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Qian Y, Jia Y. Identification of Key Efferocytosis-Related Genes and Mechanisms in Diabetic Retinopathy. Mol Biotechnol 2025; 67:2785-2797. [PMID: 39085562 DOI: 10.1007/s12033-024-01239-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 07/09/2024] [Indexed: 08/02/2024]
Abstract
This study aimed to explore the key efferocytosis-related genes in diabetic retinopathy (DR) and their regulatory mechanisms. Public DR-related gene expression datasets, GSE160306 (training) and GSE60436 (validation), were downloaded. Differentially expressed efferocytosis-related genes (DEERGs) were analyzed using differential expression analysis and weighted gene co-expression network analysis. Functional enrichment analysis was conducted. Moreover, efferocytosis-related signature genes were identified using machine learning analysis, and their expression levels and diagnostic value were analyzed. Furthermore, nomograms were constructed; immune cell infiltration was analyzed; and gene set enrichment analysis, transcriptional regulation analysis, and small-molecule drug (SMD) prediction of efferocytosis-related signature genes were performed. In total, 36 DEERGs were identified in DR, and were markedly enriched in multiple functions, such as visual system development. Through further machine learning analysis, two efferocytosis-related signature genes, Ferritin Light Chain (FTL) and Fc Gamma Binding Protein (FCGBP), were identified, and were found to be upregulated in DR samples and showed high diagnostic performance for DR. A nomogram constructed using FTL and FCGBP accurately predicted the risk of DR. Moreover, the level of infiltration of immature B cells was positively correlated with FTL and FCGBP expression levels. Multiple transcription factors (TFs), such as CCCTC-Binding Factor (CTCF) and KLF Transcription Factor 9 (KLF9), were found to interact with both FTL and FCGBP. In addition, FTL can be targeted by miRNAs, such as miR-22-3p, and FCGBP can be targeted by miR-7973. In addition, both FTL and FCGBP can be targeted by SMDs, such as bisphenol A. Key efferocytosis-related genes, such as FTL and FCGBP, may promote DR development. Detecting or targeting FTL and FCGBP may aid in the prevention, diagnosis, and treatment of DR.
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Affiliation(s)
- Yu Qian
- Department of Ophthalmology, The First People's Hospital of Zhaoqing, 9 Donggang East Road, Zhaoqing, 526060, Guangdong, China.
| | - Yanwen Jia
- Department of Ophthalmology, Changzhou Second People's Hospital Affiliated Nanjing Medical University, Changzhou, 213004, Jiangsu, China
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2
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Islam K, Islam R, Nguyen I, Malik H, Pirzadah H, Shrestha B, Lentz IB, Shekoohi S, Kaye AD. Diabetes Mellitus and Associated Vascular Disease: Pathogenesis, Complications, and Evolving Treatments. Adv Ther 2025; 42:2659-2678. [PMID: 40252164 PMCID: PMC12085338 DOI: 10.1007/s12325-025-03185-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 03/19/2025] [Indexed: 04/21/2025]
Abstract
Diabetes mellitus is a metabolic disorder, characterized by elevated blood sugar levels (hyperglycemia) and insulin dysregulation. This disease is associated with morbidity and mortality, including significant potential vascular complications. High levels of hyperglycemia lead to not only elevated levels of reactive oxygen species but also advanced glycation end products, which are detrimental to the vascular endothelium and reduce protective compounds such as nitric oxide and prostacyclin. This damage contributes to the development of both macrovascular and microvascular complications. The present investigation explores the pathophysiological mechanisms of diabetic vascular complications and evaluates current management strategies, including lifestyle modifications, pharmacological treatments, and emerging therapies. The review underscores the importance of ongoing progress in diabetes management and patient education to lead to optimal patient-health outcomes and quality of life for individuals with diabetes mellitus.
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Affiliation(s)
- Kazi Islam
- Central State University, 1400 Brush Row Road, Wilberforce, OH, 45384, USA
| | - Rahib Islam
- LSU Health Sciences Center New Orleans School of Medicine, 1901 Gravier Street, New Orleans, LA, 70112, USA
| | - Ivan Nguyen
- LSU Health Sciences Center New Orleans School of Medicine, 1901 Gravier Street, New Orleans, LA, 70112, USA
| | - Hassan Malik
- LSU Health Sciences Center New Orleans School of Medicine, 1901 Gravier Street, New Orleans, LA, 70112, USA
| | - Humza Pirzadah
- LSU Health Sciences Center New Orleans School of Medicine, 1901 Gravier Street, New Orleans, LA, 70112, USA
| | - Barsha Shrestha
- LSU Health Sciences Center New Orleans School of Medicine, 1901 Gravier Street, New Orleans, LA, 70112, USA
| | - Isabella B Lentz
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, 71103, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, 71103, USA.
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, 71103, USA
- Department of Pharmacology, Toxicology, and Neurosciences, Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, 71103, USA
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3
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Hu W, Tu Y, Tan J, Lin Y, Wang Y, Zhou Q. Global research trends on endoplasmic reticulum stress in retinal diseases from 2000 to 2024. Int Ophthalmol 2025; 45:210. [PMID: 40419840 DOI: 10.1007/s10792-025-03584-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Accepted: 05/10/2025] [Indexed: 05/28/2025]
Abstract
PURPOSE To comprehensively explore global research trends on endoplasmic reticulum stress (ERS) in retinal diseases over the past 24 years. METHODS An analysis of 917 publications from the Web of Science Core Collection, spanning from 1 January 2000 to 15 April 2024, was conducted to explore ERS research in retinal diseases. Bibliometric and visualisation software was employed to identify key contributors and research trends. RESULTS Hideaki Hara and Sarah X. Zhang were identified as the most published and most cited authors, respectively. The United States led in both publications and citations. Sun Yat-sen University ranked highest in publications, while the University of Oklahoma received the most citations. Investigative Ophthalmology & Visual Science was the leading journal in both publications and citations. A total of 108 of the 1385 author keywords, each occurring five or more times, clustered into four major themes: retinal photoreceptor degeneration, glaucoma and optic nerve damage, diabetic retinopathy and age-related macular degeneration. Keywords such as "in vivo", "dominant retinitis pigmentosa", "endothelial growth factor", "molecular", and "quality control" displayed the strongest citation bursts. ERS research (2000 ~ 2024) has evolved from retinal neuroprotection to include specific cell types and diseases, explored signalling pathways and therapeutic mechanisms, and more recently has focused on molecular insights and gene therapy applications. CONCLUSION This bibliometric analysis highlighted significant growth in publications on ERS in retinal diseases, reflecting an increasing scholarly focus. ERS represents a potential target for exploring pathological changes in retinal neuro-microvascular and related disorders, warranting further investigation.
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Affiliation(s)
- Weiwen Hu
- Department of Ophthalmology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
| | - Yahan Tu
- Department of Ophthalmology, the First Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, People's Republic of China
| | - Jian Tan
- Department of Ophthalmology, the Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, Jiangxi Province, People's Republic of China
| | - Yeting Lin
- Department of Ophthalmology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
| | - Yicang Wang
- Department of Ophthalmology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China
| | - Qiong Zhou
- Department of Ophthalmology, the First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi Province, People's Republic of China.
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Ahmed O, Prabhu SR, Shetty AP, Nousy A, Zackariya M, Jayaramaraju D, Sivan A, Shanmuganathan R. "Exploring The Nexus": Chronic musculoskeletal pain in diabetic vs non-diabetic population. J Orthop 2025; 63:123-129. [PMID: 39564084 PMCID: PMC11570861 DOI: 10.1016/j.jor.2024.10.046] [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: 10/08/2024] [Accepted: 10/30/2024] [Indexed: 11/21/2024] Open
Abstract
Introduction Diabetes-mellitus (DM) has transcended the boundaries and affected populations across globe, it predisposes individual to stiffness and musculoskeletal-pain due to accumulation of glycation-end-products. Musculoskeletal-pain is a common yet frequently neglected complication. Pain mechanisms have been categorized as nociceptive, neuropathic, nociplastic, and idiopathic. Four criteria were put by Kosek-et-al to identify nociplastic pain that affects the musculoskeletal-system. Study aimed to evaluate prevalence of chronic musculoskeletal (cMSK) pain and its association with diabetes and glycaemic control and to evaluate comorbid conditions of cMSK pain. Methods and materials A prospective case-control study was conducted at a level-1-tertiary-care-facility. Patients with type-2 DM above 30-years-age who visited outpatient department participated in the study (study group). Age-matched equal number of healthy individuals (control-cohort) were recruited in the study. We collected data from 300 participants in each group. Analysis was done based-on HbA1c-levels, random-blood-sugar (RBS),clinical-history, and comorbidities. Information regarding cMSK-pain was gathered using modified version of Nordic standard questionnaire. Results Overall prevalence of cMSK pain was 23.3 % (140 out of 600). Among Group-1/Diabetic group, it was 27.7 % and among group-2/Healthy Cohort it was 19 % and the odds ratio was 1.6. Most commonly reported region with cMSK among group-1 and group-2 was shoulder (32.5 %) and knee (36.8 %) respectively. We found a significant association between cMSK-pain and HbA1c levels (p < 0.005). and individuals with HbA1c levels of more than 12 reported involvements in multiple regions. We didn't find significant association between cMSK and DM, HTN, dyslipidemia, or hypothyroidism (P > 0.05). Conclusion Study highlights higher-prevalence and significant impact of cMSK pain in diabetic patients compared to non-diabetic individuals. Addressing musculoskeletal-pain is crucial for improving overall quality-of-life in diabetic patients. Clinicians should adopt a proactive and comprehensive approach to pain management in diabetics. Using a simple Nordic questionnaire during routine check-ups helps with screening of joint and surrounding soft tissue pathology, preventing future complications that could lead to disability.
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Affiliation(s)
- Owais Ahmed
- Department of Orthopaedics and Trauma, Ganga Medical Center & Hospital, Coimbatore, India
| | - Suresh R Prabhu
- Department of Endocrinology, Ganga Medical Center & Hospital, Coimbatore, India
| | - Ajoy Prasad Shetty
- Department of Orthopaedics and Spine Surgery, Ganga Medical Center & Hospital, Coimbatore, India
| | - A Nousy
- Department of Endocrinology, Ganga Medical Center & Hospital, Coimbatore, India
| | - Mohamed Zackariya
- Department of Orthopaedics and Trauma, Ganga Medical Center & Hospital, Coimbatore, India
| | | | - Abishek Sivan
- Department of Endocrinology, Ganga Medical Center & Hospital, Coimbatore, India
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Li Q, Onizuka S, Park K, Ma M, Fickweiler W, Park H, Li Q, Simao F, Boisclair J, Sharawy M, Wu IH, Yu MG, Aiello LP, Sun JK, King GL. Differential Effects of Retinol-Binding Protein 3 and Anti-VEGF Antibodies on Retinal Dysfunctions in Diabetic Retinopathy. Diabetes 2025; 74:787-797. [PMID: 39937209 PMCID: PMC12015138 DOI: 10.2337/db24-0822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 02/06/2025] [Indexed: 02/13/2025]
Abstract
Anti-vascular endothelial growth factor (anti-VEGF) therapies are effective treatment for severe diabetic retinopathy (DR) and macular edema, but a significant subset of people had inadequate response to anti-VEGF intervention. Because elevation or overexpression of retinol binding protein 3 (RBP3) decreases risks for retinal pathologies and progression to severe DR, we compared the therapeutic profiles of RBP3 and anti-VEGF antibody to normalize retinal dysfunctions induced by diabetes. Intravitreous injection of recombinant human RBP3 (rhRBP3) and anti-VEGF antibody (namely, bevacizumab) inhibited retinal vascular permeability in Lewis rats induced by VEGF-A or after 2 months of diabetes induced by streptozotocin, in parallel with reductions of retinal VEGF and VEGF receptor 2 expressions and tyrosine phosphorylation of VEGF receptor. Only rhRBP3 ameliorated diabetes-induced reduction of neural retinal function, measured by electroretinogram. Furthermore, rhRBP3 reduced retinal expressions of inflammatory cytokines (TNF-α and IL-6) in retinal pigmented epithelial and Müller cells exposed to hyperglycemia. Metabolic studies, using a Seahorse flux analyzer, showed only rhRBP3 normalized retinal glycolytic rates in diabetic rats. Thus, both intravitreous anti-VEGF antibody and RBP3 injections normalized retinal vascular dysfunctions caused by diabetes. Only RBP3 targeted both neural and vascular retina to reduce glycolytic rates, reverse neural-retinal dysfunctions, and reduce inflammatory cytokines induced by diabetes, to delay early changes of DR. ARTICLE HIGHLIGHTS
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Affiliation(s)
- Qin Li
- Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Satoru Onizuka
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Kyoungmin Park
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Ophthalmology, Harvard Medical School, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Mingming Ma
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
- Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Ward Fickweiler
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Ophthalmology, Harvard Medical School, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Hyunseok Park
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Qian Li
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Fabricio Simao
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Jared Boisclair
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Maha Sharawy
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - I-Hsien Wu
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Marc Gregory Yu
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Lloyd P. Aiello
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Ophthalmology, Harvard Medical School, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Jennifer K. Sun
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Ophthalmology, Harvard Medical School, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - George L. King
- Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Joslin Diabetes Center, Harvard Medical School, Boston, MA
- Department of Ophthalmology, Harvard Medical School, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
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6
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Kumar V, Sharma N, Mishra VK, Mall S, Kumar A, Dev K, Patel CN. Computational Evaluation of Phytocompounds From Selective Medicinal Plants as Potential Antidiabetic Agents. Chem Biodivers 2025:e202403368. [PMID: 40273195 DOI: 10.1002/cbdv.202403368] [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: 12/18/2024] [Revised: 04/23/2025] [Accepted: 04/24/2025] [Indexed: 04/26/2025]
Abstract
The distinguishing characteristic of diabetes mellitus (DM), chronic hyperglycemia emphasizes the need for safer, more efficient antidiabetic treatments. This study employs computational approaches to explore the therapeutic potential of phytochemicals from medicinal plants as antidiabetic drugs. Molecular docking against phosphorylated insulin receptor (IR) tyrosine kinase and human dipeptidyl peptidase IV (DPP-IV) identified eriodictyol (-7.13 kcal/mol) and petunidin (-6.61 kcal/mol) as potent inhibitors. Molecular dynamics simulations confirmed the structural stability of these complexes, with root mean square deviation values stabilizing within 2.8-4.5 Å. Binding free energy calculations using Molecular Mechanics Generalized Born Surface Area evealed strong binding affinities of eriodictyol-IR (ΔGbinding = -44.63 ± 4.05 kcal/mol), and petunidin-DPP-IV complex (ΔGbinding = -49.86 ± 6.13 kcal/mol). Additionally, pharmacokinetic assessments showed that these compounds adhered to Lipinski's rule, with no significant hepatotoxicity or cytotoxicity. These findings underscore the potential of these phytocompounds as antidiabetic candidates, warranting further in vitro and in vivo investigations.
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Affiliation(s)
- Vikas Kumar
- University Institute of Biotechnology, Chandigarh University, Mohali, India
| | - Nitin Sharma
- Department of Biotechnology, Chandigarh Group of Colleges, Mohali, India
| | - Vipin Kumar Mishra
- Chemistry Division, School of Advanced Sciences and Language, VIT Bhopal University, Bhopal, India
| | - Smita Mall
- Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, India
| | - Ashwani Kumar
- University Institute of Biotechnology, Chandigarh University, Mohali, India
| | - Kamal Dev
- Faculty of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, India
- Department of Pharmacology and Toxicology, Wright State University, Dayton, Ohio, USA
| | - Chirag N Patel
- Biotechnology Research Centre, Technology Innovation Institute, Abu Dhabi, UAE
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland, USA
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Liu Y, Wu Z, Li Y, Chen Y, Zhao X, Wu M, Xia Y. Metabolic reprogramming and interventions in angiogenesis. J Adv Res 2025; 70:323-338. [PMID: 38704087 PMCID: PMC11976431 DOI: 10.1016/j.jare.2024.05.001] [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: 03/15/2024] [Revised: 04/30/2024] [Accepted: 05/01/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Endothelial cell (EC) metabolism plays a crucial role in the process of angiogenesis. Intrinsic metabolic events such as glycolysis, fatty acid oxidation, and glutamine metabolism, support secure vascular migration and proliferation, energy and biomass production, as well as redox homeostasis maintenance during vessel formation. Nevertheless, perturbation of EC metabolism instigates vascular dysregulation-associated diseases, especially cancer. AIM OF REVIEW In this review, we aim to discuss the metabolic regulation of angiogenesis by EC metabolites and metabolic enzymes, as well as prospect the possible therapeutic opportunities and strategies targeting EC metabolism. KEY SCIENTIFIC CONCEPTS OF REVIEW In this work, we discuss various aspects of EC metabolism considering normal and diseased vasculature. Of relevance, we highlight that the implications of EC metabolism-targeted intervention (chiefly by metabolic enzymes or metabolites) could be harnessed in orchestrating a spectrum of pathological angiogenesis-associated diseases.
