood glucose levels, a phenomenon known as metabolic memory. It is believed that epigenetic mechanisms such as DNA methylation, histone modifications, and microRNAs, play an important role in metabolic memory. The aim of this review is to address the impact of long-term hyperglycemia on epigenetic marks in late complications of type 1 diabetes.
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Keating ST, El-Osta A. Metaboloepigenetics in cancer, immunity and cardiovascular disease. Cardiovasc Res 2022; 119:357-370. [PMID: 35389425 PMCID: PMC10064843 DOI: 10.1093/cvr/cvac058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/12/2022] [Accepted: 02/02/2022] [Indexed: 11/14/2022] Open
Abstract
The influence of cellular metabolism on epigenetic pathways are well documented but misunderstood. Scientists have long known of the metabolic impact on epigenetic determinants. More often than not, that title role for DNA methylation was portrayed by the metabolite SAM or S-adenosylmethionine. Technically speaking there are many other metabolites that drive epigenetic processes that instruct seemingly distant - yet highly connect pathways - and none more so than our understanding of the cancer epigenome. Recent studies have shown that available energy link the extracellular environment to influence cellular responses. This focused review examines the recent interest in epigenomics and casts cancer, metabolism and immunity in unfamiliar roles - cooperating. There are not only language lessons from cancer research, we have come round to appreciate that reaching into areas previously thought of as too distinct are also object lessons in understanding health and disease. The Warburg effect is one such signature of how glycolysis influences metabolic shift during oncogenesis. That shift in metabolism - now recognised as central to proliferation in cancer biology - influence core enzymes that not only control gene expression but are also central to replication, condensation and the repair of nucleic acid. These nuclear processes rely on metabolism and with glucose at center stage the role of respiration and oxidative metabolism are now synonymous with the mitochondria as the powerhouses of metaboloepigenetics. The emerging evidence for metaboloepigenetics in trained innate immunity has revealed recognisable signalling pathways with antecedent extracellular stimulation. With due consideration to immunometabolism we discuss the striking signalling similarities influencing these core pathways. The immunometabolic-epigenetic axis in cardiovascular disease has deeply etched connections with inflammation and we examine the chromatin template as a carrier of epigenetic indices that determine the expression of genes influencing atherosclerosis and vascular complications of diabetes.
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Affiliation(s)
- Samuel T Keating
- Department of Biology, University of Copenhagen, Copenhagen DK-2200, Denmark
| | - Assam El-Osta
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.,Epigenetics in Human Health and Disease Laboratory, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR.,Hong Kong Institute of Diabetes and Obesity, Prince of Wales Hospital, The Chinese University of Hong Kong, 3/F Lui Che Woo Clinical Sciences Building, 30-32 Ngan Shing Street, Sha Tin, Hong Kong SAR.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR.,University College Copenhagen, Faculty of Health, Department of Technology, Biomedical Laboratory Science, Copenhagen, Denmark
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Naserrudin NA, Jeffree MS, Kaur N, Syed Abdul Rahim SS, Ibrahim MY. Diabetic retinopathy among type 2 diabetes mellitus patients in Sabah primary health clinics–Addressing the underlying factors. PLoS One 2022; 17:e0261249. [PMID: 35089931 PMCID: PMC8797256 DOI: 10.1371/journal.pone.0261249] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 11/28/2021] [Indexed: 11/18/2022] Open
Abstract
Every person diagnosed with diabetes mellitus (T2DM) is at risk of developing Diabetic retinopathy (DR). Thus, DR is one of the major chronic microvascular complications of T2DM. However, in Malaysia, research about DR is still scarce. This study aimed to determine the prevalence of DR among diabetic patients across 46 primary healthcare clinics in Sabah, Malaysia. Secondly, it purported to identify the factors influencing the development of DR. This cross-sectional study involved a total of 22,345 Type 2 diabetes mellitus (T2DM) patients in the Sabah Diabetic Registry from 2008 to 2015. Of the 22,345 T2DM patients, 13.5% (n = 3,029) of them were diagnosed with DR. Multiple logistic regression revealed seven major risk factors of DR, i.e. patients with diabetic foot ulcer [aOR: 95% CI 3.08 (1.96–4.85)], patients with diabetic nephropathy [aOR: 95% CI 2.47 (2.13–2.86)], hypertension [aOR: 95% CI 1.63 (1.43–1.87)], dyslipidaemia [aOR: 95% CI 1.30 (1.17–1.44)], glycated haemoglobin [(HbA1c) > 6.5 (aOR: 95% CI 1.25 (1.14–1.38)], duration of diabetes mellitus (T2DM) [aOR: 95% CI 1.06 (1.05–1.07)] and age of patient [aOR: 95% CI 1.01 (1.00–1.02)] respectively. DR is a preventable complication. The effective glycaemic control is crucial in preventing DR. In minimizing the prevalence of DR, the healthcare authorities should institute programmes to induce awareness on the management of DR’s risk factors among patient and practitioner.
