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Akasha R, Shahab U, Pandey RP, Khan S, Puri P, Rafi Z, Alouffi S, Ahmad S. Inhibition of DNA glycoxidation by mannitol and Pyridoxamine: Implications for DNA-antibody development in diabetes and diabetic retinopathy. Anal Biochem 2025; 703:115886. [PMID: 40320156 DOI: 10.1016/j.ab.2025.115886] [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: 02/12/2025] [Revised: 04/28/2025] [Accepted: 04/29/2025] [Indexed: 05/09/2025]
Abstract
Chronic exposure to reactive carbonyl species such as glyoxal and methylglyoxal, along with hydroxyl radicals (•OH), leads to glycative and oxidative damage, contributing to insulin resistance and diabetic complications. Pyridoxamine (PM) is known to counteract these effects, but its potential synergy with mannitol (MN), a hydroxyl radical scavenger, remains unexplored. This study investigates the combined efficacy of MN and PM in preventing glycation and oxidative damage in vitro. Calf thymus DNA was subjected to glycation using 10 mM glyoxal, oxidation via the Fenton reaction, and sequential glycoxidation (glycation followed by oxidation). The inhibitory effects of MN, PM, and their combination were assessed using NBT reduction for early glycation, GK-ribose for AGEs, TBARS for hydroxyl radicals, and spectroscopic analyses for AGEs formation. A clinical study also examined autoantibody prevalence in diabetes and diabetic retinopathy (DR). Results showed that glycoxidated DNA exhibited structural alterations, with MN and PM individually reducing ketoamine content. Their combination further enhanced glycation and glycoxidation inhibition. Additionally, MN-PM co-administration synergistically reduced AGEs and hydroxyl radicals. Autoantibody levels were elevated in diabetes and DR. These findings suggest PM-MN co-administration as a promising strategy to mitigate diabetic complications.
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Affiliation(s)
- Rihab Akasha
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, 2440, Saudi Arabia.
| | - Uzma Shahab
- Department of Pharmacology, College of Pharmacy, University of Hail, Hail City, 2440, Saudi Arabia.
| | - Ramendra Pati Pandey
- Department of Biotechnology, SRM University, Delhi-NCR, Sonepat, Haryana, 131029, India.
| | - Saif Khan
- Department of Basic Dental and Medical Sciences, College of Dentistry, University of Hail, Saudi Arabia.
| | - Paridhi Puri
- University Centre for Research and Development, Chandigarh University, Mohali, Punjab, 140413, India.
| | - Zeeshan Rafi
- Department of Bioengineering, Integral University, Lucknow, 226026, India.
| | - Sultan Alouffi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, 2440, Saudi Arabia.
| | - Saheem Ahmad
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, 2440, Saudi Arabia.
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Phungphong S, Suthivanich P, Boonhoh W, Punsawad C, Cheng Z, Bupha-Intr T. Targeting NLRP3 inflammasome attenuates cardiac pyroptosis and fibrosis in estrogen-deficient diabetic rats. Pflugers Arch 2025; 477:935-952. [PMID: 40383837 DOI: 10.1007/s00424-025-03092-6] [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: 01/30/2025] [Revised: 04/15/2025] [Accepted: 05/04/2025] [Indexed: 05/20/2025]
Abstract
Cardiac diastolic dysfunction is a hallmark of diabetic cardiomyopathy (DCM), particularly in postmenopausal women where estrogen deficiency exacerbates cardiac remodeling. This study investigated the roles of NLRP3 inflammasome activation and cardiac mast cell (CMC) behavior in diabetic ovariectomized (OVX) rat models. Female Wistar rats were divided into five groups: sham-operated, OVX, diabetic (Sham-DM), OVX-diabetic (OVX-DM), and OVX-DM treated with the NLRP3 inhibitor MCC950. Diabetes was induced using a high-calorie quick fat diet (13.8% crude fat, 24.35% crude protein, 25% sucrose; 406.80 kcal/100 g) followed by a single intraperitoneal injection of streptozotocin (30 mg/kg). MCC950 (10 mg/kg BW, intraperitoneally) was administered daily for 4 weeks. Echocardiography revealed significant diastolic dysfunction in OVX-DM rats, with increased left ventricular