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Affiliation(s)
- Yun Liu
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Zifang Wu
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yikun Li
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China; College of Animal Science, South China Agricultural University, Guangzhou, Guangdong 510642, China
| | - Yating Chen
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China
| | - Xuan Zhao
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
| | - Miaomiao Wu
- Animal Nutritional Genome and Germplasm Innovation Research Center, College of Animal Science and Technology, Hunan Agricultural University, Changsha, Hunan 410128, China.
| | - Yaoyao Xia
- College of Animal Science and Technology, Southwest University, Chongqing 400715, China.
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Hassan HA. Exploring the impact of advanced glycation end products on diabetic salivary gland dysfunctions. Glycoconj J 2025; 42:97-106. [PMID: 40131578 DOI: 10.1007/s10719-025-10182-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 09/30/2024] [Accepted: 02/24/2025] [Indexed: 03/27/2025]
Abstract
The role of Advanced Glycation End Products (AGEs) in the pathophysiology of salivary gland dysfunction in diabetes has not been fully addressed. In this work, we discuss the pathophysiological mechanisms of salivary gland dysfunctions in diabetes, focusing on the role of AGEs. Hyperglycemia induces the generation and accumulation of AGEs, induces oxidative stress, and activates the receptor for AGEs (RAGE), with detrimental effects on the salivary glands and the submandibular autonomic innervation. Structural and ultrastructural alterations have been described in the three major salivary glands, and hypo-salivation development has been linked to early autonomic neuropathy. Poor metabolic control aggravates the salivary flow rate via injury to the autonomic nerve fiber bundles or direct damage to the secretory acinar cells of the glands. Chronic hyperglycemia, the most crucial feature of diabetes, leads to the generation and accumulation of advanced glycation end products (AGEs). The interest in the role of AGEs in the pathogenesis of diabetic complications has grown exponentially, and AGEs have been implicated as a primary culprit in the pathophysiology of diabetes and its various complications, including neuropathy, nephropathy, retinopathy, vasculopathy, and cardiomyopathy.
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Affiliation(s)
- Heba A Hassan
- Department of Clinical Pharmacology, Faculty of Medicine, Mutah University, P.O. Box 7, Al-Karak, 61710, Jordan.
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Lim GM, Cho GW. Mangiferin protects mesenchymal stem cells against DNA damage and cellular aging via SIRT1 activation. Mech Ageing Dev 2025; 224:112038. [PMID: 39874993 DOI: 10.1016/j.mad.2025.112038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 12/27/2024] [Accepted: 01/22/2025] [Indexed: 01/30/2025]
Abstract
The protective effects of mangiferin (MAG) against etoposide- and high glucose (HG)-induced DNA damage and aging were investigated in human bone marrow-mesenchymal stem cells (hBM-MSCs). Etoposide, a topoisomerase II inhibitor, was used to induce double-strand breaks (DSBs) in hBM-MSCs, resulting in increased genotoxicity, elevated levels of the DNA damage sensor ATM and CDKN1A, and decreased levels of the aging markers H3 and H4. MAG activated AMPK and SIRT1, thus protecting against DSB-induced damage. Following long-term exposure to HG, MAG significantly mitigated DNA damage and delayed cellular aging, as evidenced by the preservation of H3, H4, LMNB1, and SIRT1 mRNA levels and reduction in γ-H2AX foci and DSBs. Furthermore, MAG improved genome stability, as indicated by decreased LINE1 expression and increased levels of the heterochromatin marker TRIM28, thereby maintaining H3K9me3 levels. MAG and metformin treatment enhanced cell proliferation, reduced senescence-associated β-galactosidase staining, and lowered the levels of the senescence-associated secretory phenotype factors IL-1A, IL-1B, IL-6, IL-8, CCL2, and CCL20 and senescence marker CDKN1A, CDKN2A and p53. MAG may reduce DNA damage and delay aging in hBM-MSCs under HG conditions, highlighting their potential as therapeutic agents for aging-related diseases.
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Affiliation(s)
- Gyeong Min Lim
- Department of Biological Science, College of Natural Science, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea; BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju 61452, Republic of Korea
| | - Gwang-Won Cho
- Department of Biological Science, College of Natural Science, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Republic of Korea; BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Department of Integrative Biological Science, Chosun University, Gwangju 61452, Republic of Korea; The Basic Science Institute of Chosun University, Chosun University, Gwangju 61452, Republic of Korea.
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Rajala R, Griffin CT. A novel function for endothelial protease-activated receptors in modulating insulin receptor activity with implications for diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.21.644607. [PMID: 40196641 PMCID: PMC11974755 DOI: 10.1101/2025.03.21.644607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Thrombin, a serine protease with increased activity in diabetics, signals through protease-activated receptors 1 and 4 (PAR1/PAR4) on endothelial cells (ECs). While studying the roles of endothelial PAR1/4 in diabetic pathology, we found that mice with inducible deletion of both receptors on ECs (Par1/4 iECko ) displayed increased insulin sensitivity and were protected against streptozotocin (STZ)-induced diabetes. Concordantly, we found that cultured primary ECs with PAR1/4 deficiency had increased basal activity/phosphorylation of the insulin receptor (IR) and insulin transcytosis. This elevated IR activity correlated with reduced activity of protein tyrosine phosphatase 1B (PTP1B), which is a negative regulator of IR activity. Lastly, Par1/4 iECko mice with additional deletion of one allele of the IR gene demonstrated restoration of diabetic phenotypes after STZ treatment, indicating that these phenotypes are driven by heightened IR activity. These findings establish a novel link between endothelial PAR signaling and IR regulation, underscoring the critical role of ECs in metabolic homeostasis and identifying a potential therapeutic target for diabetes.
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Affiliation(s)
- Rahul Rajala
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | - Courtney T. Griffin
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
- Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
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Xu D, Qi P, He Q, Shan D, Yang G, Yang H, Liu P, Liang H, Lei S, Guo F, Wang D, Lu J. Systolic Blood Pressure Modifies the Effect of Endovascular Thrombectomy in Acute Ischemic Stroke: A Mediation Analysis. Am J Hypertens 2025; 38:206-216. [PMID: 39708361 DOI: 10.1093/ajh/hpae155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/16/2024] [Accepted: 12/12/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Systolic blood pressure (BP) is a key factor in the outcomes of patients with acute ischemic stroke (AIS) receiving endovascular thrombectomy (EVT). However, the factors that mediate the association between BP and clinical outcome are unclear. METHODS Consecutive patients with AIS in the anterior circulation underwent continuous BP monitoring for 24 hours. The 3-month modified Rankin scale (mRS) score was defined as the clinical functional outcome. The systolic BPI indices (BPIs) were successive variation, standard deviation, variability independent of mean BP (VIM), and 24-hour mean BP. Regression analysis was used to assess the correlation between different BPIs and functional outcomes, whereas mediation analysis was employed to assess the potential mediating effects of baseline risk factors through BP on functional outcomes. RESULTS A total of 140 of 292 patients (47.9%) achieved functional independence, and 87 (29.8%) experienced hemorrhagic transformation (HT). A history of stroke or hypertension and NIHSS score at onset were associated with SD and VIM (P < 0.05). BP variation (BPV) was still strongly associated with functional outcomes after adjustment for different risk factors. Mediation analysis revealed that stroke affected functional outcomes by affecting BPV, while the hypertension history affected functional prognosis by impacting the 24-hour mean BP and BPV. In addition, higher National Institute of Health stroke scale (NIHSS) scores were associated with increased BPV, whereas increased BPV was correlated with a greater proportion of unfavorable outcomes. CONCLUSIONS To our knowledge, this study is the first to explore the mediating effects of different BPIs on the relationships between risk factors and functional outcomes and may provide new insights and potential mechanisms for improving AIS prognosis.
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Affiliation(s)
- Dingkang Xu
- Department of Neurosurgery, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
- Department of Neurosurgery, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
| | - Peng Qi
- Department of Neurosurgery, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Qiang He
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Dezhi Shan
- Department of Neurosurgery, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
| | - Guozheng Yang
- Department of Neurosurgery, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
| | - Hongchun Yang
- Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Peng Liu
- Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Hui Liang
- Department of Neurology, Medical Center and Hainan Academician Innovation Platform, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Hainan Province Clinical, Haikou, Hainan, China
| | - Shixiong Lei
- Department of Neurosurgery, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
| | - Fuyou Guo
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Daming Wang
- Department of Neurosurgery, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
| | - Jun Lu
- Department of Neurosurgery, National Center of Gerontology, Institute of Geriatric Medicine, Beijing Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Graduate School of Peking Union Medical College, Beijing, China
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12
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Matsathit U, Komolkriengkrai M, Khimmaktong W. Glabridin and gymnemic acid alleviates choroid structural change and choriocapillaris impairment in diabetic rat's eyes. World J Diabetes 2025; 16:97336. [PMID: 40093291 PMCID: PMC11885962 DOI: 10.4239/wjd.v16.i3.97336] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 11/11/2024] [Accepted: 12/25/2024] [Indexed: 01/21/2025] Open
Abstract
BACKGROUND Small blood vessels in the eyes are more susceptible to injury, which can lead to complications. However, since diabetic retinopathy is often a serious clinical condition, most of this study focuses on the vascular system of the choroid. As part of this study, we looked at how gymnemic acid (from Gymnema sylvestre) and glabridin (from Glycyrrhiza glabra, or licorice) might help diabetic rats' choroid structural change and blood vessels. AIM To explore the effects of glabridin and gymnemic acid on the structural changes of the choroidal layer and choriocapillaris as well as the expression of vascular endothelial growth factor (VEGF) and cluster of differentiation (CD) 31 in diabetic rat's eye. METHODS The male Wistar rats were separated into five groups: The control group (control), the diabetic group (DM), the diabetic rats treated with glabridin 40 mg/kg body weight (DM + GB), the diabetic rats treated with gymnemic acid 400 mg/kg body weight (DM + GM), and the diabetic rats treated with glyburide 4 mg/kg body weight (DM + GR). RESULTS There was an increase in the thickness of both the choroid layer and the wall of the arteries in the DM. A decrease in vascularity and choroidal impairment was found in DM rats. After eight weeks of experimentation, the choroidal thickness increased, and the walls of choroid arteries. The choroidal thickness in the DM + GB was 15.69 ± 1.54 μm, DM + GM was 14.84 ± 1.31, and DM + GR groups was 16.45 ± 1.15 when compared with DM group (27.22 ± 2.05), the walls thickness of choroid arteries in the DM + GB was 10.23 ± 1.11, DM + GM was 10.41 ± 1.44, and DM + GR was 9.80 ± 1.78 when compared with DM group (16.35 ± 5.01), The expression of VEGF and CD31 was lower compared to the DM group. CONCLUSION In diabetic choroidopathy, hyperglycemia and inflammation cause damage to the neurovascular unit and blood-retinal barrier. Anti-VEGF treatments can slow or reverse the progression of the disease. According to current research findings, glabridin and gymnemic acid can reduce damage to the choroid, which is a factor that can sometimes result in vision loss.
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Affiliation(s)
- Udomlak Matsathit
- Department of Food Science and Nutrition, Faculty of Science and Technology, Prince of Songkla University, Pattani 94000, Thailand
| | - Manaras Komolkriengkrai
- Department of Anatomy, Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand
| | - Wipapan Khimmaktong
- Department of Anatomy, Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat Yai 90110, Songkhla, Thailand
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13
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Haron A, Li L, Shuang J, Lin C, Mansoubi M, Shi X, Horn D, Reeves N, Bowling F, Bradbury K, Eccles A, Dogan S, Dawes H, Cooper G, Weightman A. In-shoe plantar temperature, normal and shear stress relationships during gait and rest periods for people living with and without diabetes. Sci Rep 2025; 15:8804. [PMID: 40087292 PMCID: PMC11909256 DOI: 10.1038/s41598-025-91934-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 02/24/2025] [Indexed: 03/17/2025] Open
Abstract
Diabetic foot ulcers (DFUs) are a common complication of diabetes. This study aims to investigate the relationships between in-shoe plantar temperature, normal and shear stress during walking and rest periods for participants with and without diabetes. For this purpose, a novel temperature, normal and shear stress sensing system was developed and embedded in an insole at the hallux, first metatarsal head and calcaneus region. Ten participants living with diabetes with no history of previous ulceration and ten healthy participants were recruited. Participants walked on a treadmill for 15 min and then rested for 20 min wearing the sensing insole. Results showed high correlation (Spearman's rs ≥ 0.917) between heat energy, total plantar temperature change, during walking and strain energy, cumulative stress squared in all participants. Importantly, between-group comparisons showed indications of thermal regulation differences in participants with and without diabetes, with the first metatarsal head site showing significantly higher temperature at the end of the active period (P = 0.0097) although walking speed and mechanical stress were similar. This research demonstrates for the first time the correlation between strain energy and heat energy in-shoe during gait. Further research is needed to quantify relationships and investigate thermal regulation as a mechanism for DFU formation.
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Affiliation(s)
- Athia Haron
- School of Engineering, University of Manchester, Manchester, UK
| | - Lutong Li
- School of Engineering, University of Manchester, Manchester, UK
| | - Jiawei Shuang
- College of Mechanical Engineering, Yangzhou University, Yangzhou, 225127, People's Republic of China
| | - Chaofan Lin
- School of Engineering, University of Manchester, Manchester, UK
| | - Maedeh Mansoubi
- Medical School, NIHR Exeter BRC, University of Exeter, Exeter, UK
| | - Xiyu Shi
- Institute for Digital Technologies, Loughborough University London, Queen Elizabeth Olympic Park, Here East, London, UK
| | - Daniel Horn
- Survey of Health, Ageing, and Retirement in Europe (SHARE Berlin Institute), Berlin, Germany
| | - Neil Reeves
- Lancaster Medical School, Faculty of Health and Medicine, Lancaster University, Lancaster, UK
| | - Frank Bowling
- Manchester University NHS Foundation Trust within the Departments of Diabetes and Vascular Surgery, Manchester, UK
| | | | - Andrew Eccles
- School of Social Work & Social Policy, University of Strathclyde, Glasgow, UK
| | - Safak Dogan
- Institute for Digital Technologies, Loughborough University London, Queen Elizabeth Olympic Park, Here East, London, UK
| | - Helen Dawes
- Medical School, NIHR Exeter BRC, University of Exeter, Exeter, UK
| | - Glen Cooper
- School of Engineering, University of Manchester, Manchester, UK
| | - Andrew Weightman
- School of Engineering, University of Manchester, Manchester, UK.
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14
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Alrubaiee GG. Prevalence of chronic diabetic complications and associated risk factors among follow-up diabetic patients: estimates from a referral national diabetes center in Yemen. BMC Endocr Disord 2025; 25:68. [PMID: 40082878 PMCID: PMC11907894 DOI: 10.1186/s12902-025-01893-5] [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: 09/09/2024] [Accepted: 03/03/2025] [Indexed: 03/16/2025] Open
Abstract
BACKGROUND Emergence and progression of diabetic complications are associated with several risk factors. Identifying these risk factors related to diabetes helps avoid such complications and develop preventive measures to protect patients and improve their quality of life. This study aimed to estimate the prevalence of chronic complications among Yemeni diabetic patients and investigate the associations between these complications, sociodemographic characteristics, and diabetic risk factors. METHODS This cross-sectional study was conducted at the National Diabetic Referral Center in Sana'a, Yemen, from September 1 to October 30, 2023. Of the 228 respondents, 222 were considered valid for analysis. Data for this study were collected using the World Health Organization (WHO) STEPS Surveillance questionnaire and a simple physical assessment. IBM SPSS version 24.0 was utilized to manage and analyze the data. Descriptive statistics were used to determine the prevalence of diabetes complications. The chi-square test and binary logistic regression were used to determine the associations and risk factors. A p-value of less than 0.05 was used to determine statistical significance. RESULTS Diabetes-related complications were reported by 62.6% of respondents, with females having a greater risk of diabetic foot, nephropathy, and retinopathy, while males had an increased risk of neuropathy complications. Unemployment, obesity, non-adherence to diabetes regimens, uncontrolled hypertension, longer duration of type 1 diabetes (T1DM), and irregular physician check-ups were identified as key predictors of diabetes-related complications. Administration of statins as lipid-lowering medications was associated with a reduced risk of coronary artery disease (CAD) or ischemic stroke complications. CONCLUSION Chronic complications related to diabetes were common among patients in Yemen. Factors such as unemployment, obesity, non-adherence to diabetes regimens, uncontrolled hypertension, longer duration of T1DM, and irregular physician check-ups were identified as key predictors of these complications. Implementation of the WHO non-communicable disease package is strongly recommended. This package comprises comprehensive measures aimed at detecting, treating, preventing, and controlling diabetic complications and ultimately improving the overall management of diabetes in Yemen. CLINICAL TRIAL NUMBER Not applicable.