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Affiliation(s)
- Nurul Athirah Naserrudin
- Department of Community Health, Faculty of Medicine, National University of Malaysia, Cheras, Kuala Lumpur, Malaysia
- Sabah State Health Department, Malaysia Ministry of Health, Sabah, Malaysia
- * E-mail:
| | - Mohammad Saffree Jeffree
- Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu Sabah, Malaysia
| | - Nirmal Kaur
- Sabah State Health Department, Malaysia Ministry of Health, Sabah, Malaysia
| | | | - Mohd Yusof Ibrahim
- Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu Sabah, Malaysia
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Kuo FC, Chao CT, Lin SH. The Dynamics and Plasticity of Epigenetics in Diabetic Kidney Disease: Therapeutic Applications Vis-à-Vis. Int J Mol Sci 2022; 23:ijms23020843. [PMID: 35055027 PMCID: PMC8777872 DOI: 10.3390/ijms23020843] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 01/11/2022] [Accepted: 01/11/2022] [Indexed: 02/01/2023] Open
Abstract
Chronic kidney disease (CKD) refers to the phenomenon of progressive decline in the glomerular filtration rate accompanied by adverse consequences, including fluid retention, electrolyte imbalance, and an increased cardiovascular risk compared to those with normal renal function. The triggers for the irreversible renal function deterioration are multifactorial, and diabetes mellitus serves as a major contributor to the development of CKD, namely diabetic kidney disease (DKD). Recently, epigenetic dysregulation emerged as a pivotal player steering the progression of DKD, partly resulting from hyperglycemia-associated metabolic disturbances, rising oxidative stress, and/or uncontrolled inflammation. In this review, we describe the major epigenetic molecular mechanisms, followed by summarizing current understandings of the epigenetic alterations pertaining to DKD. We highlight the epigenetic regulatory processes involved in several crucial renal cell types: Mesangial cells, podocytes, tubular epithelia, and glomerular endothelial cells. Finally, we highlight epigenetic biomarkers and related therapeutic candidates that hold promising potential for the early detection of DKD and the amelioration of its progression.
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Affiliation(s)
- Feng-Chih Kuo
- National Defense Medical Center, Department of Internal Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, Taipei 114, Taiwan
| | - Chia-Ter Chao
- Department of Internal Medicine, Nephrology Division, National Taiwan University Hospital, Taipei 100, Taiwan
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei 100, Taiwan
- Department of Internal Medicine, Nephrology Division, National Taiwan University College of Medicine, Taipei 100, Taiwan
| | - Shih-Hua Lin
- National Defense Medical Center, Graduate Institute of Medical Sciences, Taipei 114, Taiwan
- National Defense Medical Center, Department of Internal Medicine, Nephrology Division, Taipei 114, Taiwan
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Dinić S, Arambašić Jovanović J, Uskoković A, Mihailović M, Grdović N, Tolić A, Rajić J, Đorđević M, Vidaković M. Oxidative stress-mediated beta cell death and dysfunction as a target for diabetes management. Front Endocrinol (Lausanne) 2022; 13:1006376. [PMID: 36246880 PMCID: PMC9554708 DOI: 10.3389/fendo.2022.1006376] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/05/2022] [Indexed: 11/14/2022] Open
Abstract
The biggest drawback of a current diabetes therapy is the treatment of the consequences not the cause of the disease. Regardless of the diabetes type, preservation and recovery of functional pancreatic beta cells stands as the biggest challenge in the treatment of diabetes. Free radicals and oxidative stress are among the major mediators of autoimmune destruction of beta cells in type 1 diabetes (T1D) or beta cell malfunction and death provoked by glucotoxicity and insulin resistance in type 2 diabetes (T2D). Additionally, oxidative stress reduces functionality of beta cells in T2D by stimulating their de-/trans-differentiation through the loss of transcription factors critical for beta cell development, maturity and regeneration. This review summarizes up to date clarified redox-related mechanisms involved in regulating beta cell identity and death, underlining similarities and differences between T1D and T2D. The protective effects of natural antioxidants on the oxidative stress-induced beta cell failure were also discussed. Considering that oxidative stress affects epigenetic regulatory mechanisms involved in the regulation of pancreatic beta cell survival and insulin secretion, this review highlighted huge potential of epigenetic therapy. Special attention was paid on application of the state-of-the-art CRISPR/Cas9 technology, based on targeted epigenome editing with the purpose of changing the differentiation state of different cell types, making them insulin-producing with ability to attenuate diabetes. Clarification of the above-mentioned mechanisms could provide better insight into diabetes etiology and pathogenesis, which would allow development of novel, potentially more efficient therapeutic strategies for the prevention or reversion of beta cell loss.
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36
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Zhan J, Chen C, Wang DW, Li H. Hyperglycemic memory in diabetic cardiomyopathy. Front Med 2021; 16:25-38. [PMID: 34921674 DOI: 10.1007/s11684-021-0881-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 06/25/2021] [Indexed: 12/26/2022]
Abstract
Cardiovascular diseases account for approximately 80% of deaths among individuals with diabetes mellitus, with diabetic cardiomyopathy as the major diabetic cardiovascular complication. Hyperglycemia is a symptom that abnormally activates multiple downstream pathways and contributes to cardiac hypertrophy, fibrosis, apoptosis, and other pathophysiological changes. Although glycemic control has long been at the center of diabetes therapy, multicenter randomized clinical studies have revealed that intensive glycemic control fails to reduce heart failure-associated hospitalization and mortality in patients with diabetes. This finding indicates that hyperglycemic stress persists in the cardiovascular system of patients with diabetes even if blood glucose level is tightly controlled to the normal level. This process is now referred to as hyperglycemic memory (HGM) phenomenon. We briefly reviewed herein the current advances that have been achieved in research on the underlying mechanisms of HGM in diabetic cardiomyopathy.
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Affiliation(s)
- Jiabing Zhan
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China
| | - Chen Chen
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China
| | - Dao Wen Wang
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China.
| | - Huaping Li
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China.
