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Ding S, Xie Y, Wang F, Liu J, Li H, Su H, Zhao Z, Wei Q, Pi S, Chen F, Gu Q, Xiao B, He Y. Association between multiple metals mixture and diabetic retinopathy in older adults with diabetes mellitus: a cross-sectional study in China. ENVIRONMENTAL GEOCHEMISTRY AND HEALTH 2025; 47:149. [PMID: 40169416 DOI: 10.1007/s10653-025-02462-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 03/17/2025] [Indexed: 04/03/2025]
Abstract
Previous studies have linked single metal with diabetic retinopathy (DR), but information about the combined effects of multiple metals mixture was scarce. Thus, we performed this cross-sectional study to investigate the single and joint associations between multiple metals mixture and DR risk among elderly diabetic population in China. A total of 1127 elderly adults (aged ≥ 60) with diabetes mellitus from a large-scale DR screening program in southern China included. Metals (beryllium, magnesium, chromium, manganese, iron, nickel, copper, arsenic, thallium and lead) in serum were quantified by inductively coupled plasma mass spectrometer. DR was diagnosed according to the consensus of the global DR project group. The relationships between metals and DR risks were estimated by logistic regression, Bayesian kernel machine regression (BKMR) and weighted quantile sum (WQS) regression. Of 1127 older adults with diabetes mellitus, there were 324 DR and 803 non-DR participants. Logistic regression models found serum magnesium and iron were negatively related to DR risks. Both BKMR model and WQS regression revealed that higher serum levels of multiple metals mixture were associated with lower risks of DR, with Be contributing the most to the overall effect. Additionally, in subgroup analyses, the interaction between beryllium and blood pressure on DR risk was also observed (Pinteraction = 0.008). Overall, these results provided new evidence of direct association between multiple metals mixture and DR risk among elderly diabetic population in China.
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Affiliation(s)
- Shuren Ding
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Yirong Xie
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Feng Wang
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Jieyi Liu
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Hongya Li
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Heng Su
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Zhiqiang Zhao
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Qing Wei
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Shurong Pi
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Fubin Chen
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Qian Gu
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China
| | - Baixiang Xiao
- Affiliated Eye Hospital, Jiangxi Medical College, Nanchang University, #463 Bayi Ave, Donghu District, Nanchang City, 330002, China.
- Centre for Public Health, Queen's University, Belfast, UK.
| | - Yun He
- Department of Health Toxicology, School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong, 510080, China.
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Taylor BE, Howell SJ, Lee C, Taylor Z, Barber K, Taylor PR. Diabetes-Mediated STEAP4 Enhances Retinal Oxidative Stress and Impacts the Development of Diabetic Retinopathy. Antioxidants (Basel) 2025; 14:205. [PMID: 40002391 PMCID: PMC11851923 DOI: 10.3390/antiox14020205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/22/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025] Open
Abstract
Diabetic retinopathy is the most common diabetic complication of the microvasculature and one of the leading causes of acquired vision loss worldwide. Yet, the current treatments for this blinding disease are futile to many diabetics. Accordingly, new biomarkers and therapeutics for diabetic retinopathy are needed. We discovered that STEAP4 (Six-Transmembrane Epithelial Antigen of the Prostate 4) is significantly increased in peripheral blood mononuclear cells of diabetics. STEAP4 expression was gradiently increased from low levels in diabetics without retinopathy to successively higher levels in diabetics with more severe disease. Although the role of STEAP4 in the diabetic retina is unclear, these results provide strong evidence that this metabolic enzyme could be a potential biomarker for diabetic retinopathy progression. Thus, the central goal of this study was to evaluate if this potential biomarker impacts the intrinsic pathologies that lead to the development of diabetic retinopathy. In diabetic mice, STEAP4 was significantly increased and co-localized with 4-Hydroxy-2-nonenal in the Müller glia and photoreceptor layers of the retina. STEAP4 inhibition significantly decreased reactive oxygen species in murine photoreceptor cells, human Müller glia, and retinas of diabetic mice. Administering an intravitreal injection of anti-STEAP4 to diabetic mice halted Occludin degradation in the retinal vasculature. Similarly, anti-STEAP4 treatment of human retina endothelial cells halted cell death mediated by diabetic donor sera. Collectively, our findings provide strong evidence that STEAP4 impacts the intrinsic pathologies that initiate the development of diabetic retinopathy. Suggesting that STEAP4 could be a novel biomarker and clinically relevant therapeutic target for this diabetic complication and blinding disease.
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Affiliation(s)
- Brooklyn E. Taylor
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA; (B.E.T.); (S.J.H.); (C.L.); (K.B.)
- Department of Ophthalmology and Vision Science, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Scott J. Howell
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA; (B.E.T.); (S.J.H.); (C.L.); (K.B.)
| | - Chieh Lee
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA; (B.E.T.); (S.J.H.); (C.L.); (K.B.)
- Department of Ophthalmology and Vision Science, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Zakary Taylor
- Department of Ophthalmology and Vision Science, Case Western Reserve University, Cleveland, OH 44106, USA;
| | - Katherine Barber
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA; (B.E.T.); (S.J.H.); (C.L.); (K.B.)
| | - Patricia R. Taylor
- Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA; (B.E.T.); (S.J.H.); (C.L.); (K.B.)