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Affiliation(s)
- Gamil Ghaleb Alrubaiee
- Department of Community Health, College of Nursing, University of Hail, Hail, 2440, Saudi Arabia.
- Department of Community Health and Nutrition, Al-Razi University, Sana'a, Yemen.
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15
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Zanchetta M, Adani GL, Micheletti G, Poto GE, Piccioni SA, Carbone L, Monteleone I, Sandini M, Marrelli D, Calomino N. Perforated Calculous Cholecystitis and Incidental Squamous Cell Carcinoma of the Gallbladder-A Complex Relationship with a Difficult Management in the Acute Setting. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:452. [PMID: 40142263 PMCID: PMC11944027 DOI: 10.3390/medicina61030452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/26/2025] [Revised: 02/23/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025]
Abstract
The worldwide prevalence of gallstones (GSs) is estimated to be between 10% and 15% in the general population. Gallbladder carcinoma (GBC) is the most common biliary tract neoplasia, and it is characterized by highly aggressive behavior and poor overall prognosis. Long-standing GSs and chronic inflammatory state represent the most common risk factors for GBC, promoting a carcinogenic microenvironment. Long-standing GSs expose patients to potentially severe surgical and oncological complications. A 71-year-old gentleman, who had never experienced biliary symptoms and had diabetes mellitus (DM), presented with severe peritonitis due to perforated acute calculous cholecystitis. The patient underwent an emergent laparotomic cholecystectomy. Histopathology found a rare pT2b poorly differentiated squamocellular carcinoma of the gallbladder. Although more difficult due to the concomitant inflammatory context, it is critical to identify suspicious lesions during preoperative imaging in patients at high risk of malignancy presenting with complex acute gallbladder pathologies. A review of the literature was conducted to gain a deeper insight into the relationship between long-standing GSs and GBC, evaluating also the difficult diagnosis and management of malignancy in the acute setting. Considering the existing literature, the choice to pursue a prophylactic cholecystectomy may be justifiable in selected asymptomatic GS patients at high risk for GBC.
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Affiliation(s)
- Matteo Zanchetta
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Gian Luigi Adani
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Giorgio Micheletti
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Gianmario Edoardo Poto
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Stefania Angela Piccioni
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Ludovico Carbone
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Ilaria Monteleone
- Diagnostic Imaging Unit, Department of Medical, Surgical and Neurosciences, Siena University Hospital, Azienda Ospedaliera Universitaria Senese, Viale Bracci 10, 53100 Siena, Italy
| | - Marta Sandini
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Daniele Marrelli
- Unit of General Surgery and Surgical Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
| | - Natale Calomino
- Kidney Transplant Unit, Department of Medicine, Surgery and Neuroscience, Siena University Hospital, University of Siena, Viale Mario Bracci 16, 53100 Siena, Italy
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16
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Huang RS, Balas M, Jhaveri A, Popovic MM, Kertes PJ, Muni RH. Comparison of Renal Adverse Events Between Intravitreal Anti-Vascular Endothelial Growth Factor Agents: A Meta-Analysis. Am J Ophthalmol 2025; 271:466-477. [PMID: 39746595 DOI: 10.1016/j.ajo.2024.12.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 12/17/2024] [Accepted: 12/22/2024] [Indexed: 01/04/2025]
Abstract
PURPOSE To compare the risk of renal adverse events, particularly acute kidney injury (AKI), between intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents. DESIGN Meta-analysis. METHODS A systematic literature search was conducted on Ovid Medline, Embase, and the Cochrane Library for randomized controlled trials (RCTs) published from January 2005 to February 2024 involving adult patients receiving anti-VEGF intravitreal injections for age-related macular degeneration, diabetic macular edema, and macular edema secondary to retinal vein occlusion. The primary outcome was the comparative risk of AKI between anti-VEGF agents and sham injections. Secondary outcomes involved other renal adverse events. Subgroup analyses were conducted by specific disease indications. A random-effects model was used for meta-analysis to estimate risk ratios (RRs) and their 95% confidence intervals, with a P value of <.05 representing statistical significance. Risk of bias was assessed using the Cochrane Risk of Bias 2 (ROB2) tool, and the certainty of evidence was evaluated through the Cochrane Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. RESULTS A total of 10,031 eyes from 11 RCTs were included. No significant differences were found in the risk of acute or chronic renal conditions, obstructive uropathies, neoplasia, or infectious processes between anti-VEGF agents and sham therapy. AKI was reported in 5.4% (n = 10/185) of patients treated with bevacizumab, 1.3% (n = 6/456) with sham, 1.0% (n = 48/4724) with aflibercept, 0.8% (n = 15/1929) with faricimab, 0.5% (n = 5/1098) with brolucizumab, and 0.3% (n = 5/1639) with ranibizumab. No significant differences in AKI risk were observed between any of the anti-VEGF agents and sham (P > .05 for all comparisons). However, there was an increased risk of patient-reported symptoms with 1.25 mg bevacizumab compared to 2 mg aflibercept (RR = 3.26, 95% CI = 1.07-9.93, P = .04), driven primarily by reports of hematuria: 4.3% (bevacizumab), 0.7% (sham), 0.2% (aflibercept), 0.1% (faricimab), and 0.1% (ranibizumab). CONCLUSIONS US Food and Drug Administration (FDA)-approved intravitreal anti-VEGF agents do not significantly increase the risk of AKI compared to sham injections. Nevertheless, variations in patient-reported renal symptoms were observed across different anti-VEGF drugs. These variations were influenced primarily by differences in hematuria events, which may be a result of differential systemic absorption by these agents. These results underscore the importance of continuous monitoring and pharmacovigilance.
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Affiliation(s)
- Ryan S Huang
- From the Temerty Faculty of Medicine (R.S.H., A.J.), University of Toronto, Toronto, Ontario, Canada
| | - Michael Balas
- Department of Ophthalmology and Vision Sciences (M.B., M.M.P., P.J.K., R.H.M.), University of Toronto, Toronto, Ontario, Canada
| | - Aaditeya Jhaveri
- From the Temerty Faculty of Medicine (R.S.H., A.J.), University of Toronto, Toronto, Ontario, Canada
| | - Marko M Popovic
- Department of Ophthalmology and Vision Sciences (M.B., M.M.P., P.J.K., R.H.M.), University of Toronto, Toronto, Ontario, Canada; Stein Eye Institute and Doheny Eye Institute (M.M.P.), David Geffen School of Medicine, University of California, Los Angeles, California, USA
| | - Peter J Kertes
- Department of Ophthalmology and Vision Sciences (M.B., M.M.P., P.J.K., R.H.M.), University of Toronto, Toronto, Ontario, Canada; John and Liz Tory Eye Centre (P.J.K.), Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Rajeev H Muni
- Department of Ophthalmology and Vision Sciences (M.B., M.M.P., P.J.K., R.H.M.), University of Toronto, Toronto, Ontario, Canada; Department of Ophthalmology (R.H.M.), St. Michael's Hospital/Unity Health Toronto, Toronto, Ontario, Canada.
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17
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Patel S, Yang E, Milne TJ, Hussaini H, Cooper PR, Friedlander LT. Angiogenic effects of Type 2 diabetes on the dental pulp. Int Endod J 2025; 58:434-448. [PMID: 39652136 DOI: 10.1111/iej.14181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 10/17/2024] [Accepted: 11/24/2024] [Indexed: 01/03/2025]
Abstract
AIM To investigate the influence of type 2 diabetes (T2D) and hyperglycaemia on blood vessels and angiogenic markers in the dental pulp. METHODOLOGY Extracted non-carious permanent molar teeth were collected from patients with well-controlled T2D (n = 10) and non-T2D (controls) (n = 10). The pulp was examined qualitatively using haematoxylin and eosin and Van Gieson stains. Immunohistochemistry (IHC) identified the primary receptor for VEGF, VEGFR2, and the endothelial cell marker CD34. Primary human dental pulp cell (hDPC) lines (n = 3) were established from tissue explants and cells were grown in media containing 5.5 mM D-glucose (control), 12.5 mM (prediabetes) and 25 mM (T2D) D-glucose under normoxic conditions for 24, 48 and 72 h. Assays for metabolic activity (PrestoBlue) and cell viability (Crystal Violet staining) assessed the hDPC response to hyperglycaemia. The expression of angiogenic genes VEGFA, KDR, FLT-1, ANGPT1, ANGPT2, TIE1 and TEK were analysed using quantitative real-time polymerase chain reaction. ELISAs were used to quantify the level of expressed protein for VEGFA, ANG1, ANG2, TIE1, and TIE2 in the media. Data analyses were performed using GraphPad Prism and anova tests at p < .05. RESULTS Blood vessels in T2D samples had thicker walls and stained strongly for elastin and collagen compared with non-T2D samples. VEGFR2 protein was not seen in any T2D samples but consistently detected in healthy specimens. Culturing healthy cells in high glucose (25 mM) significantly reduced cell viability at 24 h compared to the control (p = .005) and 12.5 mM glucose (p = .001) but the metabolic activity was not greatly affected by glucose and time. VEGFA mRNA and VEGFA protein expression were detected in the hDPCs in the presence of hyperglycaemia over time; however, the primary receptor, VEGFR2/KDR, was not detected. Genes for the ANG1 and ANG2 and their receptors were expressed at all glucose concentrations but hyperglycaemia upregulated ANG2 mRNA. Proteins for all growth factors were detected in the media however proteins for TIE1 and TIE2 receptors were not. CONCLUSION T2D and hyperglycaemia may impair the angiogenic response in the pulp similar to other body site. The scarcity of VEGFR2 and increased expression of ANG2 in response to hyperglycaemia suggests that VEGF and ANG-Tie1/Tie2 signalling may be compromised.
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Affiliation(s)
- S Patel
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - E Yang
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - T J Milne
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - H Hussaini
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - P R Cooper
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - L T Friedlander
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Mohammed AQ, Liu L, Alifu J, Yin G, Zhang W, Xu Y, Abdu FA, Che W. Association of novel inflammatory and metabolic markers with mortality in individuals with overweight and obesity. Nutr Metab Cardiovasc Dis 2025; 35:103859. [PMID: 39956696 DOI: 10.1016/j.numecd.2025.103859] [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: 08/16/2024] [Revised: 12/10/2024] [Accepted: 01/07/2025] [Indexed: 02/18/2025]
Abstract
BACKGROUND AND AIMS Stress hyperglycemia ratio (SHR) and pan-immune-inflammation value (PIV) are novel prognostic markers associated with metabolic changes and chronic inflammation, but their association with mortality risk in individuals with overweight and obesity remains unknown. We aimed to investigate impact of SHR and PIV on mortality risk in individuals with overweight and obesity. METHODS AND RESULTS This cohort study included 16,703 U S adults with overweight and obesity. SHR and PIV were estimated, and Cox regression, ROC, and Kaplan-Meier curves analyzed their associations with all-cause and cause-specific mortality. Subgroup and interaction analyses tested SHR and PIV consistency. Over a median follow-up of 110 months, there were 2432 all-cause deaths (14.6 %), including 677 cardiovascular, 577 cancer, and 130 cerebrovascular deaths. Participants were categorized by optimal SHR (≥1.038 or <1.038) and PIV (≥301 or <301) cutoffs. High SHR was associated with higher overall and cause-specific mortality (log-rank p < 0.001). High PIV was linked to increased risks of overall, cardiovascular, and cancer mortality (log-rank p < 0.001). Multivariate Cox models showed elevated SHR was associated with increased all-cause, cardiovascular, and cancer mortality (HR:1.59; 95%CI: 1.34-1.89; HR:1.45; 95%CI: 1.03-2.04; HR:1.66; 95%CI: 1.15-2.38, respectively). Elevated PIV was linked to higher all-cause and cardiovascular mortality (HR: 1.18; 95%CI: 1.02-1.37; HR:1.35; 95%CI: 1.02-1.79, respectively). Poorer survival was noted in obesity + high SHR and overweight + high PIV subgroups (log-rank p < 0.001). CONCLUSIONS Elevated SHR and PIV are significant predictors of increased all-cause and cause-specific mortality in individuals with overweight and obesity.
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Affiliation(s)
- Abdul-Quddus Mohammed
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lu Liu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jiasuer Alifu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guoqing Yin
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wen Zhang
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yawei Xu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fuad A Abdu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Wenliang Che
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Department of Cardiology, Shanghai Tenth People's Hospital Chongming Branch, Shanghai, China.
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Viggiano D, Joshi R, Borriello G, Cacciola G, Gonnella A, Gigliotti A, Nigro M, Gigliotti G. SGLT2 Inhibitors: The First Endothelial-Protector for Diabetic Nephropathy. J Clin Med 2025; 14:1241. [PMID: 40004772 PMCID: PMC11856817 DOI: 10.3390/jcm14041241] [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: 01/06/2025] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
Sodium-glucose co-transporter type 2 inhibitors (SGLT2i) have emerged as a class of agents relevant for managing diabetic nephropathy and cardiopathy. In a previous report, we noticed that these drugs share, with other drugs with "nephroprotective" effects, the ability to reduce the glomerular filtration rate (GFR), thus suggesting the kidney hemodynamic effect as a proxy for optimal drug dosage. We also noticed that all known nephroprotective drugs exert cardioprotective functions, suggesting the possibility of activities not mediated by the kidney. Finally, we observe that nephroprotective drugs can be grouped according to their effects on hemoglobin levels, thus suggesting their mechanism of action. While the primary mechanism of SGLT2i involves glycosuria and natriuria, growing evidence suggests broader therapeutic effects beyond hemodynamic modulation. Specifically, the evidence that SGLT2 can be expressed in several atypical regions under pathological conditions, supports the possibility that its inhibition has several extratubular effects. Evidence supports the hypothesis that SGLT2i influence mitochondrial function in various cell types affected by diabetes, particularly in the context of diabetic nephropathy. Notably, in SGLT2i-treated patients, the extent of albumin-creatinine ratio (ACR) reduction post-treatment may be correlated with mitochondrial staining intensity in glomerular endothelial cells. This implies that the anti-proteinuric effects of SGLT2i could involve direct actions on glomerular endothelial cell. Our investigation into the role of SGLT2 inhibitors (SGLT2i) in endothelial function suggests that the aberrant expression of SGLT2 in endothelial cells in T2DM would lead to intracellular accumulation of glucose; therefore, SGLT2i are the first type of endothelial protective drugs available today, with potential implications for ageing-related kidney disease. The review reveals two major novel findings: SGLT2 inhibitors are the first known class of endothelial-protective drugs, due to their ability to prevent glucose accumulation in endothelial cells where SGLT2 is aberrantly expressed in Type 2 Diabetes. Additionally, the research demonstrates that SGLT2 inhibitors share a GFR-reducing effect with other nephroprotective drugs, suggesting both a mechanism for optimal drug dosing and potential broader applications in ageing-related kidney disease through their effects on mitochondrial function and glomerular endothelial cells.
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Affiliation(s)
- Davide Viggiano
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Rashmi Joshi
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Gianmarco Borriello
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Giovanna Cacciola
- Department Translational Medical Sciences, University of Campania, 80138 Naples, Italy; (R.J.); (G.B.); (G.C.)
| | - Annalisa Gonnella
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Andrea Gigliotti
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Michelangelo Nigro
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
| | - Giuseppe Gigliotti
- Department Nephrology, Eboli Hospital, 84025 Eboli, Italy; (A.G.); (A.G.); (M.N.); (G.G.)