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Bompada P, Goncalves I, Wu C, Gao R, Sun J, Mir BA, Luan C, Renström E, Groop L, Weng J, Hansson O, Edsfeldt A, De Marinis Y. Epigenome-Wide Histone Acetylation Changes in Peripheral Blood Mononuclear Cells in Patients with Type 2 Diabetes and Atherosclerotic Disease. Biomedicines 2021; 9:biomedicines9121908. [PMID: 34944721 PMCID: PMC8698994 DOI: 10.3390/biomedicines9121908] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/30/2021] [Accepted: 12/06/2021] [Indexed: 11/16/2022] Open
Abstract
There is emerging evidence of an association between epigenetic modifications, glycemic control and atherosclerosis risk. In this study, we mapped genome-wide epigenetic changes in patients with type 2 diabetes (T2D) and advanced atherosclerotic disease. We performed chromatin immunoprecipitation sequencing (ChIP-seq) using a histone 3 lysine 9 acetylation (H3K9ac) mark in peripheral blood mononuclear cells from patients with atherosclerosis with T2D (n = 8) or without T2D (ND, n = 10). We mapped epigenome changes and identified 23,394 and 13,133 peaks in ND and T2D individuals, respectively. Out of all the peaks, 753 domains near the transcription start site (TSS) were unique to T2D. We found that T2D in atherosclerosis leads to an H3K9ac increase in 118, and loss in 63 genomic regions. Furthermore, we discovered an association between the genomic locations of significant H3K9ac changes with genetic variants identified in previous T2D GWAS. The transcription factor 7-like 2 (TCF7L2) rs7903146, together with several human leukocyte antigen (HLA) variants, were among the domains with the most dramatic changes of H3K9ac enrichments. Pathway analysis revealed multiple activated pathways involved in immunity, including type 1 diabetes. Our results present novel evidence on the interaction between genetics and epigenetics, as well as epigenetic changes related to immunity in patients with T2D and advanced atherosclerotic disease.
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Affiliation(s)
- Pradeep Bompada
- Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden; (P.B.); (C.W.); (B.A.M.); (C.L.); (E.R.); (L.G.); (O.H.)
| | - Isabel Goncalves
- Cardiovascular Research-Translational Studies, Institution of Clinical Science Malmö, Lund University, 20502 Malmö, Sweden; (I.G.); (J.S.); (A.E.)
- Department of Cardiology, Skåne University Hospital, 20502 Malmö, Sweden
| | - Chuanyan Wu
- Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden; (P.B.); (C.W.); (B.A.M.); (C.L.); (E.R.); (L.G.); (O.H.)
- School of Control Science and Engineering, Shandong University, Jinan 250061, China
- School of Intelligent Engineering, Shandong Management University, Jinan 250100, China
| | - Rui Gao
- School of Control Science and Engineering, Shandong University, Jinan 250061, China
- Correspondence: (R.G.); (Y.D.M.); Tel.: +86-135-0531-8418 (R.G.); +46-760-384-868 (Y.D.M.)
| | - Jiangming Sun
- Cardiovascular Research-Translational Studies, Institution of Clinical Science Malmö, Lund University, 20502 Malmö, Sweden; (I.G.); (J.S.); (A.E.)
| | - Bilal Ahmad Mir
- Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden; (P.B.); (C.W.); (B.A.M.); (C.L.); (E.R.); (L.G.); (O.H.)
| | - Cheng Luan
- Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden; (P.B.); (C.W.); (B.A.M.); (C.L.); (E.R.); (L.G.); (O.H.)
| | - Erik Renström
- Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden; (P.B.); (C.W.); (B.A.M.); (C.L.); (E.R.); (L.G.); (O.H.)
| | - Leif Groop
- Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden; (P.B.); (C.W.); (B.A.M.); (C.L.); (E.R.); (L.G.); (O.H.)
- Finnish Institute for Molecular Medicine, University of Helsinki, 00290 Helsinki, Finland
| | - Jianping Weng
- Clinical Research Hospital, Chinese Academy of Sciences, Hefei 230001, China;
- Department of Endocrinology and Metabolism, Division of Life Sciences of Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Ola Hansson
- Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden; (P.B.); (C.W.); (B.A.M.); (C.L.); (E.R.); (L.G.); (O.H.)
- Institute for Molecular Medicine Finland (FIMM), Helsinki University, 00290 Helsinki, Finland
| | - Andreas Edsfeldt
- Cardiovascular Research-Translational Studies, Institution of Clinical Science Malmö, Lund University, 20502 Malmö, Sweden; (I.G.); (J.S.); (A.E.)
- Department of Cardiology, Skåne University Hospital, 20502 Malmö, Sweden
- Wallenberg Center for Molecular Medicine, Lund University, 20502 Malmö, Sweden
| | - Yang De Marinis
- Department of Clinical Sciences, Lund University, 20502 Malmö, Sweden; (P.B.); (C.W.); (B.A.M.); (C.L.); (E.R.); (L.G.); (O.H.)
- School of Control Science and Engineering, Shandong University, Jinan 250061, China
- Clinical Research Hospital, Chinese Academy of Sciences, Hefei 230001, China;
- Department of Endocrinology and Metabolism, Division of Life Sciences of Medicine, University of Science and Technology of China, Hefei 230001, China
- Correspondence: (R.G.); (Y.D.M.); Tel.: +86-135-0531-8418 (R.G.); +46-760-384-868 (Y.D.M.)