- Department of Ophthalmology and Vision Science, Case Western Reserve University, Cleveland, OH 44106, USA;
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Gong L, Mai Y, Wu Z, Luo J, Wen G. Associations between iron status and diabetic kidney disease: A nationwide study. Nutr Metab Cardiovasc Dis 2025:103907. [PMID: 40087039 DOI: 10.1016/j.numecd.2025.103907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 01/01/2025] [Accepted: 02/05/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND AND AIM Iron status plays a crucial role in various physiological processes, and its dysregulation is associated with numerous health conditions. However, research on the relationship between iron status and diabetic kidney disease (DKD) is quite limited. Therefore, this study aims to investigate the connection between iron status and DKD. METHODS AND RESULTS This population-based cross-sectional survey included adult diabetes patients from five National Health and Nutrition Examination Survey (NHANES) cycles spanning 1999 to 2006 and 2017 to 2018. Regression models were used to assess the impact of iron status on the prevalence of diabetic nephropathy. Restricted cubic spline models further explored potential nonlinear dose-response relationships. Subgroup analyses clarified the effects of other covariates on these associations. Iron and TIBC were negatively correlated with DKD, albuminuria, and low estimated glomerular filtration rate (eGFR). TSAT was negatively correlated with DKD and showed an "L"-shaped nonlinear correlation with albuminuria and low-eGFR. Ferritin exhibited a "J"-shaped nonlinear correlation with DKD, albuminuria, and low-eGFR. Subgroup analysis revealed that the association between TIBC and reduced risk of low eGFR was more pronounced in individuals with hypertension. The associations between iron and TSAT with a reduced risk of DKD were more significant in smokers, while the association between ferritin and an increased risk of albuminuria was also more pronounced in smokers. CONCLUSIONS In diabetic patients, iron status is closely associated with DKD. Monitoring these iron status markers can help improve the prevention and management of kidney health in diabetic patients.
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Affiliation(s)
- Liya Gong
- Department of Medical Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Yanpei Mai
- School of Medicine, South China University of Technology, Guangzhou, 510006, China
| | - Ziqi Wu
- Department of Medical Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jingwen Luo
- Department of Medical Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Ge Wen
- Department of Medical Imaging, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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Li H, Yue H, Li H, Zhu M, He X, Liu M, Li X, Qiu F. High-throughput point-of-care serum iron testing utilizing machine learning-assisted deep eutectic solvent fluorescence detection platform. J Colloid Interface Sci 2024; 680:389-404. [PMID: 39577236 DOI: 10.1016/j.jcis.2024.11.110] [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: 09/17/2024] [Revised: 11/03/2024] [Accepted: 11/15/2024] [Indexed: 11/24/2024]
Abstract
In this study, a high-throughput point-of-care testing (HT-POCT) system for detecting serum iron was developed using a hydrophobic deep eutectic solvent (HDES) fluorescence detection platform. This machine learning-assisted portable platform enables intelligent and rapid detection of trace iron ions. Blue fluorescent hydrophobic carbon quantum dots (CQDs) were synthesized using the solvothermal method. The CQDs exhibit a notable quantum yield (QY) of 36.6%, demonstrating exceptional luminescent characteristics and precise, sensitive detection capabilities for Fe3+ ions. By incorporating CQDs into specially filtered HDESs, this blend serves a dual function of concentrating iron ions from the sample and facilitating their detection. The collaboration between the two enhances the fluorescence detection signal significantly, while reducing interference from hydrophilic substances. The limit of detection can be as low as 33 nM. The principles of synthesizing HDESs and the process of extracting Fe3+ using HDESs fluorescence detection system were modeled using density functional theory (DFT). As the concentration of Fe3+ increases, the fluorescence signal detected from the sample decreases, accompanied by visible color changes when exposed to ultraviolet light. The machine learning-assisted portable platform is designed to capture fluorescence images of samples directly. The application developed using the YOLOv8 algorithm efficiently analyzes multiple samples in single or multiple images, simultaneously extracting color data from each sample and determining the concentration of iron ions. The Relative Standard Deviations (RSDs) for both single-sample and multi-sample tests were less than 10%. The machine learning-assisted portable platform provides a reliable method for detecting trace iron ions.
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Affiliation(s)
- Hui Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Hengmao Yue
- School of Astronautics, Beihang University, Beijing 100191, China
| | - Haixiang Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Maolin Zhu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Xicheng He
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Meng Liu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Xiaoxia Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
| | - Feng Qiu
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China; National Key Laboratory of Chinese Medicine Modernization, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
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Sun WJ, An XD, Zhang YH, Tang SS, Sun YT, Kang XM, Jiang LL, Zhao XF, Gao Q, Ji HY, Lian FM. Autophagy-dependent ferroptosis may play a critical role in early stages of diabetic retinopathy. World J Diabetes 2024; 15:2189-2202. [PMID: 39582563 PMCID: PMC11580571 DOI: 10.4239/wjd.v15.i11.2189] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 06/10/2024] [Accepted: 09/10/2024] [Indexed: 10/16/2024] Open
Abstract
Diabetic retinopathy (DR), as one of the most common and significant microvascular complications of diabetes mellitus (DM), continues to elude effective targeted treatment for vision loss despite ongoing enrichment of the understanding of its pathogenic mechanisms from perspectives such as inflammation and oxidative stress. Recent studies have indicated that characteristic neuroglial degeneration induced by DM occurs before the onset of apparent microvascular lesions. In order to comprehensively grasp the early-stage pathological changes of DR, the retinal neurovascular unit (NVU) will become a crucial focal point for future research into the occurrence and progression of DR. Based on existing evidence, ferroptosis, a form of cell death regulated by processes like ferritinophagy and chaperone-mediated autophagy, mediates apoptosis in retinal NVU components, including pericytes and ganglion cells. Autophagy-dependent ferroptosis-related factors, including BECN1 and FABP4, may serve as both biomarkers for DR occurrence and development and potentially crucial targets for future effective DR treatments. The aforementioned findings present novel perspectives for comprehending the mechanisms underlying the early-stage pathological alterations in DR and open up innovative avenues for investigating supplementary therapeutic strategies.