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20
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Li S, Zhou Y, Kong D, Miao Y, Guan N, Gao G, Jin J, Ye H. A visually-induced optogenetically-engineered system enables autonomous glucose homeostasis in mice. J Control Release 2025; 378:27-37. [PMID: 39645086 DOI: 10.1016/j.jconrel.2024.12.006] [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: 08/20/2024] [Revised: 12/02/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
With the global population increasing and the demographic shifting toward an aging society, the number of patients diagnosed with conditions such as peripheral neuropathies resulting from diabetes is expected to rise significantly. This growing health burden has emphasized the need for innovative solutions, such as brain-computer interfaces. brain-computer interfaces, a multidisciplinary field that integrates neuroscience, engineering, and computer science, enable direct communication between the human brain and external devices. In this study, we developed an autonomous diabetes therapeutic system that employs visually-induced electroencephalography devices to capture and decode event-related potentials using machine learning techniques. We present the visually-induced optogenetically-engineered system for therapeutic expression regulation (VISITER), which generates diverse output commands to control illumination durations. This system regulates insulin expression through optogenetically-engineered cells, achieving blood glucose homeostasis in mice. Our results demonstrate that VISITER effectively and precisely modulates therapeutic protein expression in mammalian cells, facilitating the rapid restoration of blood glucose homeostasis in diabetic mice. These findings underscore the potential for diabetic patients to manage insulin levels autonomously by focusing on target images, paving the way for a more self-directed approach to blood glucose control.
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Affiliation(s)
- Shurui Li
- School of Mathematics, East China University of Science and Technology, Shanghai 200237, China
| | - Yang Zhou
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Wuhu Hospital, Health Science Center, East China Normal University, Anhui 241001, China
| | - Deqiang Kong
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Yangyang Miao
- School of Electrical Engineering and Automation, Nantong University, Jiangsu 226019, China
| | - Ningzi Guan
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
| | - Ganglong Gao
- Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.
| | - Jing Jin
- School of Mathematics, East China University of Science and Technology, Shanghai 200237, China; Key Laboratory of Smart Manufacturing in Energy Chemical Process, Ministry of Education, East China University of Science and Technology, Shanghai 200237, China.
| | - Haifeng Ye
- Synthetic Biology and Biomedical Engineering Laboratory, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Wuhu Hospital, Health Science Center, East China Normal University, Anhui 241001, China.
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21
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Lecce E, Bellini A, Greco G, Martire F, Scotto di Palumbo A, Sacchetti M, Bazzucchi I. Physiological mechanisms of neuromuscular impairment in diabetes-related complications: Can physical exercise help prevent it? J Physiol 2025. [PMID: 39898972 DOI: 10.1113/jp287589] [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: 09/20/2024] [Accepted: 01/14/2025] [Indexed: 02/04/2025] Open
Abstract
Diabetes mellitus is a chronic disorder that progressively induces complications, compromising daily independence. Among these, diabetic neuropathy is particularly prevalent and contributes to substantial neuromuscular impairments in both types 1 and 2 diabetes. This condition leads to structural damage affecting both the central and peripheral nervous systems, resulting in a significant decline in sensorimotor functions. Alongside neuropathy, diabetic myopathy also contributes to muscle impairment and reduced motor performance, intensifying the neuromuscular decline. Diabetic neuropathy typically implicates neurogenic muscle atrophy, motoneuron loss and clustering of muscle fibres as a result of aberrant denervation-reinervation processes. These complications are associated with compromised neuromuscular junctions, where alterations occur in pre-synaptic vesicles, mitochondrial content and post-synaptic signalling. Neural damage is intensified by chronic hyperglycaemia and oxidative stress, exacerbating vascular dysfunction and reducing oxygen delivery. These complications imply a severe decline in neuromuscular performance, evidenced by reductions in maximal force and power output, rate of force development and muscle endurance. Furthermore, diabetes-related complications are compounded by age-related degenerative changes in long-term patients. Aerobic and resistance training offer promising approaches for managing blood glucose levels and neuromuscular function. Aerobic exercise promotes mitochondrial biogenesis and angiogenesis, supporting metabolic and cardiovascular health. Resistance training primarily enhances neural plasticity, muscle strength and hypertrophy, which are crucial factors for mitigating sarcopenia and preserving functional independence. This topical review examines current evidence on the physiological mechanisms underlying diabetic neuropathy and the potential impact of physical activity in counteracting this decline.
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Affiliation(s)
- Edoardo Lecce
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Alessio Bellini
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Giuseppe Greco
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Fiorella Martire
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Alessandro Scotto di Palumbo
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Massimo Sacchetti
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
| | - Ilenia Bazzucchi
- Laboratory of Exercise Physiology, Department of Movement, Human, and Health Sciences, University of 'Foro Italico', Rome, Italy
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22
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Li X, Zhu D, Zhao B, Li Q, Jin P. Alternative splicing: Therapeutic target for vasculopathy in diabetic complications. Life Sci 2025; 362:123331. [PMID: 39734014 DOI: 10.1016/j.lfs.2024.123331] [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: 08/25/2024] [Revised: 12/03/2024] [Accepted: 12/19/2024] [Indexed: 12/31/2024]
Abstract
It is becoming increasingly evident that diabetic vascular complications seriously threaten human health. The most prevalent microvascular complications include kidney disease, retinal disease, cardiovascular diseases and amputation. Conventional treatments can only relieve the progression of the diseases, and is no longer appropriate for the long-term management of diabetic patients. Exploring a novel therapeutic regimens and improvements in management of Diabetic Complications is required. Alternative splicing has been found to play a crucial role in the occurrence and treatment of diseases, including the destruction and generation of blood vessels in diabetes. Alternative splicing is an important factor in the high complexity of multicellular eukaryotic transcriptome, and angiogenesis, which is an important process controlled by alternative splicing mechanism. This review mainly introduces the current understanding of alternative splicing and the role that alternative splicing plays in the diabetic complications, with a special focus on vascular system. In this study, we summarized alternative splicing in relation to diabetes complications and the pathogenesis of diabetic vasculopathy. It discussed potential treatment strategies for correcting aberrant splicing and suggested novel approaches for addressing diabetes complications.
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Affiliation(s)
- Xiaoyue Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Dong Zhu
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China; Xuzhou Medical University, Xuzhou, China
| | - Bingkun Zhao
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Qiang Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
| | - Peisheng Jin
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
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23
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Perissiou M, Saynor ZL, Feka K, Edwards C, James TJ, Corbett J, Mayes H, Shute J, Cummings M, Black MI, Strain WD, Little JP, Shepherd AI. Ketone monoester ingestion improves cardiac function in adults with type 2 diabetes: a double-blind, placebo-controlled, randomized, crossover trial. J Appl Physiol (1985) 2025; 138:546-558. [PMID: 39818982 DOI: 10.1152/japplphysiol.00800.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 11/01/2024] [Accepted: 01/08/2025] [Indexed: 01/19/2025] Open
Abstract
Type 2 diabetes (T2D) is a metabolic disease associated with cardiovascular dysfunction. The myocardium preferentially uses ketones over free fatty acids as a more energy-efficient substrate. The primary aim was to assess the effects of ketone monoester (Kme) ingestion on cardiac output index ([Formula: see text]i). The secondary aims were to assess the effects of Kme ingestion on markers of cardiac hemodynamics, muscle oxygenation, and vascular function at rest, during and following step-incremental cycling. We undertook a double-blind, randomized, crossover design study in 13 adults [age, 66 ± 10 yr; body mass index (BMI), 31.3 ± 7.0 kg·m-2] with T2D. Participants completed two conditions, where they ingested a Kme (0.115 g·kg-1) or a placebo taste-matched drink. Cardiac function was measured using thoracic impedance cardiography, and muscle oxygenation of the calf was determined via near-infrared spectroscopy. Macrovascular endothelial function was measured by flow-mediated dilation (FMD), and microvascular endothelial function was measured via transdermal delivery of acetylcholine (ACh) and insulin. Circulating β-hydroxybutyrate [β-Hb] was measured throughout. Kme ingestion raised circulating β-Hb throughout the protocol (peak 1.9 mM; P = 0.001 vs. placebo). Kme ingestion increased [Formula: see text]i by 0.75 ± 0.5 L·min-1·m-2 (P = 0.003), stroke volume index by 7.2 ± 4.5 mL·m-2 (P = 0.001), and peripheral muscle oxygenation by 9.9 ± 7.1% (P = 0.001) and reduced systemic vascular resistance index by -420 ± -225 dyn·s-1·cm-5·m-2 (P = 0.031) compared with the placebo condition. There were no differences between Kme and placebo in heart rate (P = 0.995), FMD (P = 0.542), ACh max (P = 0.800), and insulin max (P = 0.242). Ingestion of Kme improved [Formula: see text], stroke volume index, and peripheral muscle oxygenation but did not alter macro- or microvascular endothelial function in people with T2D.NEW & NOTEWORTHY For the first time, we show that acute ketone monoester ingestion (Kme) can increase cardiac output and stroke volume and reduce systemic vascular resistance at rest and during exercise in sodium glucose transporter inhibitors naïve (i.e. no drug-induced ketosis) people with type 2 diabetes. Acute Kme ingestion improves peripheral skeletal muscle oxygenation during moderate intensity and maximal exercise. Kme has no effect on macro- or microvascular endothelial function in people with type 2 diabetes.
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Affiliation(s)
- M Perissiou
- Physical Activity, Health and Rehabilitation Thematic Research Group, School of Psychology, Sport & Health Sciences, Faculty of Science and Health, University of Portsmouth, Portsmouth, United Kingdom
| | - Z L Saynor
- School of Health Sciences, Faculty of Environmental and Life Sciences, University of Southampton, Southampton, United Kingdom
| | - K Feka
- VasoActive Research Group, School of Health, University of Sunshine Coast, Sippy Downs, Queensland, Australia
| | - C Edwards
- Physical Activity, Health and Rehabilitation Thematic Research Group, School of Psychology, Sport & Health Sciences, Faculty of Science and Health, University of Portsmouth, Portsmouth, United Kingdom
| | - T J James
- School of Sport and Exercise Science, Liverpool John Moores University, Liverpool, United Kingdom
| | - J Corbett
- Physical Activity, Health and Rehabilitation Thematic Research Group, School of Psychology, Sport & Health Sciences, Faculty of Science and Health, University of Portsmouth, Portsmouth, United Kingdom
| | - H Mayes
- Physical Activity, Health and Rehabilitation Thematic Research Group, School of Psychology, Sport & Health Sciences, Faculty of Science and Health, University of Portsmouth, Portsmouth, United Kingdom
| | - J Shute
- School of Pharmacy and Biomedical Science, Faculty of Science and Health, University of Portsmouth, Portsmouth, United Kingdom
| | - M Cummings
- Academic Department of Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom
| | - M I Black
- College of Life and Environmental Sciences, St Luke's Campus, University of Exeter, Exeter, United Kingdom
| | - W D Strain
- College of Life and Environmental Sciences, St Luke's Campus, University of Exeter, Exeter, United Kingdom
| | - J P Little
- School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, British Columbia, Canada
| | - A I Shepherd
- Physical Activity, Health and Rehabilitation Thematic Research Group, School of Psychology, Sport & Health Sciences, Faculty of Science and Health, University of Portsmouth, Portsmouth, United Kingdom
- Academic Department of Diabetes and Endocrinology, Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Portsmouth, United Kingdom
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24
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Yuan CY, Zuo L, Dong YC, Liu BX, Qi H. Secretogranin III: a promising therapeutic target for intraocular neovascular lesions. Int Ophthalmol 2025; 45:26. [PMID: 39832055 PMCID: PMC11746947 DOI: 10.1007/s10792-024-03393-2] [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: 05/19/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025]
Abstract
PURPOSE The purpose of this study is to investigate the role of Secretogranin III (Scg3) in the pathogenesis of intraocular neovascular diseases and assess its potential as a therapeutic target for novel treatment strategies. METHODS A literature review was conducted to examine the expression of Scg3 in intraocular neovascular diseases. We reviewed studies on the interaction of Scg3 with its homologous receptors and its effect on endothelial cell proliferation, migration, and vascular permeability-key processes involved in angiogenesis and neovascularization. RESULTS Scg3 was found to be upregulated in the tissues affected by diabetic retinopathy (DR), retinopathy of prematurity (ROP), and choroidal neovascularization. In DR, Scg3 expression was linked to retinal neovascularization, where it facilitated endothelial cell proliferation and migration, essential processes for the formation of new blood vessels. Similarly, in ROP, Scg3 was associated with fibrovascular tissue proliferation within avascular retinal zones, contributing to the pathological neovascularization seen in premature infants. In the context of age-related macular degeneration (AMD), Scg3 appeared to play a role in choroidal neovascularization, where it promoted the invasion of choroidal capillaries into the retinal pigment epithelium. Furthermore, Scg3's binding to its homologous receptors was shown to enhance vascular permeability, potentially exacerbating fluid leakage and edema in these diseases, which is a hallmark of exudative conditions. Collectively, these findings suggest that Scg3 plays a pivotal role in driving angiogenesis and vascular permeability in intraocular neovascular diseases CONCLUSION: The upregulation of Scg3 in DR, ROP, and choroidal neovascularization highlights its potential as a novel therapeutic target. Inhibition of Scg3 could offer a new avenue for treating these sight-threatening conditions.
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Affiliation(s)
- Chao-Yi Yuan
- Department of Ophthalmology, The Second Hospital of Jilin University, #218 Ziqiang Street, Changchun, 130041, Jilin, China
| | - Ling Zuo
- Department of Ophthalmology, The Second Hospital of Jilin University, #218 Ziqiang Street, Changchun, 130041, Jilin, China
| | - Yu-Chen Dong
- Department of Ophthalmology, The Second Hospital of Jilin University, #218 Ziqiang Street, Changchun, 130041, Jilin, China
| | - Bao-Xing Liu
- Department of Ophthalmology, The Second Hospital of Jilin University, #218 Ziqiang Street, Changchun, 130041, Jilin, China
| | - Hui Qi
- Department of Ophthalmology, The Second Hospital of Jilin University, #218 Ziqiang Street, Changchun, 130041, Jilin, China.
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25
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Belge Bilgin G, Bilgin C, Jabal MS, Kobeissi H, Ghozy S, Senol YC, Orscelik A, Kadirvel R, Brinjikji W, Kallmes DF, Rabinstein AA. The effects of admission hyperglycemia and diabetes mellitus on mechanical thrombectomy outcomes: A systematic review and meta-analysis. Interv Neuroradiol 2025:15910199241306774. [PMID: 39819212 PMCID: PMC11748406 DOI: 10.1177/15910199241306774] [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: 02/07/2024] [Accepted: 11/13/2024] [Indexed: 01/19/2025] Open
Abstract
BACKGROUND The impact of certain comorbidities on mechanical thrombectomy (MT) outcomes remains largely unexplored. Diabetes mellitus (DM) and admission hyperglycemia have been associated with poor clinical outcomes for patients treated with MT. In this study, we sought to investigate the effects of DM and admission hyperglycemia on MT outcomes. METHODS Following PRISMA guidelines, a systematic literature search was conducted in Medline, Embase, Scopus, and Web of Science databases. Data regarding successful recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] ≥2b), functional independence (modified Rankin Scale [mRS] 0-2), excellent outcomes (mRS 0-1), symptomatic intracranial hemorrhage (sICH), and mortality were extracted from the included studies. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using random effects model. RESULTS Twenty-one studies comprising 9708 patients were included. A total of 2311 patients (24%) had a history of DM, and 2026 patients (21%) had admission hyperglycemia. Admission hyperglycemia was associated with significantly lower odds of mTICI ≥2b (OR = 0.7, 95% CI = 0.55-0.89), mRS 0-2 (OR = 0.47, 95% CI = 0.41-0.53), and mRS 0-1 (OR = 0.43, 95% CI = 0.34-0.55) as compared to normoglycemic state. Patients with hyperglycemia had significantly higher rates of sICH (OR = 2.05, 95% CI = 1.66-2.54) and mortality (OR = 1.99, 95% CI = 1.58-2.52) than normoglycemic patients. Diabetes mellitus was associated with significantly high rates of mortality (OR = 1.74, 95% CI = 1.31-2.3) and lower rates of mRS 0-2 (OR = 0.60, 95% CI = 0.48-0.76) in sensitivity analyses. CONCLUSION Our results indicate that admission blood glucose levels and DM can negatively affect MT outcomes. Further research should focus on optimizing MT outcomes for these patients.