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Uto A, Miyashita K, Endo S, Sato M, Ryuzaki M, Kinouchi K, Mitsuishi M, Meguro S, Itoh H. Transient Dexamethasone Loading Induces Prolonged Hyperglycemia in Male Mice With Histone Acetylation in Dpp-4 Promoter. Endocrinology 2021; 162:6364113. [PMID: 34480538 PMCID: PMC8475716 DOI: 10.1210/endocr/bqab193] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Indexed: 12/21/2022]
Abstract
Glucocorticoid causes hyperglycemia, which is common in patients with or without diabetes. Prolonged hyperglycemia can be experienced even after the discontinuation of glucocorticoid use. In the present study, we examined the time course of blood glucose level in hospital patients who received transient glucocorticoid treatment. In addition, the mechanism of prolonged hyperglycemia was investigated by using dexamethasone (Dexa)-treated mice and cultured cells. The blood glucose level in glucose tolerance tests, level of insulin and glucagon-like peptide 1 (GLP-1), and the activity of dipeptidyl peptidase 4 (DPP-4) were examined during and after Dexa loading in mice, with histone acetylation level of the promoter region. Mice showed prolonged hyperglycemia during and after transient Dexa loading accompanied by persistently lower blood GLP-1 level and higher activity of DPP-4. The expression level of Dpp-4 was increased in the mononuclear cells and the promoter region of Dpp-4 was hyperacetylated during and after the transient Dexa treatment. In vitro experiments also indicated development of histone hyperacetylation in the Dpp-4 promoter region during and after Dexa treatment. The upregulation of Dpp-4 in cultured cells was significantly inhibited by a histone acetyltransferase inhibitor. Moreover, the histone hyperacetylation induced by Dexa was reversible by treatment with a sirtuin histone deacetylase activator, nicotinamide mononucleotide. We identified persistent reduction in blood GLP-1 level with hyperglycemia during and after Dexa treatment in mice, associated with histone hyperacetylation of promoter region of Dpp-4. The results unveil a novel mechanism of glucocorticoid-induced hyperglycemia, and suggest therapeutic intervention through epigenetic modification of Dpp-4.
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Affiliation(s)
- Asuka Uto
- Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, Tokyo, 160-8582, Japan
| | - Kazutoshi Miyashita
- Correspondence: Kazutoshi Miyashita, MD, Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan.
| | - Sho Endo
- Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, Tokyo, 160-8582, Japan
| | - Masaaki Sato
- Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, Tokyo, 160-8582, Japan
| | - Masaki Ryuzaki
- Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, Tokyo, 160-8582, Japan
| | - Kenichiro Kinouchi
- Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, Tokyo, 160-8582, Japan
| | - Masanori Mitsuishi
- Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, Tokyo, 160-8582, Japan
| | - Shu Meguro
- Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, Tokyo, 160-8582, Japan
| | - Hiroshi Itoh
- Division of Endocrinology, Metabolism and Nephrology, Keio University, School of Medicine, Tokyo, 160-8582, Japan
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Pothen L, Balligand JL. Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies? Antioxidants (Basel) 2021; 10:antiox10111849. [PMID: 34829720 PMCID: PMC8614708 DOI: 10.3390/antiox10111849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022] Open
Abstract
In medicine, a legacy effect is defined as the sustained beneficial effect of a given treatment on disease outcomes, even after cessation of the intervention. Initially described in optimized control of diabetes, it was also observed in clinical trials exploring intensification strategies for other cardiovascular risk factors, such as hypertension or hypercholesterolemia. Mechanisms of legacy were particularly deciphered in diabetes, leading to the concept of metabolic memory. In a more discreet manner, other memory phenomena were also described in preclinical studies that demonstrated long-lasting deleterious effects of lipids or angiotensin II on vascular wall components. Interestingly, epigenetic changes and reactive oxygen species (ROS) appear to be common features of “memory” of the vascular wall.
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Micro-RNA Implications in Type-1 Diabetes Mellitus: A Review of Literature. Int J Mol Sci 2021; 22:ijms222212165. [PMID: 34830046 PMCID: PMC8621893 DOI: 10.3390/ijms222212165] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/24/2021] [Accepted: 11/04/2021] [Indexed: 02/07/2023] Open
Abstract
Type-1 diabetes mellitus (T1DM) is one of the most well-defined and complex metabolic disorders, characterized by hyperglycemia, with a constantly increasing incidence in children and adolescents. While current knowledge regarding the molecules related to the pathogenesis and diagnosis of T1DM is vast, the discovery of new molecules, such as micro ribonucleic acids (micro-RNAs, miRNAs), as well as their interactions with T1DM, has spurred novel prospects in the diagnosis of the disease. This review aims at summarizing current knowledge regarding miRNAs' biosynthesis and action pathways and their role as gene expression regulators in T1DM. MiRNAs follow a complex biosynthesis pathway, including cleaving and transport from nucleus to cytoplasm. After assembly of their final form, they inhibit translation or cause messenger RNA (mRNA) degradation, resulting in the obstruction of protein synthesis. Many studies have reported miRNA involvement in T1DM pathogenesis, mainly through interference with pancreatic b-cell function, insulin production and secretion. They are also found to contribute to β-cell destruction, as they aid in the production of autoreactive agents. Due to their elevated accumulation in various biological specimens, as well as their involvement in T1DM pathogenesis, their role as biomarkers in early preclinical T1DM diagnosis is widely hypothesized, with future studies concerning their diagnostic value deemed a necessity.