internal diameter (LVIDd) and reduced mitral valve E/A ratio, while MCC950 treatment partially restored diastolic function (p < 0.05). Masson's trichrome staining showed increased myocardial fibrosis in OVX-DM rats (2.59 ± 0.20%) compared to Sham-DM (1.94 ± 0.16%, p < 0.05), which was reduced with MCC950 treatment (0.88 ± 0.13%, p < 0.05). Western blot analysis demonstrated elevated expression of NLRP3, cleaved caspase-1, IL-1β, and GSDMD-N in OVX-DM hearts. MCC950 significantly reduced cleaved caspase-1, IL-1β, and GSDMD-N expression without altering NLRP3 protein levels. Additionally, mast cell degranulation was markedly increased in OVX-DM rats (62.14%) compared to controls (P < 0.05) and was attenuated by MCC950 (31.06%, P < 0.05). These findings suggest that NLRP3 inflammasome activation under conditions of estrogen deficiency and diabetes contributes to myocardial pyroptosis and mast cell degranulation, driving cardiac remodeling in postmenopausal DCM. Targeting NLRP3 pathways may provide an effective therapeutic strategy to mitigate diastolic dysfunction, fibrosis, and inflammation in diabetic hearts.
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Affiliation(s)
- Sukanya Phungphong
- Department of Medical Science, School of Medicine, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
- Center of Excellence in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat, 80160, Thailand.
| | - Phichaya Suthivanich
- Doctor of Philosophy Program in Physiology, Graduate School, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Worakan Boonhoh
- Akkhraratchakumari Veterinary College, Walailak University, Nakhon Si Thammarat, 80160, Thailand
| | - Chuchard Punsawad
- Department of Medical Science, School of Medicine, Walailak University, Nakhon Si Thammarat, 80160, Thailand
- Center of Excellence in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat, 80160, Thailand
| | - Zhaokang Cheng
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, 99202-2131, USA
| | - Tepmanas Bupha-Intr
- Department of Physiology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
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Tan Y, Lin X, Xie L. The role of oxidative stress in the association between metabolic score for insulin resistance and stroke: evidence from two large population-based studies. Exp Gerontol 2025; 205:112761. [PMID: 40254106 DOI: 10.1016/j.exger.2025.112761] [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: 09/12/2024] [Revised: 04/11/2025] [Accepted: 04/16/2025] [Indexed: 04/22/2025]
Abstract
OBJECTIVE This study endeavors to unveil the association between the Metabolic Score for Insulin Resistance (METS-IR) and stroke among adults utilizing data of the National Health and Nutrition Examination Survey (NHANES) and the China Health and Retirement Longitudinal Study (CHARLS), and whether oxidative stress (OS) mediates their association. METHODS Our study cohort comprised 101,316 individuals from NHANES and 17,708 individuals from CHARLS. The intricate relationships among the METS-IR, stroke, and OS biomarkers were evaluated via logistic regression, restricted cubic splines (RCS), as well as mediation analysis. RESULTS The final analysis included 22,542 American and 9521 Chinese participants, among whom 844 and 887 were diagnosed with stroke, respectively. Regression analysis indicated a positive association of METS-IR with stroke [NHANES: OR = 1.01, 95 % CI (1.01, 1.02), p < 0.001; CHARLS: OR = 1.02, 95 % CI (1.02, 1.03), p < 0.001], with higher METS-IR quartiles being associated with elevated stroke incidence [NHANES: OR = 1.39, 95 % CI (1.11, 1.73), p = 0.004; CHARLS: OR = 1.74, 95 % CI (1.39, 2.17), p < 0.001]. Participants with elevated METS-IR and serum uric acid (SUA) exhibited the greatest probability of stroke. Mediation analysis proved that OS partially mediated this association [Mediation effect: NHANES β = -8.45e-5, 95 % CI (-1.41e-4, -4.01e-5), p < 0.001; CHARLS β = -4.02e-5, 95 % CI (-8.14e-5, -7.76e-6), p = 0.012]. CONCLUSION The METS-IR was positively associated with stroke in NHANES and CHARLS cohorts, and OS partially mediated this association.