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Affiliation(s)
| | - Cem Bilgin
- Department of Radiology, Mayo Clinic Rochester, Rochester, MN, USA
| | | | - Hassan Kobeissi
- Department of Radiology, Mayo Clinic Rochester, Rochester, MN, USA
| | - Sherief Ghozy
- Department of Radiology, Mayo Clinic Rochester, Rochester, MN, USA
| | - Yigit Can Senol
- Department of Neurologic Surgery, UCSF, San Francisco, CA, USA
| | - Atakan Orscelik
- Department of Neurologic Surgery, Medical University of South Carolina, Charleston, SC, USA
| | | | - Waleed Brinjikji
- Department of Radiology, Mayo Clinic Rochester, Rochester, MN, USA
- Department of Neurologic Surgery, Mayo Clinic Rochester, Rochester, MN, USA
| | - David F. Kallmes
- Department of Radiology, Mayo Clinic Rochester, Rochester, MN, USA
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Pejkova S, Manevska N, Tusheva S, Georgieva G, Srbov B, Vrajnko E, Jordanova SP, Makazlieva T, Stojanovski S, Nickerson DS, Dellon AL. Methods for tissue perfusion assessment after Dellon decompression of tarsal tunnels in diabetic neuropathy: key to effective management-a narrative review. Quant Imaging Med Surg 2025; 15:1012-1022. [PMID: 39838985 PMCID: PMC11744174 DOI: 10.21037/qims-24-822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 10/31/2024] [Indexed: 01/23/2025]
Abstract
Background and Objective Diabetic neuropathy significantly elevates the risk of foot ulceration and lower-limb amputation, underscoring the need for precise assessment of tissue perfusion to optimize management. This narrative review explores the intricate relationship between sympathetic nerves and tissue perfusion in diabetic neuropathy, highlighting the important role of autonomic neuropathy in blood flow dynamics and subsequent compromises in tissue perfusion. The consequences extend to the development of diabetic peripheral neuropathy and related foot complications. By analyzing both non-invasive diagnostic methods and surgical interventions, such as tarsal tunnel decompression, the paper seeks to highlight their effectiveness in improving tissue perfusion, preventing ulcers, and reducing the risk of amputations in patients with diabetic peripheral neuropathy. Methods We reviewed current literature on both non-invasive diagnostic tools and surgical techniques for assessing and improving tissue perfusion in diabetic neuropathy. Methods discussed include transcutaneous oxygen pressure (TcPO2), Doppler ultrasound, Tissue-Muscle Perfusion Scintigraphy with 99mTc-MIBI, and the SPY Laser Angiographic System. Key Content and Findings Emphasizing the critical importance of surgical interventions, such as tarsal tunnel decompression and neurolysis of the posterior tibial nerve, the article underscores their efficacy in enhancing tissue perfusion and preventing ulcers and amputations. Additionally, it addresses the significance of precise blood flow measurement and timely intervention in the management of diabetic neuropathy and foot ulcers. The non-invasive techniques for assessing tissue perfusion and blood flow in diabetic neuropathy such as TcPO2, Doppler ultrasound and Tissue-Muscle Perfusion Scintigraphy with 99mTc-MIBI are explained. Also, this review introduces the SPY Laser Angiographic System, which employs near-infrared fluorescence imaging to assess blood flow and perfusion in tissues. This advanced tool generates real-time microvascular blood flow images and proves instrumental in diagnosing and monitoring diabetic foot ulcers. Conclusions In conclusion, surgical interventions, both vascular and peripheral nerve are pivotal for optimizing patient care. Early identification of foot ulcers and peripheral arterial disease is imperative, and an understanding of blood flow dynamics, combined with effective surgical techniques, constitutes key elements in managing diabetic neuropathy, healing and preventing ulcers, and limb salvage.
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Affiliation(s)
- Sofija Pejkova
- University Clinic for Plastic and Reconstructive Surgery, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Nevena Manevska
- Institute of Pathophysiology and Nuclear Medicine, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Sofija Tusheva
- University Clinic for Plastic and Reconstructive Surgery, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Gordana Georgieva
- University Clinic for Plastic and Reconstructive Surgery, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Blagoja Srbov
- University Clinic for Plastic and Reconstructive Surgery, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Ersin Vrajnko
- University Clinic for Plastic and Reconstructive Surgery, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Savetka Paljoskovska Jordanova
- University Clinic for Cardiology, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Tanja Makazlieva
- Institute of Pathophysiology and Nuclear Medicine, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | - Sinisa Stojanovski
- Institute of Pathophysiology and Nuclear Medicine, Faculty of Medicine, University Ss. Cyril and Methodius, Skopje, Republic of North Macedonia
| | | | - A. Lee Dellon
- Division of Plastic Surgery, Johns Hopkins University, Baltimore, MD, USA
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Lee SH, Tseng BY, Wu MC, Wang JH, Chiu CJ. Incidence and Progression of Diabetic Retinopathy After Cataract Surgery: A Systematic Review and Meta-Analysis. Am J Ophthalmol 2025; 269:105-115. [PMID: 39179126 DOI: 10.1016/j.ajo.2024.08.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 08/01/2024] [Accepted: 08/14/2024] [Indexed: 08/26/2024]
Abstract
PURPOSE The impact of cataract surgery on diabetic retinopathy (DR) in patients with diabetes mellitus (DM) remains uncertain. This study aimed to investigate the incidence and progression of DR in patients with DM who underwent cataract surgery. DESIGN Meta-analysis. METHODS A systematic search of PubMed, Cochrane CENTRAL, and Embase databases was conducted from inception to April 2024. Randomized controlled trials or observational cohort studies involving adult patients with DM who underwent cataract surgery were included. Studies reporting data on the incidence or progression of postoperative DR were considered. Effect sizes were determined using risk ratios (RRs) with 95% confidence intervals (CIs), and meta-analysis was performed using a random-effects model. Subgroup analysis and meta-regression were conducted on perioperative demographic factors such as types of cataract surgery, DM durations, preoperative glycated hemoglobin A1c levels, and postoperative follow-up durations. RESULTS Data from 15 studies, involving 7,287 patients were analyzed. Postoperative DR incidence was elevated compared to the control group (RR, 1.38; 95% CI: 1.16-1.63; P < .001), although not significantly different in paired studies (RR, 0.85; 95% CI: 0.39-1.83; P = .671). DR progression was significantly higher after cataract surgery (RR, 1.46; 95% CI: 1.28-1.66; P < .001), irrespective of cataract surgery type and study design. Our analysis also revealed a significant increase in DR progression to sight-threatening DR, which includes clinically significant macular edema and proliferative diabetic retinopathy, following cataract surgery (RR, 1.84; 95% CI: 1.21-2.81; P = .005). Additionally, various risk factors such as preoperative HbA1c level, duration of postoperative follow-up, duration of diabetic diagnosis, age, and use of insulin therapy were investigated, However, none of these parameters significantly influenced the incidence or progression of postoperative DR. CONCLUSIONS Further research is needed to fully understand the incidence of DR after cataract surgery. However, our study provides moderate evidence supporting the progression of DR following such surgical interventions. Therefore, it is imperative to closely monitor DR progression within one year following cataract surgery in patients with DM.
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Affiliation(s)
- Ssu-Hsien Lee
- From the School of Medicine, Tzu Chi University (S.-H.L., B.-Y.T., M.-C.W.), Hualien, Taiwan
| | - Bor-Yuan Tseng
- From the School of Medicine, Tzu Chi University (S.-H.L., B.-Y.T., M.-C.W.), Hualien, Taiwan
| | - Meng-Chien Wu
- From the School of Medicine, Tzu Chi University (S.-H.L., B.-Y.T., M.-C.W.), Hualien, Taiwan
| | - Jen-Hung Wang
- Department of Medical Research, Buddhist Tzu Chi General Hospital (J.-H.W.), Hualien, Taiwan
| | - Cheng-Jen Chiu
- Department of Ophthalmology and Visual Science, Tzu Chi University (C.-J.C.), Hualien, Taiwan; Department of Ophthalmology, Hualien Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation (C.-J.C.), Hualien, Taiwan.
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Liu Y, Zhan W, Wang L, Wang W. NAD Pathways in Diabetic Coronary Heart Disease: Unveiling the Key Players. Curr Med Chem 2025; 32:2202-2218. [PMID: 38409700 DOI: 10.2174/0109298673293982240221050207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 01/23/2024] [Accepted: 02/02/2024] [Indexed: 02/28/2024]
Abstract
Diabetic coronary heart disease is a global medical problem that poses a serious threat to human health, and its pathogenesis is complex and interconnected. Nicotinamide adenine dinucleotide (NAD) is an important small molecule used in the body that serves as a coenzyme in redox reactions and as a substrate for non-redox processes. NAD levels are highly controlled by various pathways, and increasing evidence has shown that NAD pathways, including NAD precursors and key enzymes involved in NAD synthesis and catabolism, exert both positive and negative effects on the pathogenesis of diabetic coronary heart disease. Thus, the mechanisms by which the NAD pathway acts in diabetic coronary heart disease require further investigation. This review first briefly introduces the current understanding of the intertwined pathological mechanisms of diabetic coronary heart disease, including insulin resistance, dyslipidemia, oxidative stress, chronic inflammation, and intestinal flora dysbiosis. Then, we mainly review the relationships between NAD pathways, such as nicotinic acid, tryptophan, the kynurenine pathway, nicotinamide phosphoribosyltransferase, and sirtuins, and the pathogenic mechanisms of diabetic coronary heart disease. Moreover, we discuss the potential of targeting NAD pathways in the prevention and treatment of diabetic coronary heart disease, which may provide important strategies to modulate its progression.
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Affiliation(s)
- Yuan Liu
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Wenjing Zhan
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Lexun Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
| | - Weixuan Wang
- Traditional Chinese Medicine Research Institute, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
- Guangdong Provincial Research Center of Integration of Traditional Chinese Medicine and Western Medicine in Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, Guangdong Province, China
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Mistry PS, Chorawala MR, Sivamaruthi BS, Prajapati BG, Kumar A, Chaiyasut C. The Role of Dietary Anthocyanins for Managing Diabetes Mellitus-Associated Complications. Curr Diabetes Rev 2025; 21:e15733998322754. [PMID: 39136514 DOI: 10.2174/0115733998322754240802063730] [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: 05/08/2024] [Revised: 07/15/2024] [Accepted: 07/23/2024] [Indexed: 01/06/2025]
Abstract
Diabetes mellitus (DM) is an intricate metabolic disorder marked by persistent hyperglycemia, arising from disruptions in glucose metabolism, with two main forms, type 1 and type 2, involving distinct etiologies affecting β-cell destruction or insulin levels and sensitivity. The islets of Langerhans, particularly β-cells and α-cells, play a pivotal role in glucose regulation, and both DM types lead to severe complications, including retinopathy, nephropathy, and neuropathy. Plant-derived anthocyanins, rich in anti-inflammatory and antioxidant properties, show promise in mitigating DM-related complications, providing a potential avenue for prevention and treatment. Medicinal herbs, fruits, and vegetables, abundant in bioactive compounds like phenolics, offer diverse benefits, including glucose regulation and anti-inflammatory, antioxidant, anticancer, anti-mutagenic, and neuroprotective properties. Anthocyanins, a subgroup of polyphenols, exhibit diverse isoforms and biosynthesis involving glycosylation, making them potential natural replacements for synthetic food colorants. Clinical trials demonstrate the efficacy and safety of anthocyanins in controlling glucose, reducing oxidative stress, and enhancing insulin sensitivity in diabetic patients, emphasizing their therapeutic potential. Preclinical studies revealed their multifaceted mechanisms, positioning anthocyanins as promising bioactive compounds for managing diabetes and its associated complications, including retinopathy, nephropathy, and neuropathy.
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Affiliation(s)
- Priya S Mistry
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad 380009, Gujarat, India
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad 380009, Gujarat, India
| | - Bhagavathi Sundaram Sivamaruthi
- Office of Research Administration, Chiang Mai University, Chiang Mai 50200, Thailand
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
| | - Bhupendra G Prajapati
- Department of Pharmaceutics and Pharmaceutical Technology, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Mehsana, Gujarat, India
| | - Akash Kumar
- MM Institute of Hotel Management, Maharishi Markandeshwar (Deemed to be University), Mullana 133207, India
- Department of Food Technology, SRM University, Delhi-NCR, Sonepat 131029, India
| | - Chaiyavat Chaiyasut
- Innovation Center for Holistic Health, Nutraceuticals, and Cosmeceuticals, Faculty of Pharmacy, Chiang Mai University, Chiang Mai 50200, Thailand
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Ma J, Dong Y, Liu J, Gao S, Quan J. The role of GRB2 in diabetes, diabetes complications and related disorders. Diabetes Obes Metab 2025; 27:23-34. [PMID: 39478285 DOI: 10.1111/dom.16015] [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: 06/10/2024] [Revised: 09/28/2024] [Accepted: 09/30/2024] [Indexed: 12/06/2024]
Abstract
Growth factor receptor-bound protein 2 (GRB2) is a key adaptor protein involved in multiple signalling pathways, and its dysregulation is associated with various diseases. Type 2 diabetes is a systemic condition characterized by insulin resistance and impaired β-cell function. The complications of diabetes significantly reduce life expectancy and quality of life, imposing a substantial burden on society. However, the role of GRB2 in diabetes and associated complications is largely unknown. Emerging evidence suggests that GRB2 plays a crucial role in insulin resistance, inflammation, immune activation and the regulation of cellular processes such as cell proliferation, growth, metabolism, angiogenesis, apoptosis and differentiation. Dysregulation of GRB2-mediated pathways contributes to the progression of diabetic neuropathy, cognitive dysfunction, nephropathy, retinopathy and related disorders. This review provides a comprehensive overview of the current understanding of the role of GRB2 in diabetes, diabetes complications and related disorders, alongside recent advances in the development of GRB2-targeted therapies. Elucidating the complex role of GRB2 in these disorders provides valuable insights into potential therapeutic strategies targeting GRB2-mediated pathways.
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Affiliation(s)
- Jing Ma
- Department of Endocrinology and Metabolism, Gansu Provincial Hospital, The First Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Endocrinology and Metabolism, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Endocrine and Metabolic Diseases of Gansu Province, Lanzhou, China
| | - Yuyan Dong
- Clinical College of Ningxia Medical University, Yinchuan, China
| | - Juxiang Liu
- Department of Endocrinology and Metabolism, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Endocrine and Metabolic Diseases of Gansu Province, Lanzhou, China
| | - Shuo Gao
- Department of Endocrinology and Metabolism, Gansu Provincial Hospital, The First Clinical Medical School, Lanzhou University, Lanzhou, China
| | - Jinxing Quan
- Department of Endocrinology and Metabolism, Gansu Provincial Hospital, The First Clinical Medical School, Lanzhou University, Lanzhou, China
- Department of Endocrinology and Metabolism, Gansu Provincial Hospital, Lanzhou, China
- Key Laboratory of Endocrine and Metabolic Diseases of Gansu Province, Lanzhou, China
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Morya AK, Ramesh PV, Nishant P, Kaur K, Gurnani B, Heda A, Salodia S. Diabetic retinopathy: A review on its pathophysiology and novel treatment modalities. World J Methodol 2024; 14:95881. [PMID: 39712561 PMCID: PMC11287547 DOI: 10.5662/wjm.v14.i4.95881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/28/2024] [Accepted: 07/10/2024] [Indexed: 07/26/2024] Open
Abstract
Diabetes mellitus (DM) is a chronic metabolic non-communicable disease with the ability to cause serious microvascular and macrovascular complications throughout the body, including in the eye. Diabetic retinopathy (DR), present in one-third of patients with diabetes, is a vision-threatening complication caused by uncontrolled diabetes, which greatly affects the retinal blood vessels and the light-sensitive inner retina, eventually leading to blindness. Several epidemiological studies elucidate that DR can vary by age of onset, duration, types of diabetes, and ethnicity. Recent studies show that the pathogenesis of diabetic retinopathy has spread its roots beyond merely being the result of hyperglycemia. The complexity of its etiopathology and diagnosis makes therapeutic intervention challenging. This review throws light on the pathological processes behind DR, the cascade of events that follow it, as well as the available and emerging treatment options.