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Vasishta S, Umakanth S, Adiga P, Joshi MB. Extrinsic and intrinsic factors influencing metabolic memory in type 2 diabetes. Vascul Pharmacol 2021; 142:106933. [PMID: 34763098 DOI: 10.1016/j.vph.2021.106933] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/18/2021] [Accepted: 11/04/2021] [Indexed: 12/24/2022]
Abstract
Direct and indirect influence of pathological conditions in Type 2 Diabetes (T2D) on vasculature manifests in micro and/or macro vascular complications that act as a major source of morbidity and mortality. Although preventive therapies exist to control hyperglycemia, diabetic subjects are always at risk to accrue vascular complications. One of the hypotheses explained is 'glycemic' or 'metabolic' memory, a process of permanent epigenetic change in different cell types whereby diabetes associated vascular complications continue despite glycemic control by antidiabetic drugs. Epigenetic mechanisms including DNA methylation possess a strong influence on the association between environment and gene expression, thus indicating its importance in the pathogenesis of a complex disease such as T2D. The vascular system is more prone to environmental influences and present high flexibility in response to physiological and pathological challenges. DNA methylation based epigenetic changes during metabolic memory are influenced by sustained hyperglycemia, inflammatory mediators, gut microbiome composition, lifestyle modifications and gene-nutrient interactions. Hence, understanding underlying mechanisms in manifesting vascular complications regulated by DNA methylation is of high clinical importance. The review provides an insight into various extrinsic and intrinsic factors influencing the regulation of DNA methyltransferases contributing to the pathogenesis of vascular complications during T2D.
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Affiliation(s)
- Sampara Vasishta
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Shashikiran Umakanth
- Department of Medicine, Dr. T.M.A. Pai Hospital, Manipal Academy of Higher Education, Udupi 576101, Karnataka, India
| | - Prashanth Adiga
- Department of Reproductive Medicine and Surgery (MARC), Kasturba Hospital, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India
| | - Manjunath B Joshi
- Department of Ageing Research, Manipal School of Life Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka, India.
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Kim H, Bae JH, Park KS, Sung J, Kwak SH. DNA Methylation Changes Associated With Type 2 Diabetes and Diabetic Kidney Disease in an East Asian Population. J Clin Endocrinol Metab 2021; 106:e3837-e3851. [PMID: 34214161 DOI: 10.1210/clinem/dgab488] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Indexed: 01/13/2023]
Abstract
CONTEXT There is a growing body of evidence that epigenetic changes including DNA methylation influence the risk of type 2 diabetes (T2D) and its microvascular complications. OBJECTIVE We conducted a methylome-wide association study (MWAS) to identify differentially methylated sites (DMSs) of T2D and diabetic kidney disease (DKD) in a Korean population. METHODS We performed an MWAS in 232 participants with T2D and 197 nondiabetic controls with the Illumina EPIC bead chip using peripheral blood leukocytes. The T2D group was subdivided into 87 DKD patients and 80 non-DKD controls. An additional 819 individuals from 2 population-based cohorts were used to investigate the association of identified DMSs with quantitative metabolic phenotypes. A mendelian randomization (MR) approach was applied to evaluate the causal effect of metabolic phenotypes on identified DMSs. RESULTS We identified 8 DMSs (each at BMP8A, NBPF20, STX18, ZNF365, CPT1A, and TRIM37, and 2 at TXNIP) that were significantly associated with the risk of T2D (P < 9.0 × 10-8), including 3 that were previously known (DMSs in TXNIP and CPT1A). We also identified 3 DMSs (in COMMD1, TMOD1, and FHOD1) associated with DKD. With our limited sample size, we were not able to observe a significant overlap between DMSs of T2D and DKD. DMSs in TXNIP and CTP1A were associated with fasting glucose and glycated hemoglobin A1c. In MR analysis, fasting glucose was causally associated with DMS in CPT1A. CONCLUSION In an East Asian population, we identified 8 DMSs, including 5 novel CpG loci, associated with T2D and 3 DMSs associated with DKD at methylome-wide statistical significance.
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Affiliation(s)
- Hakyung Kim
- Genome & Health Big Data Branch, Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
| | - Jae Hyun Bae
- Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Joohon Sung
- Genome & Health Big Data Branch, Department of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul, Republic of Korea
- Institute of Health and Environment, Seoul National University, Seoul, Republic of Korea
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
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Copur S, Rossing P, Afsar B, Sag AA, Siriopol D, Kuwabara M, Ortiz A, Kanbay M. A primer on metabolic memory: why existing diabesity treatments fail. Clin Kidney J 2021; 14:756-767. [PMID: 34512957 PMCID: PMC8422888 DOI: 10.1093/ckj/sfaa143] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Indexed: 11/28/2022] Open
Abstract
Despite massive government and private sector investments into prevention of cardiovascular disease, diabetes mellitus and obesity, efforts have largely failed, and the burden of cost remains in the treatment of downstream morbidity and mortality, with overall stagnating outcomes. A new paradigm shift in the approach to these patients may explain why existing treatment strategies fail, and offer new treatment targets. This review aims to provide a clinician-centred primer on metabolic memory, defined as the sum of irreversible genetic, epigenetic, cellular and tissue-level alterations that occur with long-time exposure to metabolic derangements.