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Affiliation(s)
- Wen-Jie Sun
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Xue-Dong An
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Yue-Hong Zhang
- Department of Endocrinology, Fangshan Hospital of Beijing University of Chinese Medicine, Beijing 102400, China
| | - Shan-Shan Tang
- Department of Endocrinology, Changchun University of Chinese Medicine, Changchun 130117, Jilin Province, China
| | - Yu-Ting Sun
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Xiao-Min Kang
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Lin-Lin Jiang
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Xue-Fei Zhao
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Qing Gao
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Hang-Yu Ji
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Feng-Mei Lian
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
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Ruan Y, Zhang P, Jia X, Hua S, Yao D. Association between controlling nutritional status score and diabetic retinopathy: Data from National Health and Nutrition Examination Survey. Eur J Ophthalmol 2024:11206721241289971. [PMID: 40123147 DOI: 10.1177/11206721241289971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
ObjectiveThis study aimed to examine the association between controlling nutritional status (CONUT) score and diabetic retinopathy (DR) risk, as well as investigate the impact of CONUT score on mortality risk among DR patients.MethodsThis retrospective study included 5,256 patients with diabetes from National Health and Nutrition Examination Surveys. These participants were classified into two groups: the DR group (n = 641) and the non-DR group (n = 4,615). We used weighted univariate and multivariate logistic regression models to assess the correlation of CONUT score and DR risk. Weighted univariate and multivariate Cox models were adopted to explore the association of CONUT score with all-cause mortality and cardiovascular disease (CVD)-related mortality in patients with DR.Results305 patients diagnosed with DR had died by the end of the follow-up period, among whom 111 individuals died due to CVD. After adjusting all potential confounding factors, there was an association between CONUT score and DR development in patients with diabetes [odd ratio (OR) = 1.18, 95% confidence interval (CI): 1.05-1.33]. Additionally, CONUT score was found to be associated with all-cause mortality of patients with DR [hazard ratio (HR) = 1.11, 95%CI: 1.01-1.22, P= 0.041]. However, there was no significant difference in the CONUT score and CVD-related mortality of patients with DR.ConclusionsCONUT score may be a valuable tool for assessing the risk of developing DR, and predicting prognosis in patients with DR. However, as this was a cross-sectional study, we cannot infer the causality of CONUT score and DR risk.
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Affiliation(s)
- Yimeng Ruan
- Department of Ophthalmology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, P.R. China
| | - Ping Zhang
- Department of Ophthalmology, Ningbo Eye Center Hospital, Ningbo, Zhejiang Province, P.R. China
| | - Xinru Jia
- Department of Ophthalmology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, P.R. China
| | - Shanshan Hua
- Department of Ophthalmology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, P.R. China
| | - Dongwei Yao
- Department of Ophthalmology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, P.R. China
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Yang C, Hu T, Li C, Gong A. Dietary iron intake predicts all-cause and cardiovascular mortality in patients with diabetes. Nutr Diabetes 2024; 14:68. [PMID: 39179569 PMCID: PMC11343882 DOI: 10.1038/s41387-024-00286-2] [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: 01/12/2024] [Revised: 04/26/2024] [Accepted: 04/29/2024] [Indexed: 08/26/2024] Open
Abstract
BACKGROUND Limited data exists on the link between dietary iron intake and mortality in diabetes. Our investigation aimed to explore how dietary iron intake correlates with overall and cause-specific mortality in diabetic individuals. METHODS This analysis encompassed 5970 participants with diabetes from the National Health and Nutrition Examination Survey spanning 1999 to 2014. Baseline data were collected through surveys and examinations, with mortality status tracked via National Death Index records until December 31, 2015. Cox proportional hazard models were utilized to calculate hazard ratios (HR) and 95% confidence intervals (CI) for mortality from various causes, including cardiovascular disease (CVD) and cancer. RESULTS The average iron intake among the cohort was 14.1 ± 7.4 mg daily, with an average participant age of 61.3 and 3059 (51.3%) male adults. Over 41,425 person-years of follow-up, 1497 deaths were recorded. Following adjustments for multiple variables, an iron intake between 11.1 and 14.4 mg was associated with the lowest risk of all-cause mortality (HR 0.83 [0.70, 0.99], P < 0.05) compared to the reference group (<8.3 mg). Analysis of dose-response curves revealed an L-shaped pattern in men and a J-shaped pattern in women concerning the relationship between iron intake and all-cause mortality. CONCLUSIONS Our findings suggest a nonlinear association between dietary iron intake and all-cause mortality in individuals with diabetes. Specifically, higher iron intake may increase all-cause mortality risk in men, while potentially exert a protective effect in women.
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Affiliation(s)
- Chenchen Yang
- Department Emergency, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Tingting Hu
- Department Cardiology, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Chenglin Li
- Department Cardiothoracic Surgery, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China
| | - Aifeng Gong
- Department General Practice, The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University, Huai'an, 223300, China.
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Sang T, Gao F, Lu X, Yang Y, Liu L, Zhang G, Han G. Associations of oxidative stress markers with the prevalence of sarcopenia in the United States general population. Clinics (Sao Paulo) 2024; 79:100450. [PMID: 39096855 PMCID: PMC11334777 DOI: 10.1016/j.clinsp.2024.100450] [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: 03/27/2024] [Revised: 06/12/2024] [Accepted: 06/30/2024] [Indexed: 08/05/2024] Open
Abstract
OBJECTIVE The purpose of the present study was to examine the association of oxidative stress markers with sarcopenia in the general United States population under the age of 60. METHODS We used the National Health and Nutrition Examination Survey data from 2011‒2014 and performed Restricted Cubic Spline (RCS) plots, weighted multivariable logistic regression analysis to calculate ratio ratios and 95% Confidence Intervals, and subgroup analysis based on age, sex, hypertension, diabetes mellitus, and body mass index stratification to determine the association of markers of oxidative stress with the prevalence of sarcopenia. RESULTS The present analysis included a total of 8,782 participants. Firstly, the RCS plots showed a roughly L-shaped curve association of total bilirubin and serum iron with a prevalence of sarcopenia. Secondly, albumin was negatively and linearly associated with the risk of sarcopenia. Finally, with the increase in gamma-glutamyl transferase, the prevalence of sarcopenia showed a trend of first rising and then declining as a result of the iron increase. CONCLUSIONS We demonstrated a nonlinear association between markers of oxidative stress and sarcopenia. The need to focus more on levels of oxidative stress in the body could provide better prevention strategies for sarcopenia.