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Affiliation(s)
- Arvind Kumar Morya
- Head of the Department, Department of Ophthalmology, All India Institute of Medical Sciences, Hyderabad 508126, Telangana, India
| | - Prasanna Venkatesh Ramesh
- Glaucoma Medical Officer, Department of Glaucoma and Research, Mahathma Eye Hospital Private Limited, Trichy 620017, Tamil Nadu, India
| | - Prateek Nishant
- Department of Ophthalmology, ESIC Medical College, Patna 801103, Bihar, India
| | - Kirandeep Kaur
- Department of Pediatric Ophthalmology and Strabismus, Gomabai Netralaya and Research Centre, Neemuch 458441, Madhya Pradesh, India
| | - Bharat Gurnani
- Cornea and Refractive Services, Gomabai Netralaya and Research Centre, Neemuch 458441, Madhya Pradesh, India
| | - Aarti Heda
- Department of Ophthalmology, National Institute of Ophthalmology, Pune 411000, Maharashtra, India
| | - Sarika Salodia
- Global Medical Safety, Lundbeck, Singapore 569933, Singapore, Singapore
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Li F, Luo Y, Li X, Dai Y, Xiang Q. Association between metabolic syndrome and the risk of glaucoma: a meta-analysis of observational studies. Diabetol Metab Syndr 2024; 16:300. [PMID: 39696489 DOI: 10.1186/s13098-024-01532-4] [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: 09/23/2024] [Accepted: 11/14/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND The potential link between metabolic syndrome (MetS) and the risk of glaucoma has been proposed but remains inconclusive. This meta-analysis aimed to systematically evaluate the association between MetS and the risk of glaucoma. METHODS We conducted a comprehensive search of PubMed, Embase, and Web of Science from inception to August 12, 2024, for observational studies assessing the relationship between MetS and glaucoma risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the association. Heterogeneity was assessed using I² statistics, and a random-effects model was applied. RESULTS Nine studies involving 2,258,797 participants were included. The pooled results showed that MetS was significantly associated with an increased risk of glaucoma (OR: 1.34, 95% CI 1.15-1.55, p < 0.001; I² = 75%). Subgroup analyses according to the individual component of MetS suggested that hypertension and hyperglycemia were significantly associated with glaucoma, but not for obesity or dyslipidemia, although the difference among subgroups was not significant (p = 0.05). Further subgroup and meta-regression analyses suggested that the results were not significantly affected by study design, average age, sex, method of glaucoma diagnosis, or glaucoma subtype (primary open-angle glaucoma or normal-tension glaucoma). Sensitivity analysis confirmed the robustness of the findings. CONCLUSIONS This meta-analysis suggests that MetS is significantly associated with an increased risk of glaucoma. These findings highlight the need for heightened awareness and potential screening strategies for glaucoma in individuals with MetS. Further studies are required to elucidate underlying mechanisms and causality.
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Affiliation(s)
- Fei Li
- Department of ophthalmology, Chengdu Fifth People's Hospital, No. 33 Mashi Street, Wenjiang District, Chengdu, 610000, Sichuan, China
| | - Yanjun Luo
- Department of ophthalmology, Chengdu Fifth People's Hospital, No. 33 Mashi Street, Wenjiang District, Chengdu, 610000, Sichuan, China
| | - Xin Li
- Department of ophthalmology, Chengdu Fifth People's Hospital, No. 33 Mashi Street, Wenjiang District, Chengdu, 610000, Sichuan, China
| | - Yan Dai
- Department of ophthalmology, Chengdu Fifth People's Hospital, No. 33 Mashi Street, Wenjiang District, Chengdu, 610000, Sichuan, China
| | - Qingping Xiang
- Department of ophthalmology, Chengdu Fifth People's Hospital, No. 33 Mashi Street, Wenjiang District, Chengdu, 610000, Sichuan, China.
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Hernyák M, Tóth LI, Csiha S, Molnár Á, Lőrincz H, Paragh G, Harangi M, Sztanek F. Kallistatin as a Potential Marker of Therapeutic Response During Alpha-Lipoic Acid Treatment in Diabetic Patients with Sensorimotor Polyneuropathy. Int J Mol Sci 2024; 25:13276. [PMID: 39769041 PMCID: PMC11675709 DOI: 10.3390/ijms252413276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/07/2024] [Accepted: 12/09/2024] [Indexed: 01/04/2025] Open
Abstract
Diabetic sensorimotor neuropathy (DSPN) is strongly associated with the extent of cellular oxidative stress and endothelial dysfunction in type 2 diabetes (T2DM). Alpha-lipoic acid (ALA) attenuates the progression of DSPN through its antioxidant and vasculoprotective effects. Kallistatin has antioxidant and anti-inflammatory properties. We aimed to evaluate changes in kallistatin levels and markers of endothelial dysfunction in patients with T2DM and DSPN following six months of treatment with 600 mg/day of ALA. A total of 54 patients with T2DM and DSPN and 24 control patients with T2DM but without neuropathy participated in this study. The serum concentrations of kallistatin, ICAM-1, VCAM-1, oxLDL, VEGF, ADMA, and TNF-alpha were measured by an ELISA. Peripheral sensory neuropathy was assessed with neuropathy symptom questionnaires and determination of the current perception threshold. After ALA treatment, the level of kallistatin significantly decreased, as well as the levels of TNF-alpha and ADMA. Changes in kallistatin levels were positively correlated with changes in oxLDL. The improvement in DSPN symptoms following ALA treatment showed a positive correlation with changes in kallistatin, VEGF, oxLDL, and ADMA levels. Based on our results, kallistatin could represent a potential new biomarker for assessing therapeutic response during ALA treatment in patients with DSPN.
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Affiliation(s)
- Marcell Hernyák
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (M.H.); (L.I.T.); (S.C.); (Á.M.); (H.L.); (G.P.); (M.H.)
- Doctoral School of Health Sciences, University of Debrecen, H-4032 Debrecen, Hungary
| | - László Imre Tóth
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (M.H.); (L.I.T.); (S.C.); (Á.M.); (H.L.); (G.P.); (M.H.)
- Doctoral School of Health Sciences, University of Debrecen, H-4032 Debrecen, Hungary
| | - Sára Csiha
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (M.H.); (L.I.T.); (S.C.); (Á.M.); (H.L.); (G.P.); (M.H.)
| | - Ágnes Molnár
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (M.H.); (L.I.T.); (S.C.); (Á.M.); (H.L.); (G.P.); (M.H.)
| | - Hajnalka Lőrincz
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (M.H.); (L.I.T.); (S.C.); (Á.M.); (H.L.); (G.P.); (M.H.)
| | - György Paragh
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (M.H.); (L.I.T.); (S.C.); (Á.M.); (H.L.); (G.P.); (M.H.)
| | - Mariann Harangi
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (M.H.); (L.I.T.); (S.C.); (Á.M.); (H.L.); (G.P.); (M.H.)
- Institute of Health Studies, Faculty of Health Sciences, University of Debrecen, H-4032 Debrecen, Hungary
- ELKH-UD Vascular Pathophysiology Research Group 11003, University of Debrecen, H-4032 Debrecen, Hungary
| | - Ferenc Sztanek
- Division of Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary; (M.H.); (L.I.T.); (S.C.); (Á.M.); (H.L.); (G.P.); (M.H.)
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Peng Y, Pan L, Zhu Q, Lin R, Huang C, Liu Y, Huang Y, Li G, Yao Y, Yu Y, Tang J. Impact of diabetes on the association between serum urate levels and incident dementia: a cohort study in the UK biobank. J Nutr Health Aging 2024; 28:100399. [PMID: 39437577 DOI: 10.1016/j.jnha.2024.100399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 10/11/2024] [Accepted: 10/13/2024] [Indexed: 10/25/2024]
Abstract
OBJECTIVES Diabetes was associated with increased serum urate levels and a higher risk of dementia. However, current evidence regarding the association between serum urate and dementia is controversial.The research gap on how to effectively control urate levels in the population with diabetes still remains. We aim to examine the association of diabetes status and serum urate with dementia incidence, and the differences in this association among participants with different diabetes statuses. METHODS A total of 321,896 participants was recruited from the UK Biobank and followed up until 2022. Diabetes status was classified into diabetes, prediabetes and normoglycaemia according to the American Diabetes Association 2023 guideline. Serum urate levels were stratified using gender-specific quartiles of concentrations. All-cause dementia, Alzheimer's disease and vascular dementia were ascertained using the International Classification of Diseases-10th revision (ICD-10). Cox proportional hazards regression models were used to examine the association between serum urate, diabetes status, and dementia incidence. RESULTS Of the 321,896 participants (mean age, 57 years old; 43.5% males), 7,087 (2.20%) individuals were diagnosed with dementia during the follow-up period. Diabetes was associated with a 70% 58%, and 134% increased risk for all-cause dementia, Alzheimer's disease, and vascular dementia respectively. Elevated serum urate levels were associated with a lower risk of all-cause and cause-specific dementia regardless of the status of diabetes. Each standard deviation increase in urate concentration was related to a 11% reduced risk for all-cause dementia (HR, 0.89; 95% CI, 0.86 to 0.91), 7% for Alzheimer's disease (HR, 0.93; 95% CI, 0.88 to 0.98), and 12% for vascular dementia (HR, 0.88; 95% CI, 0.81 to 0.95). CONCLUSION Appropriately higher urate levels within the threshold of hyperuricemia can reduce the adverse health effects of excessively high urate levels and better protect the cognitive health of people with varying diabetes status.
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Affiliation(s)
- Yuwei Peng
- Department of Biostatistics, Key Laboratory for Health Technology Assessment, National Commission of Health, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China
| | - Lulu Pan
- Department of Biostatistics, Key Laboratory for Health Technology Assessment, National Commission of Health, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China
| | - Qiuli Zhu
- Healthcare-Associated Infection Prevention and Control Office, Shanghai General Hospital, Shanghai 200080, China
| | - Ruilang Lin
- Department of Biostatistics, Key Laboratory for Health Technology Assessment, National Commission of Health, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China
| | - Chen Huang
- Department of Biostatistics, Key Laboratory for Health Technology Assessment, National Commission of Health, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China
| | - Yahang Liu
- Department of Biostatistics, Key Laboratory for Health Technology Assessment, National Commission of Health, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China
| | - Yifang Huang
- Department of Biostatistics, Key Laboratory for Health Technology Assessment, National Commission of Health, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China
| | - Guochen Li
- Department of Epidemiology, Key Laboratory for Health Technology Assessment, National Commission of Health, School of Public Health, Fudan University, Shanghai 200032, China
| | - Ye Yao
- Department of Biostatistics, Key Laboratory for Health Technology Assessment, National Commission of Health, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China
| | - Yongfu Yu
- Department of Biostatistics, Key Laboratory for Health Technology Assessment, National Commission of Health, Key Laboratory of Public Health Safety of Ministry of Education, School of Public Health, Fudan University, Shanghai 200032, China
| | - Jianguo Tang
- Department of Trauma-Emergency & Critical Care Medicine, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, China.
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Ayça B, Yıldız C, Yüksel Y, Katkat F, Arpaç A, Çağlar FNT, Erkol C. Evaluation of Triglyceride Glucose Index in Patients with Patent Foramen Ovale Who Experienced Cryptogenic Stroke. J Clin Med 2024; 13:7271. [PMID: 39685728 DOI: 10.3390/jcm13237271] [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: 10/13/2024] [Revised: 11/21/2024] [Accepted: 11/26/2024] [Indexed: 12/18/2024] Open
Abstract
Background/Objectives: The prevalence of patent foramen ovale (PFO) has been found to be increased in patients with cryptogenic stroke, suggesting an association between these two clinical settings. Insulin resistance is a risk factor for the occurrence of stroke. The triglyceride glucose (TyG) index is a biomarker that reflects the IR status of the body. Our aim was to evaluate the TyG index values in patients with PFO who experienced cryptogenic stroke. Methods: One hundred and twenty nine patients with PFO who experienced embolic stroke and one hundred and eight control subjects were enrolled. All patients in the study group experienced embolic stroke within 2 weeks of enrollment. The TyG index value of each patient was calculated. Results: Patients with stroke were significantly older, had higher levels of glucose, creatinine, triglyceride (TG), leukocyte, and TyG index and lower high-density lipoprotein-cholesterol values. The TyG index had the highest sensitivity for the prediction of stroke in comparison to TG and glucose values. Comparison of ROC curves showed that the TyG index had the highest AUC compared to that of TG and glucose. The TyG index value of 8.89 predicted stroke occurrence with a sensitivity and specificity of 63.2% and 72.3%, respectively. The results of multivariable regression analyses showed that the TyG index had a higher odds ratio than TG, which indicated that it had a better predictive value. Conclusions: Assessment of the TyG index in cryptogenic stroke patients with PFO might be helpful for the management of these patients.
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Affiliation(s)
- Burak Ayça
- Cardiology Department, Istanbul Training and Research Hospital, Istanbul 34098, Turkey
| | - Cennet Yıldız
- Cardiology Department, Bakırkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul 34147, Turkey
| | - Yasin Yüksel
- Cardiology Department, Private Reyap Hospital, Istanbul 34515, Turkey
| | - Fahrettin Katkat
- Cardiology Department, Istanbul Training and Research Hospital, Istanbul 34098, Turkey
| | - Atakan Arpaç
- Cardiology Department, Bakırkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul 34147, Turkey
| | - Fatma Nihan Turhan Çağlar
- Cardiology Department, Bakırkoy Dr. Sadi Konuk Training and Research Hospital, Istanbul 34147, Turkey
| | - Cansu Erkol
- Department of Neurology, Istanbul Training and Education Hospital, Istanbul 34098, Turkey
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Lian XN, Zhu MM. Factors related to type 2 diabetic retinopathy and their clinical application value. Front Endocrinol (Lausanne) 2024; 15:1484197. [PMID: 39634174 PMCID: PMC11614660 DOI: 10.3389/fendo.2024.1484197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024] Open
Abstract
Objective To compare the differences in clinical-related factors between patients with type 2 diabetes (T2DM) and those without diabetic retinopathy (DR) and to explore the risk factors or protective factors affecting DR in T2DM patients. Methods We performed a retrospective analysis of 380 patients with type 2 diabetes admitted to Handan Central Hospital from June 2023 to May 2024. Clinical data collected included baseline characteristics, hematological tests, metabolic indicators, and information on diabetic complications and comorbidities. Results Our findings identified intervention, neck vascular disease, bilateral lower limb venous thrombosis, high creatinine, high glomerular filtration rate, high chloride, high fasting C-peptide, and high lactate dehydrogenase as risk factors for DR. In contrast, High 2-hour postprandial C-peptide is a protective factor for diabetic retinopathy. A logistic regression model was constructed using stepwise regression to predict DR occurrence, achieving an accuracy of 0.80 and an AUC of 0.83.
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Affiliation(s)
- Xue-Nan Lian
- School of Graduate Studies, Hebei North University, Zhangjiakou, China
- Department of Endocrinology, Handan Central Hospital, Handan, China
| | - Ming-Ming Zhu
- Department of Endocrinology, Handan Central Hospital, Handan, China
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37
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Mahmoud NN, Hamad S, Shraim S. Inflammation-Modulating Biomedical Interventions for Diabetic Wound Healing: An Overview of Preclinical and Clinical Studies. ACS OMEGA 2024; 9:44860-44875. [PMID: 39554458 PMCID: PMC11561615 DOI: 10.1021/acsomega.4c02251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 05/15/2024] [Accepted: 07/01/2024] [Indexed: 11/19/2024]
Abstract
A diabetic wound exemplifies the challenge of chronic, nonhealing wounds. Elevated blood sugar levels in diabetes profoundly disrupt macrophage function, impairing crucial activities such as phagocytosis, immune response, cell migration, and blood vessel formation, all essential for effective wound healing. Moreover, the persistent presence of pro-inflammatory cytokines and reactive oxygen species, coupled with a decrease in anti-inflammatory factors, exacerbates the delay in wound healing associated with diabetes. This review emphasizes the dysfunctional inflammatory responses underlying diabetic wounds and explores preclinical studies of inflammation-modulating bioactives and biomaterials that show promise in expediting diabetic wound healing. Additionally, this review provides an overview of selected clinical studies employing biomaterials and bioactive molecules, shedding light on the gap between extensive preclinical research and limited clinical studies in this field.