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Affiliation(s)
- Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, University of Copenhagen, Copenhagen, Denmark
| | - Baris Afsar
- Department of Internal Medicine, Division of Nephrology, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - Alan A Sag
- Department of Radiology, Division of Vascular and Interventional Radiology, Duke University Medical Center, Durham, NC, USA
| | - Dimitrie Siriopol
- Nephrology Clinic, Dialysis and Renal Transplant Center, 'C.I. PARHON' University Hospital, 'Grigore T. Popa' University of Medicine, Iasi, Romania
| | | | - Alberto Ortiz
- School of Medicine, Dialysis Unit, IIS-Fundacion Jimenez Diaz, Universidad Autónoma de Madrid, Madrid, Spain
| | - Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
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Yamunadevi A, Pratibha R, Rajmohan M, Mahendraperumal S, Ganapathy N. Basics of Epigenetics and Role of Epigenetics in Diabetic Complications. JOURNAL OF PHARMACY AND BIOALLIED SCIENCES 2021; 13:S336-S343. [PMID: 34447105 PMCID: PMC8375876 DOI: 10.4103/jpbs.jpbs_771_20] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 12/27/2020] [Indexed: 11/11/2022] Open
Abstract
The term “Epigenetics” includes mechanisms by which genetic expression is altered without a change in the underlying DNA sequence. The changes caused by epigenetic mechanisms are inheritable and are one way in direction (irreversible) and also explains why there is differences in genetic expressions of monozygotic twins. The epigenetic mechanisms alter the genetic expressions through DNA methylation, posttranslational modifications (PTMs) of histone, and noncoding RNAs. DNA methylation and histone PTMs cause relaxation or condensation of chromatin units. The epigenetic actions of noncoding RNAs such as microRNAs, small nucleolar RNAs, small interfering RNAs, and long noncoding RNAs act by modifying transcription factors or by degrading target messenger RNAs and their translation factors. Various pathologies and environmental factors cause changes in the cellular epigenetic mechanisms and the epigenetic alterations occurring in diabetes mellitus (DM) are reviewed. DM causes hemodynamic changes and metabolic changes like hyperglycemia and dyslipidemia. These changes induce oxidative stress and activate intracellular signaling and kinases in the target cells. Epigenetic alterations cause chromatin remodeling and altered gene expression leading to inflammation, proliferation, atrophy, hypertrophy, etc.; thereby, diabetic complications such as neuropathy, nephropathy, vasculitis result in the corresponding target organ. When these epigenetic alterations persist for a longer period without intervention, the target cells attain “metabolic memory” meaning that these epigenetic mutations cannot be reversed even after attaining normal blood glucose levels. Thus, epigenetics, an insightful and efficient tool in genomic research, has started crawling into the research arena and needs to reach leaps and bounds for the better understanding of health and diseases.
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Affiliation(s)
- Andamuthu Yamunadevi
- Department of Oral and Maxillofacial Pathology, Vivekanandha Dental College for Women, Namakkal, Tamil Nadu, India
| | - Ramani Pratibha
- Department of Oral and Maxillofacial Pathology, Saveetha Dental College, Chennai, Tamil Nadu, India
| | - Muthusamy Rajmohan
- Department of Oral and Maxillofacial Pathology, KSR Institute of Dental Science and Research, Namakkal, Tamil Nadu, India
| | - Sengottaiyan Mahendraperumal
- Department of Oral and Maxillofacial Surgery, KSR Institute of Dental Science and Research, Namakkal, Tamil Nadu, India
| | - Nalliappan Ganapathy
- Department of Oral and Maxillofacial Pathology, Vivekanandha Dental College for Women, Namakkal, Tamil Nadu, India
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Zhang XS, Yin YS, Wang J, Battaglia T, Krautkramer K, Li WV, Li J, Brown M, Zhang M, Badri MH, Armstrong AJS, Strauch CM, Wang Z, Nemet I, Altomare N, Devlin JC, He L, Morton JT, Chalk JA, Needles K, Liao V, Mount J, Li H, Ruggles KV, Bonneau RA, Dominguez-Bello MG, Bäckhed F, Hazen SL, Blaser MJ. Maternal cecal microbiota transfer rescues early-life antibiotic-induced enhancement of type 1 diabetes in mice. Cell Host Microbe 2021; 29:1249-1265.e9. [PMID: 34289377 PMCID: PMC8370265 DOI: 10.1016/j.chom.2021.06.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/27/2021] [Accepted: 06/18/2021] [Indexed: 01/04/2023]
Abstract
Early-life antibiotic exposure perturbs the intestinal microbiota and accelerates type 1 diabetes (T1D) development in the NOD mouse model. Here, we found that maternal cecal microbiota transfer (CMT) to NOD mice after early-life antibiotic perturbation largely rescued the induced T1D enhancement. Restoration of the intestinal microbiome was significant and persistent, remediating the antibiotic-depleted diversity, relative abundance of particular taxa, and metabolic pathways. CMT also protected against perturbed metabolites and normalized innate and adaptive immune effectors. CMT restored major patterns of ileal microRNA and histone regulation of gene expression. Further experiments suggest a gut-microbiota-regulated T1D protection mechanism centered on Reg3γ, in an innate intestinal immune network involving CD44, TLR2, and Reg3γ. This regulation affects downstream immunological tone, which may lead to protection against tissue-specific T1D injury.