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Affiliation(s)
- Tingting Sang
- Department of Rehabilitation, The People's Hospital of Suzhou New District, Suzhou, Jiangsu, China
| | - Feng Gao
- Department of Orthopedics, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu, China
| | - Xiao Lu
- Department of Rehabilitation, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Nanjing, Jiangsu, China
| | - Ying Yang
- Department of Rehabilitation, The People's Hospital of Suzhou New District, Suzhou, Jiangsu, China
| | - Lingling Liu
- Department of Rehabilitation, The First Affiliated Hospital of Anhui Medical University, Shushan District, Hefei, Anhui, China
| | - Gang Zhang
- Department of Rehabilitation, The First Affiliated Hospital of Anhui Medical University, Shushan District, Hefei, Anhui, China
| | - Guosong Han
- Department of Orthopaedics, The First People's Hospital of Hefei City, Hefei, Anhui, China.
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Aschner M, Skalny AV, Paoliello MMB, Tinkova MN, Martins AC, Santamaria A, Lee E, Rocha JBT, Farsky SHP, Tinkov AA. Retinal toxicity of heavy metals and its involvement in retinal pathology. Food Chem Toxicol 2024; 188:114685. [PMID: 38663763 PMCID: PMC11818481 DOI: 10.1016/j.fct.2024.114685] [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: 02/21/2024] [Revised: 04/16/2024] [Accepted: 04/22/2024] [Indexed: 05/04/2024]
Abstract
The objective of the present review is to discuss epidemiological evidence demonstrating the association between toxic metal (Cd, Pb, Hg, As, Sn, Ti, Tl) exposure and retinal pathology, along with the potential underlying molecular mechanisms. Epidemiological studies demonstrate that Cd, and to a lesser extent Pb exposure, are associated with age-related macular degeneration (AMD), while the existing evidence on the levels of these metals in patients with diabetic retinopathy is scarce. Epidemiological data on the association between other toxic metals and metalloids including mercury (Hg) and arsenic (As), are limited. Clinical reports and laboratory in vivo studies have shown structural alterations in different layers of retina following metal exposure. Examination of retina samples demonstrate that toxic metals can accumulate in the retina, and the rate of accumulation appears to increase with age. Experimental studies in vivo and in vitro studies in APRE-19 and D407 cells demonstrate that toxic metal exposure may cause retinal damage through oxidative stress, apoptosis, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, impaired retinogenesis, and retinal inflammation. However, further epidemiological as well as laboratory studies are required for understanding the underlying molecular mechanisms and identifying of the potential therapeutic targets and estimation of the dose-response effects.
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Affiliation(s)
- Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Anatoly V Skalny
- Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, Yaroslavl, 150003, Russia; Center of Bioelementology and Human Ecology, IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119435, Russia
| | - Monica M B Paoliello
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | | | - Airton C Martins
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY 10461, USA
| | - Abel Santamaria
- Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico; Laboratorio de Nanotecnología y Nanomedicina, Departamento de Cuidado de La Salud, Universidad Autónoma Metropolitana-Xochimilco, Mexico City 04960, Mexico
| | - Eunsook Lee
- Department of Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA
| | - Joao B T Rocha
- Departamento de Bioquímica e Biologia Molecular, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria 97105-900, RS, Brazil
| | - Sandra H P Farsky
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo 05508-000, SP, Brazil
| | - Alexey A Tinkov
- Laboratory of Ecobiomonitoring and Quality Control, Yaroslavl State University, Yaroslavl, 150003, Russia; Center of Bioelementology and Human Ecology, IM Sechenov First Moscow State Medical University (Sechenov University), Moscow, 119435, Russia.
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Seyyar SA, Tokuç EÖ, Soysal GG. Effect of diabetic macular oedema on serum iron status indicators. Clin Exp Optom 2024; 107:313-317. [PMID: 37309021 DOI: 10.1080/08164622.2023.2218997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 05/24/2023] [Indexed: 06/14/2023] Open
Abstract
CLINICAL RELEVANCE The role of subclinical inflammation in the pathophysiology of diabetic macular oedema (DME), which is known to be quite complex, is of much interest. Serum ferritin level, which is an indicator of body iron stores, is both an inflammatory marker for various neurodegenerative diseases and an important indicator in the evaluation of iron-induced oxidative stress. BACKGROUND Iron metabolism indicators play a role in the formation and development of diabetic retinopathy, which is known to be associated with subclinical inflammation, and may also play a role in the pathogenesis of DME. The aim of this study was to investigate the role of serum iron metabolism markers in the pathogenesis of DME. MATERIALS AND METHODS The files of all nonproliferative diabetic retinopathy (NPDR) patients who were scheduled for the first intravitreal injection for DME in the eye clinic between January 2019 and January 2020 were reviewed retrospectively. By examining the files of all diabetes mellitus patients who attended the outpatient eye clinic on the same dates, those without retinopathy and those with NPDR but not DME were recorded. All results, including a comprehensive ophthalmological examination, laboratory data of fasting blood tests, and an internal medicine outpatient examination were collected for analysis. RESULTS Of the 157 participants, 44 were NPDR patients with oedema, 50 were NPDR patients without oedema, and 63 were patients without retinopathy. There was a significant difference between the groups in respect of creatinine, high-density lipoprotein, mean corpuscular volume, serum iron and ferritin, total iron binding capacity and transferrin saturation (p < 0.050). Ferritin values were found to be significantly higher in patients with macular oedema. Other iron status markers were found to be significantly lower (p < 0.050). CONCLUSION Evaluation of serum iron status indicators in the routine follow-up of diabetic patients may be of diagnostic and/or prognostic benefit in terms of DME.