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Affiliation(s)
- Nouf N. Mahmoud
- Faculty
of Pharmacy, Al-Zaytoonah University of
Jordan, Amman 11733, Jordan
- Department
of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha 2713, Qatar
| | - Salma Hamad
- International
School of London Qatar, Doha 18511, Qatar
| | - Sawsan Shraim
- Faculty
of Pharmacy, Al-Zaytoonah University of
Jordan, Amman 11733, Jordan
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38
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Vlachogiannis NI, Legaki AI, Kassi E, Mikelis CM, Tentolouris N, Sfikakis PP, Protogerou AD, Chatzigeorgiou A. Association of Circulating Robo4 with Obesity, Hypertension and Atherosclerotic Plaque Burden. Thromb Haemost 2024. [PMID: 39401520 DOI: 10.1055/a-2437-6308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2024]
Affiliation(s)
- Nikolaos I Vlachogiannis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Aigli-Ioanna Legaki
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Constantinos M Mikelis
- Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Patras, Greece
| | - Nikolaos Tentolouris
- First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Petros P Sfikakis
- First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Athanase D Protogerou
- Cardiovascular Prevention and Research Unit, Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- First Department of Propaedeutic Internal Medicine and Joint Academic Rheumatology Program, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Bohara S, Bagheri A, Ertugral EG, Radzikh I, Sandlers Y, Jiang P, Kothapalli CR. Integrative analysis of gene expression, protein abundance, and metabolomic profiling elucidates complex relationships in chronic hyperglycemia-induced changes in human aortic smooth muscle cells. J Biol Eng 2024; 18:61. [PMID: 39473010 PMCID: PMC11523773 DOI: 10.1186/s13036-024-00457-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 10/14/2024] [Indexed: 11/02/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a major public health concern with significant cardiovascular complications (CVD). Despite extensive epidemiological data, the molecular mechanisms relating hyperglycemia to CVD remain incompletely understood. We here investigated the impact of chronic hyperglycemia on human aortic smooth muscle cells (HASMCs) cultured under varying glucose conditions in vitro, mimicking normal (5 mmol/L), pre-diabetic (10 mmol/L), and diabetic (20 mmol/L) conditions, respectively. Normal HASMC cultures served as baseline controls, and patient-derived T2DM-SMCs served as disease controls. Results showed significant increases in cellular proliferation, area, perimeter, and F-actin expression with increasing glucose concentration (p < 0.01), albeit not exceeding the levels in T2DM cells. Atomic force microscopy analysis revealed significant decreases in Young's moduli, membrane tether forces, membrane tension, and surface adhesion in SMCs at higher glucose levels (p < 0.001), with T2DM-SMCs being the lowest among all the cases (p < 0.001). T2DM-SMCs exhibited elevated levels of selected pro-inflammatory markers (e.g., ILs-6, 8, 23; MCP-1; M-CSF; MMPs-1, 2, 3) compared to glucose-treated SMCs (p < 0.01). Conversely, growth factors (e.g., VEGF-A, PDGF-AA, TGF-β1) were higher in SMCs exposed to high glucose levels but lower in T2DM-SMCs (p < 0.01). Pathway enrichment analysis showed significant increases in the expression of inflammatory cytokine-associated pathways, especially involving IL-10, IL-4 and IL-13 signaling in genes that are up-regulated by elevated glucose levels. Differentially regulated gene analysis showed that compared to SMCs receiving normal glucose, 513 genes were upregulated and 590 genes were downregulated in T2DM-SMCs; fewer genes were differentially expressed in SMCs receiving higher glucose levels. Finally, the altered levels in genes involved in ECM organization, elastic fiber synthesis and formation, laminin interactions, and ECM proteoglycans were identified. Growing literature suggests that phenotypic switching in SMCs lead to arterial wall remodeling (e.g., change in stiffness, calcific deposits formation), with direct implications in the onset of CVD complications. Our results suggest that chronic hyperglycemia is one such factor that leads to morphological, biomechanical, and functional alterations in vascular SMCs, potentially contributing to the pathogenesis of T2DM-associated arterial remodeling. The observed differences in gene expression patterns between in vitro hyperglycemic models and patient-derived T2DM-SMCs highlight the complexity of T2DM pathophysiology and underline the need for further studies.
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Affiliation(s)
- Smriti Bohara
- Department of Chemical and Biomedical Engineering, Cleveland State University, Cleveland, OH, 44115, USA
| | - Atefeh Bagheri
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, 44115, USA
| | - Elif G Ertugral
- Department of Chemical and Biomedical Engineering, Cleveland State University, Cleveland, OH, 44115, USA
| | - Igor Radzikh
- Department of Chemistry, Cleveland State University, Cleveland, OH, 44115, USA
| | - Yana Sandlers
- Department of Chemistry, Cleveland State University, Cleveland, OH, 44115, USA
| | - Peng Jiang
- Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH, 44115, USA.
- Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH, 44115, USA.
- Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA.
| | - Chandrasekhar R Kothapalli
- Department of Chemical and Biomedical Engineering, Cleveland State University, Cleveland, OH, 44115, USA.
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Huang Y, Xing H, Naud S, Kyriakides TR. Targeting hypoxia and thrombospondin-2 in diabetic wound healing. FASEB J 2024; 38:e70091. [PMID: 39383062 PMCID: PMC11486302 DOI: 10.1096/fj.202302429rrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Revised: 08/19/2024] [Accepted: 09/23/2024] [Indexed: 10/11/2024]
Abstract
Impaired wound healing in diabetic patients is the leading cause of diabetes-associated hospitalizations and approximately 50% of lower limb amputations. This is due to multiple factors, including elevated glucose, sustained hypoxia, and cell dysfunction. Previously, diabetic wounds were found to contain excessive levels of the matricellular protein thrombospondin-2 (TSP2) and genetic ablation of TSP2 in diabetic mice or treatment of wounds with a hydrogel derived from TSP2-null mouse skin improved healing. Previously, TSP2 has been shown to be repressed by hypoxia, but in the present study we observed sustained hypoxia and overlapping TSP2 deposition in diabetic wounds. We determined this observation was due to the insufficient HIF-1α activation verified by western blot and immunofluorescent analysis of wound tissues and in vitro hypoxia experiments. Application of Dimethyloxalylglycine (DMOG), which can stabilize HIF-1α, inhibited TSP2 expression in diabetic fibroblasts in hypoxic conditions. Therefore, we prepared DMOG-containing TSP2KO hydrogel and applied it to the wounds of diabetic mice. In comparison to empty TSP2KO hydrogel or DMOG treatment, we observed improved wound healing associated with a reduction of TSP2, reduced hypoxia, and increased neovascularization. Overall, our findings shed light on the intricate interplay between hyperglycemia, hypoxia, and TSP2 in the complex environment of diabetic wounds.
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Affiliation(s)
- Yaqing Huang
- Department of Pathology, Yale University, New Haven, CT 06520, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA
| | - Hao Xing
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA
| | - Sophie Naud
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA
| | - Themis R. Kyriakides
- Department of Pathology, Yale University, New Haven, CT 06520, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
- Vascular Biology and Therapeutics Program, Yale University, New Haven, CT 06520, USA
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Mobasher MA, Shabana MA, Germoush MO, Abuzinadah NY, Abd-Elhameed A, Baioumy SA, ElKot MA, Esawy MM. LncRNA LYPLAL1, miR-204-5p, and SIRT1: novel signatures for risk assessment of diabetic macrovascular complications. Sci Rep 2024; 14:24154. [PMID: 39406930 PMCID: PMC11480381 DOI: 10.1038/s41598-024-75543-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
Long-term, uncontrolled diabetes mellitus can lead to micro- and macrovascular problems. The protective function of lncRNA LYPLAL1 is to reduce endothelium cell inflammation by upregulating sirtuin 1 (SIRT1) and reducing microRNA (miR)-204-5p. This work attempted to examine the lncRNA LYPLAL1/miR-204-5p/SIRT1 molecules as diagnostic biomarkers for diabetic MVC and to assess their clinical correlations. The study enrolled 32 controls, 32 patients with diabetes alone, and 32 patients with diabetic MVC. RT-qPCR, or quantitative real-time PCR, was utilized to determine the expression levels of lncRNA and miR. SIRT1 was measured by ELISA. When comparing cases with MVC to those without MVC, the lncRNA LYPLAL1 and SIRT1 values were significantly lower. Conversely, patients with MVC had significantly higher miR-204-5p levels than those without MVC. The LncRNA LYPLAL1 performed best in terms of detecting MVC. It attained 90.6% specificity and 96.9% sensitivity. A combination of three markers (lncRNA LYPLAL1, miR-204-5p, and SIRT1) yielded the best accuracy at 98.4%. LYPLAL1 expression appeared to be an independent MVC predictor. Adjusted OR for LYPLAL1 expression was 405 (95% CI: 1.4-1200) (p = 0.039). When we compared cases with MVC to those without MVC, the lncRNA LYPLAL1 and SIRT1 values were significantly lower. Patients with MVC had significantly higher miR-204-5p levels than those without MVC. LYPLAL1 LncRNA demonstrated the best performance characteristics. LncRNA LYPLAL1 expression is an independent predictor of MVC.
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Affiliation(s)
- Maysa A Mobasher
- Department of Pathology, Biochemistry Division, College of Medicine, Jouf University, 72388, Sakaka, Saudi Arabia.
| | - Marwa A Shabana
- Clinical Pathology Department, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt
| | - Mousa O Germoush
- Biology Department, College of Science, Jouf University, Sakakah, Saudi Arabia
| | - Najlaa Yousef Abuzinadah
- Department of biological science, College of Science, University of Jeddah, 23714, Jeddah, Saudi Arabia
| | - Amir Abd-Elhameed
- Internal Medicine Department, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt
| | - Shereen A Baioumy
- Microbiology and Immunology Department, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt
| | - Moataz A ElKot
- Cardiology Department, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt
| | - Marwa M Esawy
- Clinical Pathology Department, Faculty of Human Medicine, Zagazig University, Zagazig, Egypt
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42
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Moellmann HL, Karnatz N, Degirmenci I, Rana M. Determination of Quality Indicators for Microvascular Grafts in Cranio-Maxillofacial Surgery-A Retrospective Analysis of 251 Free Flaps. J Pers Med 2024; 14:1061. [PMID: 39452567 PMCID: PMC11509019 DOI: 10.3390/jpm14101061] [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: 09/18/2024] [Revised: 10/02/2024] [Accepted: 10/13/2024] [Indexed: 10/26/2024] Open
Abstract
BACKGROUND The use of microvascular grafts is the gold standard in oral and maxillofacial surgery for the reconstruction of soft tissue and bony and combined defects. Graft loss is one of the most serious complications in the field of reconstructive surgery. A comprehensive analysis of factors influencing this is, therefore, essential. METHODS This hypothesis-generating study analyzed 251 patient cases of oral and maxillofacial surgery at the University Hospital Düsseldorf from 2016 to 2020 regarding patient- and therapy-specific parameters for their impact on graft survival. RESULTS Statistically significant influencing factors were found among the 80 parameters examined: treatment with antiplatelet medication and a BMI ≥ 24.5 at the time of surgery had a positive influence on graft survival, while existing diabetes mellitus, atrial fibrillation, tracheostomy, and a longer operation time had a statistically relevant negative influence. CONCLUSIONS This work demonstrates the relevance of patient-specific risk stratification and the need for further research to develop a valid risk profile. Identifying high-risk patients with medium-sized defects, where alternatives to microvascular reconstruction are available, appears to be crucial for the clinical outcome.
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Affiliation(s)
- Henriette Louise Moellmann
- Cranio-and-Maxillo Facial Surgery, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany; (N.K.); (M.R.)
| | - Nadia Karnatz
- Cranio-and-Maxillo Facial Surgery, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany; (N.K.); (M.R.)
| | - Ilkan Degirmenci
- Department of Oral, Maxillofacial and Facial Plastic Surgery, Evangelical Hospital Bethesda, 41061 Mönchengladbach, Germany;
| | - Majeed Rana
- Cranio-and-Maxillo Facial Surgery, University Hospital Düsseldorf, Moorenstraße 5, 40225 Düsseldorf, Germany; (N.K.); (M.R.)
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43
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Wang X, Zhao J, Xu J, Li B, Liu X, Xie G, Duan X, Liu D. Noncaloric monosaccharides induce excessive sprouting angiogenesis in zebrafish via foxo1a-marcksl1a signal. eLife 2024; 13:RP95427. [PMID: 39365738 PMCID: PMC11452176 DOI: 10.7554/elife.95427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/06/2024] Open
Abstract
Artificially sweetened beverages containing noncaloric monosaccharides were suggested as healthier alternatives to sugar-sweetened beverages. Nevertheless, the potential detrimental effects of these noncaloric monosaccharides on blood vessel function remain inadequately understood. We have established a zebrafish model that exhibits significant excessive angiogenesis induced by high glucose, resembling the hyperangiogenic characteristics observed in proliferative diabetic retinopathy (PDR). Utilizing this model, we observed that glucose and noncaloric monosaccharides could induce excessive formation of blood vessels, especially intersegmental vessels (ISVs). The excessively branched vessels were observed to be formed by ectopic activation of quiescent endothelial cells (ECs) into tip cells. Single-cell transcriptomic sequencing analysis of the ECs in the embryos exposed to high glucose revealed an augmented ratio of capillary ECs, proliferating ECs, and a series of upregulated proangiogenic genes. Further analysis and experiments validated that reduced foxo1a mediated the excessive angiogenesis induced by monosaccharides via upregulating the expression of marcksl1a. This study has provided new evidence showing the negative effects of noncaloric monosaccharides on the vascular system and the underlying mechanisms.
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Affiliation(s)
- Xiaoning Wang
- Affiliated Hospital of Nantong University, Nantong Laboratory of Development and Diseases, School of Life Science; Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
| | - Jinxiang Zhao
- Affiliated Hospital of Nantong University, Nantong Laboratory of Development and Diseases, School of Life Science; Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
- Suqian First HospitalSuqianChina
| | - Jiehuan Xu
- Affiliated Hospital of Nantong University, Nantong Laboratory of Development and Diseases, School of Life Science; Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
| | - Bowen Li
- Medical School, Nantong UniversityNantongChina
| | - Xia Liu
- Affiliated Hospital of Nantong University, Nantong Laboratory of Development and Diseases, School of Life Science; Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
| | - Gangcai Xie
- Medical School, Nantong UniversityNantongChina
| | - Xuchu Duan
- Affiliated Hospital of Nantong University, Nantong Laboratory of Development and Diseases, School of Life Science; Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
| | - Dong Liu
- Affiliated Hospital of Nantong University, Nantong Laboratory of Development and Diseases, School of Life Science; Co-innovation Center of Neuroregeneration, Nantong UniversityNantongChina
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44
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Zhang E, Shi Y, Han X, Zhu H, Song B, Yang C, Cao Z. An injectable and biodegradable zwitterionic gel for extending the longevity and performance of insulin infusion catheters. Nat Biomed Eng 2024; 8:1197-1213. [PMID: 37884794 DOI: 10.1038/s41551-023-01108-z] [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: 09/05/2021] [Accepted: 09/18/2023] [Indexed: 10/28/2023]
Abstract
Continuous subcutaneous insulin infusion (CSII) is an essential insulin replacement therapy in the management of diabetes. However, the longevity of clinical CSII is limited by skin complications, by impaired insulin absorption and by occlusions associated with the subcutaneous insertion of CSII catheters, which require replacement and rotation of the insertion site every few days. Here we show that a biodegradable zwitterionic gel covering the tip end of commercial off-the-shelf CSII catheters fully resolves early skin irritations, extends the longevity of catheters and improves the rate of insulin absorption (also with respect to conventional syringe-based subcutaneous injection) for longer than 6 months in diabetic mice, and by 11 days in diabetic minipigs (from 2 to 13 days, under standard CSII-wearing conditions of insulin pump therapy and in a continuous basal-plus-bolus-infusion setting). The implanted gel displayed anti-inflammatory and anti-foreign-body-reaction properties and promoted the local formation of new blood vessels. The gel is subcutaneously injected before the tip of catheter is inserted into it, and should be generally applicable to CSII catheters and other implantable devices.
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Affiliation(s)
- Ershuai Zhang
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA
| | - Yuanjie Shi
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA
| | - Xiangfei Han
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA
| | - Hui Zhu
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA
| | - Boyi Song
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA
| | - Chengbiao Yang
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA
| | - Zhiqiang Cao
- Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI, USA.