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Affiliation(s)
- Yi Tan
- Department of Neurology, The First People's Hospital of Lin'an District, Hangzhou, No. 360 Yikang Street, Lin'an District, Hangzhou, Zhejiang 311300, China
| | - Xing Lin
- Department of Internal Medicine, Hangzhou Chenghong Hospital, No. 859 Shixiang West Road, Xihu District, Hangzhou, Zhejiang 310000, China
| | - Liquan Xie
- Department of Geriatrics, Hangzhou TCM Hospital of Zhejiang Chinese Medical University, No. 453 Tiyuchang Road, Hangzhou, Zhejiang 310007, China.
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Kowluru RA, Malaviya P. Mitochondrial Transport of Glutathione in Diabetic Retinopathy. Free Radic Biol Med 2025:S0891-5849(25)00753-1. [PMID: 40490204 DOI: 10.1016/j.freeradbiomed.2025.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2025] [Revised: 05/30/2025] [Accepted: 06/03/2025] [Indexed: 06/11/2025]
Abstract
Diabetes increases free radical production and impairs the antioxidant defense system and increased oxidative stress-mitochondrial damage plays a central role in the development of diabetic retinopathy. GSH, a negatively charged molecule at physiological pH, is biosynthesized in the cytosol, and cannot pass through mitochondrial inner membranes. Interestingly, mitochondria contain ∼15% of the total GSH and depend on their inner membrane solute carriers for its import from cytosol; in diabetes, retinal cellular and mitochondrial GSH (mtGSH) levels are downregulated. Our aim was to investigate the role of solute carriers in the subnormal levels of mtGSH in diabetic retinopathy. Human retinal endothelial cells, regulated for solute carriers dicarboxylate (DIC), or 2-oxyglutarate (OGC) by their respective siRNAs or by overexpressing plasmids, and incubated in 20mM glucose, were analyzed for cytosolic and mitochondrial GSH levels, mitochondrial respiration, membrane potential and cell apoptosis. Key results were confirmed in the retina from streptozotocin-induced C57BL/6J diabetic mice. High glucose decreased DIC and OGC expression, and downregulated cytosolic and mtGSH. While mtGSH was further decreased by inhibition of DIC or OGC and protected by their overexpression, cytosolic GSH was not affected by DIC or OGC regulation. Overexpression of these solute carriers also prevented glucose-induced decrease in mitochondrial structural damage, impaired membrane potential and respiration and increased cell death. Consistent with in vitro results, retinal DIC, OGC and mtGSH levels were significantly downregulated in diabetic mouse, and GSH co-staining with DIC, or with OGC, was also significantly decreased. Thus, DIC and OGC downregulation pays a major role in the impaired GSH import inside the mitochondria, making them more susceptible to the damage. Damaged mitochondria accelerate cell death, culminating in the development of diabetic retinopathy. Restoring mtGSH levels via upregulating GSH transporters could provide a novel approach to inhibit diabetic retinopathy.
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Affiliation(s)
- Renu A Kowluru
- Kresge Eye Institute, Wayne State University, Detroit, MI.