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Affiliation(s)
- Sevim Ayça Seyyar
- Ophthalmology Department, Gaziantep University Hospital, Gaziantep, Turkey
| | - Ecem Önder Tokuç
- Ophthalmology Department, Kocaeli University Hospital, Kocaeli, Turkey
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Wang R, Rao S, Zhong Z, Xiao K, Chen X, Sun X. Emerging role of ferroptosis in diabetic retinopathy: a review. J Drug Target 2024; 32:393-403. [PMID: 38385350 DOI: 10.1080/1061186x.2024.2316775] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/20/2024] [Accepted: 02/05/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND Diabetic retinopathy (DR) is a significant complication of diabetes and the primary cause of blindness among working age adults globally. The development of DR is accompanied by oxidative stress, characterised by an overproduction of reactive oxygen species (ROS) and a compromised antioxidant system. Clinical interventions aimed at mitigating oxidative stress through ROS scavenging or elimination are currently available. Nevertheless, these treatments merely provide limited management over the advanced stage of the illness. Ferroptosis is a distinctive form of cell death induced by oxidative stress, which is characterised by irondependent phospholipid peroxidation. PURPOSE This review aims to synthesise recent experimental evidence to examine the involvement of ferroptosis in the pathological processes of DR, as well as to explicate the regulatory pathways governing oxidative stress and ferroptosis in retina. METHODS We systematically reviewed literature available up to 2023. RESULTS This review included 12 studies investigating the involvement of ferroptosis in DR.
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Affiliation(s)
- Ruohong Wang
- Department of Ophthalmology Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Suyun Rao
- Department of Ophthalmology Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Zheng Zhong
- Department of Ophthalmology Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Ke Xiao
- Department of Ophthalmology Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Xuhui Chen
- Department of Ophthalmology Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Xufang Sun
- Department of Ophthalmology Tongji Hospital Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
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12
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Zhao P, Lv X, Zhou Z, Yang X, Huang Y, Liu J. Indexes of ferroptosis and iron metabolism were associated with the severity of diabetic nephropathy in patients with type 2 diabetes mellitus: a cross-sectional study. Front Endocrinol (Lausanne) 2023; 14:1297166. [PMID: 38189040 PMCID: PMC10767668 DOI: 10.3389/fendo.2023.1297166] [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: 09/19/2023] [Accepted: 12/05/2023] [Indexed: 01/09/2024] Open
Abstract
Objective To explore the correlations between diabetic nephropathy (DN) and serum levels of glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4), iron, transferrin (Tf), and ferritin in patients with type 2 diabetes mellitus (T2DM). Methods According to the urinary albumin excretion rate(UAER) or estimated glomerular filtration rate (eGFR) levels, a total of 123 patients with T2DM were separately divided into normoalbuminuria (NO), microalbuminuria (MI), macroalbuminuria (MA) groups, and G1 (eGFR ≥ 90 mL/min), G2 (eGFR ≤ 60 mL/min to < 90 mL/min), and G3 groups (eGFR< 60 mL/min), with 33 healthy participants as the control (HC). The differences in serum GPX4, ACSL4, iron, Tf, and ferritin levels between groups were compared, and the relationships between these levels were analysed. The independent correlations between UAER or DN severity and serum GPX4, ACSL4, iron, Tf, and ferritin levels were analysed by multiple linear and multinomial logistic regression, respectively. Results To the patients with T2DM, with the increase in UAER levels, GPX4, iron, and Tf levels gradually decreased, whereas ACSL4 levels increased, meanwhile with the decrease in eGFR levels, GPX4 and Tf levels gradually decreased, whereas ACSL4 levels increased. UAER were independently and positively correlated with ACSL4 [β = 17.53, 95% confidence interval (CI; 11.94, 23.13)] and negatively correlated with GPX4 [β = -1.633, 95% CI (-2.77, -0.496)] and Tf [β = -52.94, 95% CI (-95.78, -10.11)].The NO and MI groups were considered as reference groups, respectively. The severity of DN was negatively correlated with serum GPX4 [odds ratio (OR) = 0.925 and 0.902, p =0.015 and 0.001], and Tf (OR = 0.109 and 0.119, p =0.043 and 0.034), and positively correlated with ACSL4 (OR = 1.952 and 1.865, both p <0.001) in the MA group. Conclusion DN severity was negatively correlated with serum GPX4 and Tf levels and positively correlated with serum ACSL4 levels in patients with T2DM.
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Affiliation(s)
- Pingping Zhao
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Xiaoyu Lv
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | | | - Xiaolan Yang
- Clinical Laboratory of The First People’s Hospital of Baiyin, Baiyin, Gansu, China
| | - Ying Huang
- Clinical Laboratory of The First People’s Hospital of Baiyin, Baiyin, Gansu, China
| | - Jingfang Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
- Department of Endocrinology, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
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13
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Batagov A, Dalan R, Wu A, Lai W, Tan CS, Eisenhaber F. Generalized metabolic flux analysis framework provides mechanism-based predictions of ophthalmic complications in type 2 diabetes patients. Health Inf Sci Syst 2023; 11:18. [PMID: 37008895 PMCID: PMC10060506 DOI: 10.1007/s13755-023-00218-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 02/19/2023] [Indexed: 03/31/2023] Open
Abstract
Chronic metabolic diseases arise from changes in metabolic fluxes through biomolecular pathways and gene networks accumulated over the lifetime of an individual. While clinical and biochemical profiles present just real-time snapshots of the patients' health, efficient computation models of the pathological disturbance of biomolecular processes are required to achieve individualized mechanistic insights into disease progression. Here, we describe the Generalized metabolic flux analysis (GMFA) for addressing this gap. Suitably grouping individual metabolites/fluxes into pools simplifies the analysis of the resulting more coarse-grain network. We also map non-metabolic clinical modalities onto the network with additional edges. Instead of using the time coordinate, the system status (metabolite concentrations and fluxes) is quantified as function of a generalized extent variable (a coordinate in the space of generalized metabolites) that represents the system's coordinate along its evolution path and evaluates the degree of change between any two states on that path. We applied GMFA to analyze Type 2 Diabetes Mellitus (T2DM) patients from two cohorts: EVAS (289 patients from Singapore) and NHANES (517) from the USA. Personalized systems biology models (digital twins) were constructed. We deduced disease dynamics from the individually parameterized metabolic network and predicted the evolution path of the metabolic health state. For each patient, we obtained an individual description of disease dynamics and predict an evolution path of the metabolic health state. Our predictive models achieve an ROC-AUC in the range 0.79-0.95 (sensitivity 80-92%, specificity 62-94%) in identifying phenotypes at the baseline and predicting future development of diabetic retinopathy and cataract progression among T2DM patients within 3 years from the baseline. The GMFA method is a step towards realizing the ultimate goal to develop practical predictive computational models for diagnostics based on systems biology. This tool has potential use in chronic disease management in medical practice. Supplementary Information The online version contains supplementary material available at 10.1007/s13755-023-00218-x.