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Matcuk GR, Katal S, Gholamrezanezhad A, Spinnato P, Waldman LE, Fields BKK, Patel DB, Skalski MR. Imaging of lower extremity infections: predisposing conditions, atypical infections, mimics, and differentiating features. Skeletal Radiol 2024; 53:2099-2120. [PMID: 38240759 PMCID: PMC11371866 DOI: 10.1007/s00256-024-04589-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 01/04/2024] [Accepted: 01/10/2024] [Indexed: 09/05/2024]
Abstract
Imaging evaluation for lower extremity infections can be complicated, especially in the setting of underlying conditions and with atypical infections. Predisposing conditions are discussed, including diabetes mellitus, peripheral arterial disease, neuropathic arthropathy, and intravenous drug abuse, as well as differentiating features of infectious versus non-infectious disease. Atypical infections such as viral, mycobacterial, fungal, and parasitic infections and their imaging features are also reviewed. Potential mimics of lower extremity infection including chronic nonbacterial osteomyelitis, foreign body granuloma, gout, inflammatory arthropathies, lymphedema, and Morel-Lavallée lesions, and their differentiating features are also explored.
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Affiliation(s)
- George R Matcuk
- Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
| | | | - Ali Gholamrezanezhad
- Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Paolo Spinnato
- Diagnostic and Interventional Radiology, IRCCS Istituto Ortopedico Rizzoli, 40136, Bologna, Italy
| | - Leah E Waldman
- Department of Radiology, Duke University School of Medicine, Durham, NC, 27705, USA
| | - Brandon K K Fields
- Department of Radiology & Biomedical Imaging, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Dakshesh B Patel
- Department of Radiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Matthew R Skalski
- Department of Radiology, Palmer College of Chiropractic-West Campus, San Jose, CA, 95134, USA
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Deng X, Wu Q, Liu Y. Eucommia ulmoidesOliv. leaves flavonoids attenuate methylglyoxal-induced endothelial cell apoptosis in vitro and in vivo by upregulating AKT-Nrf2 signaling and downregulating oxidative stress. Food Sci Nutr 2024; 12:7938-7953. [PMID: 39479661 PMCID: PMC11521679 DOI: 10.1002/fsn3.4416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 03/19/2024] [Accepted: 08/04/2024] [Indexed: 11/02/2024] Open
Abstract
Methylglyoxal (MGO) triggers oxidative stress responses in vascular endothelial cells, leading to apoptosis linked to diabetic vascular complications. Total flavonoids of Eucommia ulmoides leaves (TFEL) display antioxidant activity, yet its prevention of MGO-induced apoptosis and mechanisms are unclear. Our study used western blotting and ELISA to evaluate protein levels and enzyme activities. Cell viability and apoptosis were evaluated using CCK8 assay and PE Annexin V/7-AAD double staining. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were measured using fluorescence probes. Vascular pathological changes and apoptosis were analyzed through H&E and TUNEL staining. In vitro, MGO-stimulated human umbilical vein endothelial cells (HUVECs) were treated with varying TFEL concentrations. Our results demonstrated that TFEL significantly enhanced cell viability, reduced apoptosis, downregulated caspase-3 activity, and Bax/Bcl-2 ratio. Moreover, TFEL markedly suppressed MGO-induced ROS and malondialdehyde (MDA) production while restoring antioxidant enzyme activity and MMP. TFEL pretreatment promoted the expression of p-Akt, Nrf2, and HO-1 proteins. Pharmacological inhibition of p-Akt significantly suppressed the upregulation of Nrf2 and HO-1 protein levels mediated by TFEL. Consistently, pharmacological inhibition of Nrf2 or p-Akt partially abrogated the protective effects of TFEL against MGO-induced damage in HUVECs. In vivo studies revealed that TFEL (100 and 200 mg/kg) partially restored antioxidant capacity and reduced aortic thickness and apoptosis in MGO-injured mice. In conclusion, the findings indicate that TFEL mitigates MGO-induced apoptosis via activation of p-Akt/Nrf2/HO-1 and scavenging of oxidative stress, highlighting its potential in diabetic vascular complication management.
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Affiliation(s)
- Xin Deng
- School of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
- Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of EducationSouthwest Medical UniversityLuzhouChina
| | - Qianfeng Wu
- School of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
| | - Youping Liu
- School of PharmacyChengdu University of Traditional Chinese MedicineChengduChina
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47
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Nanu DP, Adelsberg D, Nguyen SA, Radulovich NP, Carr MM. Unmasking Nasal Septal Hematoma/Abscess: A Systematic Review and Meta-analysis. OTO Open 2024; 8:e174. [PMID: 39381799 PMCID: PMC11460746 DOI: 10.1002/oto2.174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 06/25/2024] [Accepted: 07/06/2024] [Indexed: 10/10/2024] Open
Abstract
Objective We aim to discuss the demographics, symptoms, bacteriology, treatment, and sequelae associated with nasal septal hematoma/nasal septal abscess (NSH/NSA). Data Sources CINAHL, PubMed, and Scopus were searched from inception until October 15, 2023. Review Methods Preferred Reporting Items for Systematic Reviews and Meta-analysis 2020 guidelines were followed. Inclusion criteria included patients who were diagnosed with a traumatic NSH/NSA. NSH/NSA due to surgical procedures was excluded. Demographics included N of patients, patient age, and gender. Symptoms, antibiotics given, bacteriology, and sequelae were analyzed. Meta-analysis of continuous measures (mean, median), and proportions (%) with a 95% confidence interval (CI) was conducted. Results Thirty studies (N = 598) were included. In total, 72.1% were males (95% CI: 67-78). The total mean age was 21.6 years (range: 0.2-85, 95% CI: 17.2-26.1). The mean time from trauma to diagnosis was 8.2 days. Common symptoms at presentation included nasal obstruction/congestion at 60.3% (95% CI: 37.1-81.4), nasal pain at 30.0% (17.2-44.6), swelling at 20.4% (8.7-35.5), headache at 15.5% (7.3-26.0), and fever at 13.9% (7.3-22.2). The most common pathogens isolated included Staphylococcus aureus at 56.5% (49.0-63.8), Streptococcus species at 8.9% (5.2-14.0), and Klebsiella pneumoniae at 6.3% (3.2-10.8). Antibiotics given included amoxicillin-clavulanate at 10.3% (4.5-18.2), metronidazole at 9.5% (1.1-24.9), ampicillin-sulbactam at 8.9% (0.4-26.5), and unspecified antibiotics at 39.7% (13.8-69.2). The most common sequelae were nasal septal deformity/cartilage destruction at 14.3% (7.7-22.6). Conclusion NSA/NSH has an 8-day delay in diagnosis from the time of trauma. First-line practitioners should be made aware of the signs and symptoms of this condition to minimize the risk of morbidity.
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Affiliation(s)
- Douglas P. Nanu
- Department of Otolaryngology–Head and Neck Surgery CharlestonMedical University of South CarolinaCharlestonWashingtonUSA
- Elson S. Floyd College of Medicine at Washington State UniversitySpokaneWashingtonUSA
| | - Daniel Adelsberg
- Department of OtolaryngologyJacobs School of Medicine and Biomedical Sciences at the University of BuffaloBuffaloNew YorkUSA
| | - Shaun A. Nguyen
- Department of Otolaryngology–Head and Neck Surgery CharlestonMedical University of South CarolinaCharlestonWashingtonUSA
| | | | - Michele M. Carr
- Department of OtolaryngologyUniversity at BuffaloBuffaloNew YorkUSA
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Belosludtseva NV, Ilzorkina AI, Serov DA, Dubinin MV, Talanov EY, Karagyaur MN, Primak AL, Liu J, Belosludtsev KN. ANT-Mediated Inhibition of the Permeability Transition Pore Alleviates Palmitate-Induced Mitochondrial Dysfunction and Lipotoxicity. Biomolecules 2024; 14:1159. [PMID: 39334925 PMCID: PMC11430505 DOI: 10.3390/biom14091159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/11/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Hyperlipidemia is a major risk factor for vascular lesions in diabetes mellitus and other metabolic disorders, although its basis remains poorly understood. One of the key pathogenetic events in this condition is mitochondrial dysfunction associated with the opening of the mitochondrial permeability transition (MPT) pore, a drop in the membrane potential, and ROS overproduction. Here, we investigated the effects of bongkrekic acid and carboxyatractyloside, a potent blocker and activator of the MPT pore opening, respectively, acting through direct interaction with the adenine nucleotide translocator, on the progression of mitochondrial dysfunction in mouse primary lung endothelial cells exposed to elevated levels of palmitic acid. Palmitate treatment (0.75 mM palmitate/BSA for 6 days) resulted in an 80% decrease in the viability index of endothelial cells, which was accompanied by mitochondrial depolarization, ROS hyperproduction, and increased colocalization of mitochondria with lysosomes. Bongkrekic acid (25 µM) attenuated palmitate-induced lipotoxicity and all the signs of mitochondrial damage, including increased spontaneous formation of the MPT pore. In contrast, carboxyatractyloside (10 μM) stimulated cell death and failed to prevent the progression of mitochondrial dysfunction under hyperlipidemic stress conditions. Silencing of gene expression of the predominate isoform ANT2, similar to the action of carboxyatractyloside, led to increased ROS generation and cell death under conditions of palmitate-induced lipotoxicity in a stably transfected HEK293T cell line. Altogether, these results suggest that targeted manipulation of the permeability transition pore through inhibition of ANT may represent an alternative approach to alleviate mitochondrial dysfunction and cell death in cell culture models of fatty acid overload.
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Affiliation(s)
- Natalia V. Belosludtseva
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
- Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia; (M.V.D.); (K.N.B.)
| | - Anna I. Ilzorkina
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
- Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia; (M.V.D.); (K.N.B.)
| | - Dmitriy A. Serov
- Prokhorov General Physics Institute of the Russian Academy of Sciences, Vavilov St. 38, 119991 Moscow, Russia
- Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
| | - Mikhail V. Dubinin
- Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia; (M.V.D.); (K.N.B.)
| | - Eugeny Yu. Talanov
- Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Institutskaya 3, 142290 Pushchino, Russia
| | - Maxim N. Karagyaur
- Medical Research and Education Institute, Lomonosov Moscow State University, 27/1, Lomonosovsky Ave., 119191 Moscow, Russia
| | - Alexandra L. Primak
- Medical Research and Education Institute, Lomonosov Moscow State University, 27/1, Lomonosovsky Ave., 119191 Moscow, Russia
| | - Jiankang Liu
- School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao 266071, China;
| | - Konstantin N. Belosludtsev
- Department of Biochemistry, Cell Biology and Microbiology, Mari State University, pl. Lenina 1, 424001 Yoshkar-Ola, Russia; (M.V.D.); (K.N.B.)
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Darwitz BP, Genito CJ, Thurlow LR. Triple threat: how diabetes results in worsened bacterial infections. Infect Immun 2024; 92:e0050923. [PMID: 38526063 PMCID: PMC11385445 DOI: 10.1128/iai.00509-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2024] Open
Abstract
Diabetes mellitus, characterized by impaired insulin signaling, is associated with increased incidence and severity of infections. Various diabetes-related complications contribute to exacerbated bacterial infections, including hyperglycemia, innate immune cell dysfunction, and infection with antibiotic-resistant bacterial strains. One defining symptom of diabetes is hyperglycemia, resulting in elevated blood and tissue glucose concentrations. Glucose is the preferred carbon source of several bacterial pathogens, and hyperglycemia escalates bacterial growth and virulence. Hyperglycemia promotes specific mechanisms of bacterial virulence known to contribute to infection chronicity, including tissue adherence and biofilm formation. Foot infections are a significant source of morbidity in individuals with diabetes and consist of biofilm-associated polymicrobial communities. Bacteria perform complex interspecies behaviors conducive to their growth and virulence within biofilms, including metabolic cross-feeding and altered phenotypes more tolerant to antibiotic therapeutics. Moreover, the metabolic dysfunction caused by diabetes compromises immune cell function, resulting in immune suppression. Impaired insulin signaling induces aberrations in phagocytic cells, which are crucial mediators for controlling and resolving bacterial infections. These aberrancies encompass altered cytokine profiles, the migratory and chemotactic mechanisms of neutrophils, and the metabolic reprogramming required for the oxidative burst and subsequent generation of bactericidal free radicals. Furthermore, the immune suppression caused by diabetes and the polymicrobial nature of the diabetic infection microenvironment may promote the emergence of novel strains of multidrug-resistant bacterial pathogens. This review focuses on the "triple threat" linked to worsened bacterial infections in individuals with diabetes: (i) altered nutritional availability in diabetic tissues, (ii) diabetes-associated immune suppression, and (iii) antibiotic treatment failure.
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Affiliation(s)
- Benjamin P. Darwitz
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - Christopher J. Genito
- Division of Oral and Craniofacial Health Sciences, University of North Carolina at Chapel Hill Adams School of Dentistry, Chapel Hill, North Carolina, USA
| | - Lance R. Thurlow
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
- Division of Oral and Craniofacial Health Sciences, University of North Carolina at Chapel Hill Adams School of Dentistry, Chapel Hill, North Carolina, USA
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Kinali H, Kalaycioglu GD, Boyacioglu O, Korkusuz P, Aydogan N, Vargel I. Clinic-oriented injectable smart material for the treatment of diabetic wounds: Coordinating the release of GM-CSF and VEGF. Int J Biol Macromol 2024; 276:133661. [PMID: 38992546 DOI: 10.1016/j.ijbiomac.2024.133661] [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: 04/03/2024] [Revised: 06/16/2024] [Accepted: 07/02/2024] [Indexed: 07/13/2024]
Abstract
Chronic wounds are often caused by diabetes and present a challenging clinical problem due to vascular problems leading to ischemia. This inhibits proper wound healing by delaying inflammatory responses and angiogenesis. To address this problem, we have developed injectable particle-loaded hydrogels which sequentially release Granulocyte-macrophage- colony-stimulating-factor (GM-CSF) and Vascular endothelial growth factor (VEGF) encapsulated in polycaprolactone-lecithin-geleol mono-diglyceride hybrid particles. GM-CSF promotes inflammation, while VEGF facilitates angiogenesis. The hybrid particles (200-1000 nm) designed within the scope of the study can encapsulate the model proteins Bovine Serum Albumin 65 ± 5 % and Lysozyme 77 ± 10 % and can release stably for 21 days. In vivo tests and histological findings revealed that in the hydrogels containing GM-CSF/VEGF-loaded hybrid particles, wound depth decreased, inflammation phase increased, and fibrotic scar tissue decreased, while mature granulation tissue was formed on day 10. These findings confirm that the hybrid particles first initiate the inflammation phase by delivering GM-CSF, followed by VEGF, increasing the number of vascularization and thus increasing the healing rate of wounds. We emphasize the importance of multi-component and sequential release in wound healing and propose a unifying therapeutic strategy to sequentially deliver ligands targeting wound healing stages, which is very important in the treatment of the diabetic wounds.
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Affiliation(s)
- Hurmet Kinali
- Department of Bioengineering, Graduate School of Science and Engineering, Hacettepe University, Beytepe, Ankara 06800, Turkey
| | - Gokce Dicle Kalaycioglu
- Department of Chemical Engineering, Faculty of Engineering, Hacettepe University, Ankara 06800, Turkey
| | - Ozge Boyacioglu
- Department of Bioengineering, Graduate School of Science and Engineering, Hacettepe University, Beytepe, Ankara 06800, Turkey; Department of Medical Biochemistry, Faculty of Medicine, Atılım University, 06830 Gölbaşı, Ankara, Turkey
| | - Petek Korkusuz
- Department of Histology and Embryology, Faculty of Medicine, Hacettepe University, 06100 Sıhhiye, Ankara, Turkey
| | - Nihal Aydogan
- Department of Bioengineering, Graduate School of Science and Engineering, Hacettepe University, Beytepe, Ankara 06800, Turkey; Department of Chemical Engineering, Faculty of Engineering, Hacettepe University, Ankara 06800, Turkey.
| | - Ibrahim Vargel
- Department of Bioengineering, Graduate School of Science and Engineering, Hacettepe University, Beytepe, Ankara 06800, Turkey; Department of Plastic and Reconstructive Surgery, Faculty of Medicine, Hacettepe University, 06560 Ankara, Turkey.
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