| | - Pooja Malaviya
- Kresge Eye Institute, Wayne State University, Detroit, MI
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Rajab AM, Pearson S, Ajjan RA. Use of adjunctive glycaemic agents with vascular protective properties in individuals with type 1 diabetes: Potential benefits and risks. Diabetes Obes Metab 2025; 27:2920-2939. [PMID: 40130476 PMCID: PMC12046473 DOI: 10.1111/dom.16332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 03/02/2025] [Accepted: 03/02/2025] [Indexed: 03/26/2025]
Abstract
Glycaemic therapy in type 1 diabetes (T1D) is focused on insulin, with the majority of studies investigating different insulin preparations, delivery devices and dosing accuracy methods. While insulin deficiency is the key mechanism for hyperglycaemia in T1D, individuals with this condition can also develop insulin resistance (IR), making optimisation of glycaemia more challenging. Importantly, IR in T1D increases the risk of both microvascular and macrovascular complications; yet, it is rarely targeted in routine clinical care. In this narrative review, we briefly discuss the mechanistic pathways for diabetes complications in individuals with T1D, emphasising the adverse role of IR. We subsequently cover the use of adjunctive glycaemic therapies for improving the metabolic profile in T1D, focusing on therapies that have possible or definite cardiovascular or renal protective properties in individuals with type 2 diabetes. These include metformin and agents in the thiazolidinedione, Sodium-Glucose Cotransporter-2 inhibitor (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) groups. In addition to reviewing the role of these agents in improving metabolic parameters, we address their potential vascular and renal protective effects in individuals with T1D. We suggest a pragmatic approach for using these agents in T1D, based on current knowledge of their benefits and risks, while also highlighting gaps in knowledge and areas that require further research. It is hoped that the review raises awareness of the role of adjunctive therapies in T1D and offers healthcare professionals simple guidance on using such agents for the management of high-risk individuals with T1D.
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Affiliation(s)
- Ahmad M. Rajab
- Diabetes CentreSt James's University Hospital, Leeds Teaching Hospitals TrustLeedsUK
| | - Sam Pearson
- Diabetes CentreSt James's University Hospital, Leeds Teaching Hospitals TrustLeedsUK
| | - Ramzi A. Ajjan
- Diabetes CentreSt James's University Hospital, Leeds Teaching Hospitals TrustLeedsUK
- Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and HealthUniversity of LeedsLeedsUK
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Pedrini A, Nowosielski Y, Rehak M. Diabetic retinopathy-recommendations for screening and treatment. Wien Med Wochenschr 2025; 175:253-263. [PMID: 40343680 DOI: 10.1007/s10354-025-01088-6] [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: 08/03/2024] [Accepted: 04/06/2025] [Indexed: 05/11/2025]
Abstract
Diabetic retinopathy (DR), the prevalence of which continues to rise, is one of the most common causes of vision loss worldwide. Experimental and clinical research in recent years has contributed to a better understanding of the pathogenesis of DR, which is complex and results from many interrelated processes leading to abnormal permeability and occlusion of the retinal vasculature, with ischemia and subsequent neovascularization. According to the absence or presence of neovascularization, DR is divided into two main forms: nonproliferative and proliferative DR. From nonproliferative to proliferative disease, diabetic macular edema (DME) can develop anywhere along the spectrum. As the majority of diabetics have no ophthalmologic symptoms, screening plays an important role in preventing the development of retinal disease. Specific treatment options beyond metabolic risk factor control, including intravitreal administration of anti-vascular endothelial growth factor (VEGF) agents or corticosteroids, laser photocoagulation, and vitreous surgery, are effective approaches for ocular diabetic complications.
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Affiliation(s)
- Alisa Pedrini
- Department of Ophthalmology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
| | - Yvonne Nowosielski
- Department of Ophthalmology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria.