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Affiliation(s)
- Xue-Song Zhang
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA; Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA.
| | - Yue Sandra Yin
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA; Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA
| | - Jincheng Wang
- Department of Biochemistry and Microbiology, Rutgers University - New Brunswick, New Brunswick, NJ, USA
| | - Thomas Battaglia
- Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA
| | - Kimberly Krautkramer
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg 41345, Sweden
| | - Wei Vivian Li
- Department of Biostatistics and Epidemiology, Rutgers University School of Public Health, Piscataway, NJ, USA
| | - Jackie Li
- Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA
| | - Mark Brown
- Cardiovascular & Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Meifan Zhang
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA; Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA
| | - Michelle H Badri
- Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA; New York University, Center for Data Science, New York, NY, USA
| | - Abigail J S Armstrong
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA
| | - Christopher M Strauch
- Cardiovascular & Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
| | - Zeneng Wang
- Cardiovascular & Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
| | - Ina Nemet
- Cardiovascular & Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA
| | - Nicole Altomare
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA
| | - Joseph C Devlin
- Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA
| | - Linchen He
- Department of Population Health, New York University Langone Medical Center, New York, NY, USA
| | - Jamie T Morton
- Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA; Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA
| | - John Alex Chalk
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA
| | - Kelly Needles
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA
| | - Viviane Liao
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA
| | - Julia Mount
- Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA
| | - Huilin Li
- Department of Population Health, New York University Langone Medical Center, New York, NY, USA
| | - Kelly V Ruggles
- Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA
| | - Richard A Bonneau
- Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA; New York University, Center for Data Science, New York, NY, USA; Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, NY, USA
| | - Maria Gloria Dominguez-Bello
- Department of Biochemistry and Microbiology, Rutgers University - New Brunswick, New Brunswick, NJ, USA; Institute for Food, Nutrition and Health, Rutgers University - New Brunswick, New Brunswick, NJ, USA
| | - Fredrik Bäckhed
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Göteborg 41345, Sweden; Region västra Götaland, Sahlgrenska University Hospital, Department of Clinical Physiology, Gothenburg, Sweden; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Stanley L Hazen
- Cardiovascular & Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH 44195, USA; Heart, Vascular & Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Martin J Blaser
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, USA; Human Microbiome Program, New York University Langone Medical Center, New York, NY, USA.
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Zhu Y, Wang X, Zhou X, Ding L, Liu D, Xu H. DNMT1-mediated PPARα methylation aggravates damage of retinal tissues in diabetic retinopathy mice. Biol Res 2021; 54:25. [PMID: 34362460 PMCID: PMC8348846 DOI: 10.1186/s40659-021-00347-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 07/21/2021] [Indexed: 02/06/2023] Open
Abstract
Background Peroxisome proliferator-activated receptor alpha (PPARα) is associated with diabetic retinopathy (DR), and the underlying mechanism is still unclear. Aim of this work was to investigate the mechanism of PPARα in DR. Methods Human retinal capillary pericytes (HRCPs) were treated with high glucose (HG) to induce DR cell model. DR mouse model was established by streptozotocin injection, and then received 5-Aza-2-deoxycytidine (DAC; DNA methyltransferase inhibitor) treatment. Hematoxylin–eosin staining was performed to assess retinal tissue damage. PPARα methylation was examined by Methylation-Specific PCR. Flow cytometry and DCFH-DA fluorescent probe was used to estimate apoptosis and reactive oxygen species (ROS). The interaction between DNA methyltransferase-1 (DNMT1) and PPARα promoter was examined by Chromatin Immunoprecipitation. Quantitative real-time PCR and western blot were performed to assess gene and protein expression. Results HG treatment enhanced the methylation levels of PPARα, and repressed PPARα expression in HRCPs. The levels of apoptotic cells and ROS were significantly increased in HRCPs in the presence of HG. Moreover, DNMT1 was highly expressed in HG-treated HRCPs, and DNMT1 interacted with PPARα promoter. PPARα overexpression suppressed apoptosis and ROS levels of HRCPs, which was rescued by DNMT1 up-regulation. In DR mice, DAC treatment inhibited PPARα methylation and reduced damage of retinal tissues. Conclusion DNMT1-mediated PPARα methylation promotes apoptosis and ROS levels of HRCPs and aggravates damage of retinal tissues in DR mice. Thus, this study may highlight novel insights into DR pathogenesis. Supplementary Information The online version contains supplementary material available at 10.1186/s40659-021-00347-1.
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Affiliation(s)
- Ying Zhu
- Eye Center of Xiangya Hospital, Central South University, No. 87 Xiangya Road, Hunan, 410008, Changsha, China
| | - Xinru Wang
- Eye Center of Xiangya Hospital, Central South University, No. 87 Xiangya Road, Hunan, 410008, Changsha, China
| | - Xiaoyun Zhou
- Department of Ophthalmology, The First Hospital of Changsha, 311 Yingpan Road, Hunan, Changsha, China
| | - Lexi Ding
- Eye Center of Xiangya Hospital, Central South University, No. 87 Xiangya Road, Hunan, 410008, Changsha, China
| | - Dan Liu
- Eye Center of Xiangya Hospital, Central South University, No. 87 Xiangya Road, Hunan, 410008, Changsha, China
| | - Huizhuo Xu
- Eye Center of Xiangya Hospital, Central South University, No. 87 Xiangya Road, Hunan, 410008, Changsha, China.