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Affiliation(s)
- Arsen Batagov
- Mesh Bio Pte. Ltd., 10 Anson Rd, #22-02, 079903 Singapore, Singapore
| | - Rinkoo Dalan
- Department of Endocrinology, Tan Tock Seng Hospital, Singapore, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
| | - Andrew Wu
- Mesh Bio Pte. Ltd., 10 Anson Rd, #22-02, 079903 Singapore, Singapore
| | - Wenbin Lai
- Mesh Bio Pte. Ltd., 10 Anson Rd, #22-02, 079903 Singapore, Singapore
| | - Colin S. Tan
- Fundus Image Reading Center, National Healthcare Group Eye Institute, Singapore, Singapore
- Tan Tock Seng Hospital, National Healthcare Group Eye Institute, Singapore, Singapore
- Duke-NUS Medical School, Singapore, Singapore
| | - Frank Eisenhaber
- Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- School of Biological Science (SBS), Nanyang Technological University, Singapore, Singapore
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Bao T, Zhang X, Xie W, Wang Y, Li X, Tang C, Yang Y, Sun J, Gao J, Yu T, Zhao L, Tong X. Natural compounds efficacy in complicated diabetes: A new twist impacting ferroptosis. Biomed Pharmacother 2023; 168:115544. [PMID: 37820566 DOI: 10.1016/j.biopha.2023.115544] [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: 03/28/2023] [Revised: 09/13/2023] [Accepted: 09/18/2023] [Indexed: 10/13/2023] Open
Abstract
Ferroptosis, as a way of cell death, participates in the body's normal physiological and pathological regulation. Recent studies have shown that ferroptosis may damage glucose-stimulated islets β Insulin secretion and programmed cell death of T2DM target organs are involved in the pathogenesis of T2DM and its complications. Targeting suppression of ferroptosis with specific inhibitors may provide new therapeutic opportunities for previously untreated T2DM and its target organs. Current studies suggest that natural bioactive compounds, which are abundantly available in drugs, foods, and medicinal plants for the treatment of T2DM and its target organs, have recently received significant attention for their various biological activities and minimal toxicity, and that many natural compounds appear to have a significant role in the regulation of ferroptosis in T2DM and its target organs. Therefore, this review summarized the potential treatment strategies of natural compounds as ferroptosis inhibitors to treat T2DM and its complications, providing potential lead compounds and natural phytochemical molecular nuclei for future drug research and development to intervene in ferroptosis in T2DM.
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Affiliation(s)
- Tingting Bao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing 100053, China; Graduate school, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Xiangyuan Zhang
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing 100053, China; Graduate school, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Weinan Xie
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing 100053, China; Graduate school, Beijing University of Traditional Chinese Medicine, Beijing 100029, China
| | - Ying Wang
- Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Jingyue National High-tech Industrial Development Zone, Changchun 130117, China
| | - Xiuyang Li
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing 100053, China
| | - Cheng Tang
- Changchun University of Chinese Medicine, No. 1035, Boshuo Road, Jingyue National High-tech Industrial Development Zone, Changchun 130117, China
| | - Yingying Yang
- National Center for Integrated Traditional and Western Medicine, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jun Sun
- Affiliated Hospital of Changchun University of Traditional Chinese Medicine, No. 1478, Gongnong Road, Chaoyang District, Changchun 130021, China
| | - Jiaqi Gao
- School of Qi-Huang Chinese Medicine, Beijing University of Chinese Medicine, No. 11, North 3rd Ring East Roa, Chaoyang Distric, Beijing 10010, China
| | - Tongyue Yu
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing 100053, China
| | - Linhua Zhao
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing 100053, China.
| | - Xiaolin Tong
- Institute of Metabolic Diseases, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, No.5 BeiXianGe Street, Xicheng District, Beijing 100053, China.
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Li L, Dai Y, Ke D, Liu J, Chen P, Wei D, Wang T, Teng Y, Yuan X, Zhang Z. Ferroptosis: new insight into the mechanisms of diabetic nephropathy and retinopathy. Front Endocrinol (Lausanne) 2023; 14:1215292. [PMID: 37600716 PMCID: PMC10435881 DOI: 10.3389/fendo.2023.1215292] [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: 05/01/2023] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Diabetic nephropathy (DN) and diabetic retinopathy (DR) are the most serious and common diabetes-associated complications. DN and DR are all highly prevalent and dangerous global diseases, but the underlying mechanism remains to be elucidated. Ferroptosis, a relatively recently described type of cell death, has been confirmed to be involved in the occurrence and development of various diabetic complications. The disturbance of cellular iron metabolism directly triggers ferroptosis, and abnormal iron metabolism is closely related to diabetes. However, the molecular mechanism underlying the role of ferroptosis in DN and DR is still unclear, and needs further study. In this review article, we summarize and evaluate the mechanism of ferroptosis and its role and progress in DN and DR, it provides new ideas for the diagnosis and treatment of DN and DR.