| | - Matus Rehak
- Department of Ophthalmology, Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
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Dakota I, Huang W, Wijayanto MA, Nurhafizah A, Khairunnisa AR, Rachmayanti S, Yuliana E, Sunjaya AF, Siswanto BB. Prognostic value of triglyceride-glucose index on predicting major adverse cardiovascular events in hypertensive patients: a systematic review and meta-analysis. Am J Prev Cardiol 2025; 22:100996. [PMID: 40290417 PMCID: PMC12032867 DOI: 10.1016/j.ajpc.2025.100996] [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: 01/27/2025] [Revised: 03/23/2025] [Accepted: 04/12/2025] [Indexed: 04/30/2025] Open
Abstract
BACKGROUND Triglyceride- glucose (TyG) index, a marker of insulin resistance, has been shown to be associated with the incidence of cardiometabolic diseases including hypertension. However, the prognostic role of TyG index is unknown. Hence, we aim to determine the association of TyG index with major adverse cardiovascular events (MACE) in hypertensive patients. METHODS Systematic searching was conducted on 3 databases up till November 2024. We included studies with hypertensive patients despite their comorbidities. Outcome measured is MACE and its individual components. Random effect model meta-analysis is done to pool the results with similar reference point. RESULTS Twenty observational studies with a total of 451,455 patients of 40 - 70 years old are included. Meta-analysis result shows that higher TyG index is associated with a statistically significant increased risk of MACE (HR 1.90, CI: 1.41 - 2.57, I2 88 %), myocardial infarction (HR 1.55, CI: 1.27 - 1.88, I2 0 %), stroke (HR 1.84, CI: 1.41 - 2.39, I2 62 %), all- cause mortality (HR 1.86, CI: 1.70 - 2.03, I2 0 %) and cardiovascular mortality (HR 1.08, CI: 1.04 - 1.11, I2 0 %). Subgroups of older and younger population, male and female gender, diabetic and non- diabetic population, and higher BMI patients retains the statistically significant risk of MACE (p < 0.05). U- shaped phenomena of TyG index is also demonstrated with the risk of all- cause mortality. CONCLUSION TyG index is a reliable prognostic marker of MACE in hypertensive patients and can be utilized in population despite their age, diabetic status, and gender.
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Affiliation(s)
- Iwan Dakota
- National Cardiovascular Center Harapan Kita, Indonesia
| | - Wilbert Huang
- National Cardiovascular Center Harapan Kita, Indonesia
- Faculty of Medicine, University of Padjadjaran, Indonesia
| | - Matthew Aldo Wijayanto
- National Cardiovascular Center Harapan Kita, Indonesia
- Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Central Java, Indonesia
| | - Apridya Nurhafizah
- National Cardiovascular Center Harapan Kita, Indonesia
- Faculty of Medicine, University of Padjadjaran, Indonesia
| | - Alya Roosrahima Khairunnisa
- National Cardiovascular Center Harapan Kita, Indonesia
- Faculty of Medicine, University of Padjadjaran, Indonesia
| | | | - Enny Yuliana
- National Cardiovascular Center Harapan Kita, Indonesia
| | | | - Bambang Budi Siswanto
- National Cardiovascular Center Harapan Kita, Indonesia
- Department of Cardiology and Vascular Medicine, Universitas Indonesia, Indonesia
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Soop M, Ljungqvist O. Metabolic responses to surgical stress. Clin Nutr ESPEN 2025; 67:178-183. [PMID: 40081803 DOI: 10.1016/j.clnesp.2025.02.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 03/16/2025]
Affiliation(s)
- Mattias Soop
- Department of Inflammatory Bowel Disease and Intestinal Failure Surgery, Centre for Digestive Health, Karolinska University Hospital, Sweden.
| | - Olle Ljungqvist
- School of Medical Sciences, Dept of Surgery, Örebro University, Örebro, Sweden.