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Prattichizzo F, de Candia P, Ceriello A. Diabetes and kidney disease: emphasis on treatment with SGLT-2 inhibitors and GLP-1 receptor agonists. Metabolism 2021; 120:154799. [PMID: 34029597 DOI: 10.1016/j.metabol.2021.154799] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/06/2021] [Accepted: 05/17/2021] [Indexed: 12/12/2022]
Abstract
Kidney disease is a frequent microvascular complication of both type 1 and type 2 diabetes. Historic trials have demonstrated that a tight glycaemic control is the most powerful approach to decrease the chances of developing diabetic nephropathy. However, having an HbA1c < 7% does not completely suppress the risk of kidney disease. The observed residual risk is likely ascribable to two phenomena: 1- the presence of risk factors and alterations additive to and independent of glycaemia, and 2- the activation of long-lasting imbalances by periods of exposure to uncontrolled glycemia, a phenomenon referred to as metabolic memory or legacy effect. Long-lasting oxidative stress, epigenetic alterations, cellular senescence, and the resulting chronic low-grade inflammation are all candidate mechanisms explaining the development of nephropathy despite proper control of risk factors. Recently, two classes of drugs, i.e. glucagon-like peptide (GLP) 1 receptor agonists (RA) and sodium-glucose transporter 2 inhibitors (SGLT-i) have changed this scenario. Indeed, cardiovascular outcome and other trials have clearly shown a renoprotective effect for these drugs, well-beyond their glucose-lowering properties. In this review, we summarize: 1- selected key trials and mechanisms underlying the development of diabetic kidney disease and 2- the results relative to renal endpoints in clinical trials of GLP-1 RA and SGLT-2i. Then, we briefly discuss some of the hypotheses posited to explain the marked renoprotective properties of these two classes, evidencing the still existing gaps in knowledge and proposing future directions to further implement the use of these powerful, disease-modifying drugs.
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Abstract
Epigenetic modifications have been implicated to mediate several complications of diabetes mellitus (DM), especially nephropathy and retinopathy. Our aim was to ascertain whether epigenetic alterations in whole blood discriminate among patients with DM with normal, delayed, and rapid gastric emptying (GE).
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Dzobo K. Coronavirus Disease 19 and Future Ecological Crises: Hopes from Epigenomics and Unraveling Genome Regulation in Humans and Infectious Agents. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2021; 25:269-278. [PMID: 33904782 DOI: 10.1089/omi.2021.0024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
With coronavirus disease 19 (COVID-19), we have witnessed a shift from public health to planetary health and a growing recognition of the importance of systems science in developing effective solutions against pandemics in the 21st century. COVID-19 and the history of frequent infectious outbreaks in the last two decades suggest that COVID-19 is likely a dry run for future ecological crises. Now is the right time to plan ahead and deploy the armamentarium of systems science scholarship for planetary health. The science of epigenomics, which investigates both genetic and nongenetic traits regarding heritable phenotypic alterations, and new approaches to understanding genome regulation in humans and pathogens offer veritable prospects to boost the global scientific capacities to innovate therapeutics and diagnostics against novel and existing infectious agents. Several reversible epigenetic alterations, such as chromatin remodeling and histone methylation, control and influence gene expression. COVID-19 lethality is linked, in part, to the cytokine storm, age, and status of the immune system in a given person. Additionally, due to reduced human mobility and daily activities, effects of the pandemic on the environment have been both positive and negative. For example, reduction in environmental pollution and lesser extraction from nature have potential positive corollaries on water and air quality. Negative effects include pollution as plastics and other materials were disposed in unconventional places and spaces in the course of the pandemic. I discuss the opportunities and challenges associated with the science of epigenomics, specifically with an eye to inform and prevent future ecological crises and pandemics that are looming on the horizon in the 21st century. In particular, this article underscores that epigenetics of both viruses and the host may influence virus infectivity and severity of attendant disease.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Cape Town, South Africa.,Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
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50
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Zheng W, Guo J, Liu ZS. Effects of metabolic memory on inflammation and fibrosis associated with diabetic kidney disease: an epigenetic perspective. Clin Epigenetics 2021; 13:87. [PMID: 33883002 PMCID: PMC8061201 DOI: 10.1186/s13148-021-01079-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 04/13/2021] [Indexed: 01/19/2023] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common microvascular complication of both type 1 (T1DM) and type 2 diabetes mellitus (T2DM), and the leading cause of end-stage renal disease (ESRD) worldwide. Persistent inflammation and subsequent chronic fibrosis are major causes of loss of renal function, which is associated with the progression of DKD to ESRD. In fact, DKD progression is affected by a combination of genetic and environmental factors. Approximately, one-third of diabetic patients progress to develop DKD despite intensive glycemic control, which propose an essential concept "metabolic memory." Epigenetic modifications, an extensively studied mechanism of metabolic memory, have been shown to contribute to the susceptibility to develop DKD. Epigenetic modifications also play a regulatory role in the interactions between the genes and the environmental factors. The epigenetic contributions to the processes of inflammation and fibrogenesis involved in DKD occur at different regulatory levels, including DNA methylation, histone modification and non-coding RNA modulation. Compared with genetic factors, epigenetics represents a new therapeutic frontier in understanding the development DKD and may lead to therapeutic breakthroughs due to the possibility to reverse these modifications therapeutically. Early recognition of epigenetic events and biomarkers is crucial for timely diagnosis and intervention of DKD, and for the prevention of the progression of DKD to ESRD. Herein, we will review the latest epigenetic mechanisms involved in the renal pathology of both type 1 (T1DN) and type 2 diabetic nephropathy (T2DN) and highlight the emerging role and possible therapeutic strategies based on the understanding of the role of epigenetics in DKD-associated inflammation and fibrogenesis.
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Affiliation(s)
- Wen Zheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Jia Guo
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan Province, People's Republic of China
| | - Zhang-Suo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, People's Republic of China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, People's Republic of China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, People's Republic of China.
- Core Unit of National Clinical Medical Research Center of Kidney Disease, No. 1, Jianshe East Road, Zhengzhou, 450052, Henan Province, People's Republic of China.
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