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Affiliation(s)
- Luxin Li
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Yucen Dai
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Dan Ke
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
| | - Jieting Liu
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Peijian Chen
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Dong Wei
- Department of Ophthalmology, Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, China
| | - Tongtong Wang
- Department of Endocrinology, Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, China
| | - Yanjie Teng
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Xiaohuan Yuan
- College of Life Sciences, Mudanjiang Medical University, Mudanjiang, China
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Zhen Zhang
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
- School of First Clinical Medical College, Mudanjiang Medical University, Mudanjiang, China
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He FT, Fu XL, Li MH, Fu CY, Chen JZ. LncRNA SNHG1 targets miR-340-5p/PIK3CA axis to regulate microvascular endothelial cell proliferation, migration, and angiogenesis in DR. Kaohsiung J Med Sci 2023; 39:16-25. [PMID: 36484399 DOI: 10.1002/kjm2.12625] [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: 07/18/2022] [Revised: 09/20/2022] [Accepted: 10/03/2022] [Indexed: 12/13/2022] Open
Abstract
Diabetic retinopathy (DR) is a serious long-term complication of diabetes. However, the current treatment of DR is still challenging. We aimed to investigate the role of lncRNA SNHG1/miR-340-5p/PIK3CA in DR and the mechanisms involved. Blood samples from clinical DR patients and healthy subjects were obtained. HRMECs were induced by high glucose for 24 h to establish the DR model. The vector for interfering or overexpressing lncRNA SNHG1, miR-340-5p, and PIK3CA was constructed. LncRNA SNHG1, miR-340-5p, and PIK3CA expressions were detected by qRT-PCR or Western blot. Cell proliferation and migration were detected by CCK-8 and Transwell assays. Blood vessel formation was detected by angiogenesis assay. Dual-luciferase reporter assay tested the interaction of lncRNA SNHG1 with miR-340-5p and miR-340-5p with PIK3CA. RIP measured the binding of miR-340-5p to PIK3CA. In the blood of DR patients and the DR model, lncRNA SNHG1 was increased and miR-340-5p expression was down-regulated. In the DR model, PIK3CA expression was elevated. Downregulation of lncRNA SNHG1 inhibited HRMECs proliferation, migration, and angiogenesis. LncRNA SNHG1 interacted with miR-340-5p, and up-regulation of miR-340-5p inhibited HRMECs proliferation, migration and angiogenesis. The inhibition of cell proliferation, migration, and angiogenesis of HRMECs caused by down-regulation of lncRNA SNHG1 was reversed by knockdown of miR-340-5p. miR-340-5p targeted PIK3CA, and downregulation of PIK3CA inhibited HRMECs proliferation, migration, and angiogenesis. The inhibition of HRMECs proliferation, migration and angiogenesis caused by down-regulation of lncRNA SNHG1 could be reversed by overexpression of PIK3CA. LncRNA SNHG1 targeted miR-340-5p/PIK3CA axis to regulate microvascular endothelial cell proliferation, migration, and angiogenesis in DR.
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Affiliation(s)
- Fu-Tao He
- Department of Ophthalmology, Hainan Western Central Hospital, Danzhou, Hainan Province, People's Republic of China
| | - Xiao-Lin Fu
- Department of Ophthalmology, Hainan Western Central Hospital, Danzhou, Hainan Province, People's Republic of China
| | - Mo-Han Li
- Department of Ophthalmology, Hainan Western Central Hospital, Danzhou, Hainan Province, People's Republic of China
| | - Chun-Yan Fu
- Department of Ophthalmology, Hainan Western Central Hospital, Danzhou, Hainan Province, People's Republic of China
| | - Jian-Zhi Chen
- Department of Ophthalmology, Hainan Western Central Hospital, Danzhou, Hainan Province, People's Republic of China
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Zhang X, Zuo R, Xiao S, Wang L. Association between iron metabolism and non-alcoholic fatty liver disease: results from the National Health and Nutrition Examination Survey (NHANES 2017-2018) and a controlled animal study. Nutr Metab (Lond) 2022; 19:81. [PMID: 36514155 PMCID: PMC9749311 DOI: 10.1186/s12986-022-00715-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 11/30/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Iron metabolism may be involved in the pathogenesis of the non-alcoholic fatty liver disease (NAFLD). The relationship between iron metabolism and NAFLD has not been clearly established. This study aimed to clarify the relationship between biomarkers of iron metabolism and NAFLD. METHODS Based on the National Health and Nutrition Examination Survey (NHANES), restricted cubic spline models and multivariable logistic regression were used to examine the association between iron metabolism [serum iron (SI), serum ferritin (SF), transferrin saturation (TSAT), and soluble transferrin receptor (sTfR)] and the risk for NAFLD. In addition, stratified subgroup analysis was performed for the association between TSAT and NAFLD. Moreover, serum TSAT levels were determined in male mice with NAFLD. The expression of hepcidin and ferroportin, vital regulators of iron metabolism, were analyzed in the livers of mice by quantitative real-time PCR (qRT-PCR) and patients with NAFLD by microarray collected from the GEO data repository. RESULTS Patients with NAFLD showed decreased SI, SF, and TSAT levels and increased STfR levels based on the NHANES. After adjusting for confounding factors, TSAT was significantly negatively correlated with NAFLD. Of note, the relationship between TSAT and NAFLD differed in the four subgroups of age, sex, race, and BMI (P for interaction < 0.05). Consistently, mice with NAFLD exhibited decreased serum TSAT levels. Decreased hepcidin and increased ferroportin gene expression were observed in the livers of patients and mice with NAFLD. CONCLUSION Serum TSAT levels and hepatic hepcidin expression were decreased in both patients and mice with NAFLD. Among multiple biomarkers of iron metabolism, lower TSAT levels were significantly associated with a higher risk of NAFLD in the U.S. general population. These findings might provide new ideas for the prediction, diagnosis, and mechanistic exploration of NAFLD.