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Kumar M, Muthurayar T, Karthika S, Gayathri S, Varalakshmi P, Ashokkumar B. Anti-Diabetic Potentials of Lactobacillus Strains by Modulating Gut Microbiota Structure and β-Cells Regeneration in the Pancreatic Islets of Alloxan-Induced Diabetic Rats. Probiotics Antimicrob Proteins 2025; 17:1096-1116. [PMID: 38329697 DOI: 10.1007/s12602-024-10221-7] [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] [Accepted: 01/17/2024] [Indexed: 02/09/2024]
Abstract
Diabetes mellitus, a most common endocrine disorder of glucose metabolism, has become a global epidemic and poses a serious public health threat with an increased socio-economic burden. Escalating incidence of diabetes is correlated with changes in lifestyle and food habits that cause gut microbiome dysbiosis and β-cells damage, which can be addressed with dietary interventions containing probiotics. Hence, the search for probiotics of human origin with anti-diabetic, anti-AGE, and anti-ACE potentials has gained renewed interest for the effective management of diabetes and its associated complications. The present study used an alloxan (AXN)-induced diabetic rat model to investigate the effects of potential probiotic Lacticaseibacillus casei MKU1, Lactiplantibacillus pentosus MKU3, and Lactiplantibacillus plantarum MKU7 administration individually on physiochemical parameters related to diabetic pathogenesis. Experimental animals were randomly allotted into six groups viz. NCG (control), DCG (AXN), DGM (metformin), DGP1 (MKU1), DGP2 (MKU3), and DGP3 (MKU7), and biochemical data like serum glucose, insulin, AngII, ACE, HbA1c, and TNF-α levels were measured until 90 days. Our results suggest that oral administration with MKU1, MKU3, or MKU7 significantly improved serum insulin levels, glycemic control, glucose tolerance, and body weight. Additionally, β-cell mass was increased by preserving islet integrity in Lactobacillus-treated diabetic rats, whereas TNF-α (~40%), AngII (~30%), and ACE levels (~50%) were strongly inhibited and enhanced sIgA production (5.8 folds) abundantly. Furthermore, Lactobacillus administration positively influenced the gut microbiome with a significant increase in the abundance of Lactobacillus species and the beneficial Bacteroides uniformis and Bacteroides fragilis, while decreased the pathogenic Proteus vulgaris and Parabacteroides distasonis. Among the probiotic treatment groups, L. pentosus MKU3 performed greatly in almost all parameters, indicating its potential use for alleviating diabetes-associated complications.
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Affiliation(s)
- Manoj Kumar
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India
| | - Tharmar Muthurayar
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India
| | - Sukumaran Karthika
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India
| | - Santhalingam Gayathri
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India
| | - Perumal Varalakshmi
- Department of Molecular Microbiology, School of Biotechnology, Madurai Kamaraj University, Madurai, India
| | - Balasubramaniem Ashokkumar
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai, 625 021, India.
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Devroy P, Das D, Bala A, Mukherjee AK. A comprehensive review of scientifically reported phytochemicals to manage allodynia in chronic diabetes complications. J Pharm Pharmacol 2025:rgaf012. [PMID: 40448953 DOI: 10.1093/jpp/rgaf012] [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: 10/22/2024] [Accepted: 03/11/2025] [Indexed: 06/02/2025]
Abstract
BACKGROUND The global prevalence of diabetes mellitus and its associated complications is increasing, impacting both developed and developing nations. One common complication is neuropathy and neuropathic pain, which often manifests as symptoms such as allodynia-a condition where patients experience pain from non-painful stimuli. OBJECTIVE This review seeks to explore scientifically validated medicinal plants and phytochemicals, presenting the findings in an organized format based on published literature. METHODOLOGY Data were searched in pubmed literature and only the scientifically reported phytochemicals were considered to include in this review. KEY FINDINGS The U.S. Food and Drug Administration (FDA) has not approved many medications targeting the root causes of neuropathy. Instead, various strategies are employed to manage the symptoms of allodynia. Research on plant-based ethno-pharmaceuticals aims to address the symptoms without affecting the disease's progression, which involves the gradual loss of nerve fibres from the extremities. This article delves into allodynia's different forms, implications, and underlying signalling mechanisms. CONCLUSION The hope is that further research on phytochemicals could lead to the development of therapies for managing various forms of allodynia in diabetic patients.