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Affiliation(s)
- Xinxin Zhang
- grid.254147.10000 0000 9776 7793School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198 China
| | - Ronghua Zuo
- grid.412676.00000 0004 1799 0784Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029 Jiangsu China
| | - Shengjue Xiao
- grid.263826.b0000 0004 1761 0489Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009 China
| | - Lirui Wang
- grid.41156.370000 0001 2314 964XInstitute of Modern Biology, Nanjing University, 22 Hankou Road, Gulou, Nanjing, 210093 China
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Zimiao C, Dongdong L, Shuoping C, Peng Z, Fan Z, Rujun C, Xiaohua G. Correlations Between Iron Status and Body Composition in Patients With Type 2 Diabetes Mellitus. Front Nutr 2022; 9:911860. [PMID: 35911095 PMCID: PMC9326402 DOI: 10.3389/fnut.2022.911860] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 06/22/2022] [Indexed: 11/24/2022] Open
Abstract
Background Our study aimed to investigate the association between iron metabolism and body composition in patients with type 2 diabetes mellitus (T2DM). Methods A total of 824 patients with T2DM were enrolled. Measurements of body composition were obtained by dual-energy X-ray absorptiometry. Patients were stratified into three groups according to their sex-specific ferritin levels. Basic information, laboratory results, and body composition were collected. Results Serum iron and transferrin saturation (TSAT) were increased significantly with increased serum ferritin (all p < 0.05). Total iron-binding capacity (TIBC) was decreased significantly with increased serum ferritin (p < 0.05). Visceral fat mass (VF), android fat/total body fat mass, android-to-gynoid fat ratio (A/G ratio), and high-sensitivity C-reactive protein were all increased significantly with increased serum ferritin (all p < 0.05). Patients with a high A/G ratio (A/G ratio ≧ 1) had significantly higher serum iron, ferritin, and TSAT, but significantly lower TIBC. In the model adjusted for age and gender, higher ferritin levels were associated with a higher VF (all p < 0.05). Serum iron was positively correlated with the occurrence of a high A/G ratio (A/G ratio ≧ 1) after the adjustment of confounding factors [an odds ratio (OR = 1.09, 95% CI, 1.02–1.19, p = 0.02)]. With receiver operating curve analysis, the cutoff value of serum iron for a high A/G ratio was 18.56, and the area under the curve was 0.771 (sensitivity 88.9%and specificity 63.9%, p = 0.01). Conclusion Higher serum iron and ferritin concentrations were positively associated with a higher VF. Higher serum iron concentrations were positively correlated with a high A/G ratio. This study indicates the potential relationship between iron overload and the body composition in patients with T2DM.
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Affiliation(s)
- Chen Zimiao
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Luo Dongdong
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Dalian Medical University, Dalian Medical University, Dalian, China
| | - Chen Shuoping
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhou Peng
- Central Hospital of Qiaoxia Town, Wenzhou, China
| | - Zheng Fan
- College of Psychiatry, Wenzhou Medical University, Wenzhou, China
| | - Chen Rujun
- Department of Burn, 906 Hospital of the Joint Logistics Team, PLA, Wenzhou, China
- *Correspondence: Chen Rujun,
| | - Gong Xiaohua
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Gong Xiaohua,
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Koca S, Bozkurt E, Eroğul Ö, Yavaşoğlu F, Doğan M, Akdoğan M. Evaluation of macular and optic disc radial peripapillary vessel density with optical coherence tomography angiography in iron deficiency anemia. Photodiagnosis Photodyn Ther 2022; 38:102744. [DOI: 10.1016/j.pdpdt.2022.102744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 10/18/2021] [Accepted: 01/27/2022] [Indexed: 11/16/2022]
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Bayan N, Yazdanpanah N, Rezaei N. Role of Toll-Like Receptor 4 in Diabetic Retinopathy. Pharmacol Res 2021; 175:105960. [PMID: 34718133 DOI: 10.1016/j.phrs.2021.105960] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 10/23/2021] [Accepted: 10/23/2021] [Indexed: 12/11/2022]
Abstract
Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes mellitus (DM) and a leading cause of blindness worldwide. Evidence has shown that DR is an inflammatory disease with hyperglycemia playing a causative role in the development of its main features, including inflammation, cellular apoptosis, neurodegeneration, oxidative stress, and neovascularization. Toll-like receptors (TLRs) are a well-known family of pattern recognition receptors (PRRs) responsible for the initiation of inflammatory and immune responses. TLR4 identifies both endogenous and exogenous ligands and is associated with various physiological and pathological pathways in the body. While the detailed pathophysiology of DR is still unclear, increasing data suggests a crucial role for TLR4 in the development of DR. Due to hyperglycemia, TLR4 expression increases in diabetic retina, which activates various pathways leading to DR. Considering the role of TLR4 in DR, several studies have focused on the association of TLR4 polymorphisms and risk of DR development. Moreover, evidence concerning the effect of microRNAs in the pathogenesis of DR, through their interaction with TLR4, indicates the determinant role of TLR4 in this disease. Of note, several agents have proven as effective in alleviating DR through the inhibition of the TLR4 pathway, suggesting new avenues in DR treatment. In this review, we provided a brief overview of the TLR4 structure and biological function and a more comprehensive discussion about the mechanisms of TLR4 activation in DR. Furthermore, we summarized the relationship between TLR4 polymorphisms and risk of DR and the relationship between microRNAs and TLR4 in DR. Finally, we discussed the current progress in designing TLR4 inhibitors, which could be helpful in DR clinical management.
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Affiliation(s)
- Nikoo Bayan
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloufar Yazdanpanah
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Serum iron and risk of nonalcoholic fatty liver disease and advanced hepatic fibrosis in US adults. Sci Rep 2021; 11:10387. [PMID: 34002001 PMCID: PMC8128903 DOI: 10.1038/s41598-021-89991-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Accepted: 04/26/2021] [Indexed: 12/16/2022] Open
Abstract
Epidemiological evidence on the relationship between serum iron and liver diseases is limited. This study aims to investigate whether serum iron is associated with nonalcoholic fatty liver disease (NAFLD) and advanced hepatic fibrosis (AHF). Cross-sectional data for adults aged ≥ 18 years who participated in the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 were analyzed. Odds ratio (ORs) and 95% confidence intervals (CIs) of NAFLD and AHF associated with serum iron were estimated using multivariable logistic regression models. A total of 18,031 males and 18,989 females were included in the analysis. After multivariable adjustment for potential confounders, serum iron was significantly and inversely associated with NAFLD in both genders (P-trend < 0.001) and AHF in females (P-trend = 0.018). Compared to the bottom quartile, those in higher quartiles of serum iron had no significant ORs for AHF in males, but the trend across the quartiles was significant (P-trend = 0.046). In conclusion, higher serum iron level was associated with lower risk of NAFLD in males and females, and with lower risk of AHF in females but not in males. No significant racial/ethnical differences in these associations were observed.
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