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Affiliation(s)
- Piyali Devroy
- Pharmacology and Drug Discovery Research Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Guwahati, 781035 Assam, India
- Academy of Scientific and Innovative Research (AcSIR), AcSIR (an Indian Institute of National Importance), Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
| | - Dorothy Das
- Pharmacology and Drug Discovery Research Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Guwahati, 781035 Assam, India
- Microbial Biotechnology and Protein Research Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Guwahati, 781035 Assam, India
| | - Asis Bala
- Pharmacology and Drug Discovery Research Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Guwahati, 781035 Assam, India
- Academy of Scientific and Innovative Research (AcSIR), AcSIR (an Indian Institute of National Importance), Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
| | - Ashis Kumar Mukherjee
- Academy of Scientific and Innovative Research (AcSIR), AcSIR (an Indian Institute of National Importance), Sector 19, Kamla Nehru Nagar, Ghaziabad, Uttar Pradesh, 201002, India
- Microbial Biotechnology and Protein Research Laboratory, Division of Life Sciences, Institute of Advanced Study in Science and Technology (IASST), Vigyan Path, Guwahati, 781035 Assam, India
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Chen H, Liu K, Zhang J, Zhao X, Wang Y, Lu X, Qin F. A rapid and sensitive UHPLC-MS/MS method for epalrestat detection in micro-volumes of human plasma for the first time. Bioanalysis 2025:1-11. [PMID: 40420470 DOI: 10.1080/17576180.2025.2509480] [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: 01/03/2025] [Accepted: 05/16/2025] [Indexed: 05/28/2025] Open
Abstract
AIM A rapid and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for epalrestat detection in human plasma. MATERIALS AND METHODS A triple quadrupole tandem mass spectrometer equipped with an electrospray ionization (ESI) source was used to quantify epalrestat and the internal standard epalrestat-d5 in the negative ion mode using multiple reaction monitoring (MRM). After acetonitrile-mediated protein precipitation, chromatographic separation was achieved using a reversed-phase C18 column (ACQUITY UPLC BEH, 2.1 × 50 mm, 1.7 μm; Waters Corp) with acetonitrile and 2 mM ammonium acetate in water as the mobile phase through gradient elution. RESULTS AND CONCLUSION The retention time of epalrestat was 0.92 min and the entire run time was only 2.00 min. The calibration curve was linear in the range 10.0-8.00 × 103 ng/mL (r ≥ 0.99). The within-run and between-run relative standard deviations (RSDs) were < 9.3%. The within-run and between-run relative errors (REs) ranged -8.4-4.2%. No significant matrix effects were observed and the recovery rate was high. The method was fully validated, including reinjection reproducibility in human plasma, and was successfully applied in a pharmacokinetic study, in which 100% incurred sample reanalysis met the criteria.
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Affiliation(s)
- Hong Chen
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China
| | - Kewei Liu
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China
| | - Jiawen Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China
| | - Xihong Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China
| | - Yatian Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China
| | - Xiumei Lu
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China
| | - Feng Qin
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, P. R. China
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Goulding RP, Charlton BT, Breedveld EA, Huijts JY, van der Laan M, Strating AR, Noort W, Kolodyazhna A, Grootemaat AE, Bloemers FW, van der Wel NN, Wüst RCI. Skeletal muscle mitochondrial health in type 1 diabetes: the role of exercise capacity and lifestyle factors. Diabetologia 2025:10.1007/s00125-025-06451-1. [PMID: 40399597 DOI: 10.1007/s00125-025-06451-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/27/2025] [Indexed: 05/23/2025]
Abstract
AIMS/HYPOTHESIS Previous studies reporting lower skeletal muscle mitochondrial function in type 1 diabetes did not account for cardiorespiratory fitness, a key confounder when assessing mitochondrial function. We hypothesised that, compared with healthy individuals, muscle mitochondrial phenotypic differences would be abolished in individuals with type 1 diabetes when matched for age, sex, BMI and maximal oxygen uptake (V ˙ O 2max ). METHODS Seventeen individuals with type 1 diabetes and seventeen healthy control individuals matched for age, sex, BMI andV ˙ O 2max participated and underwent a muscle biopsy from the vastus lateralis. Mitochondrial respiration was assessed by high-resolution respirometry, and mitochondrial density and morphology were assessed by transmission electron microscopy. RESULTS V ˙ O 2max (individuals with type 1 diabetes 40±10 kg-1 min-1; control individuals 41±8 ml kg-1 min-1; p=0.51) and mitochondrial oxidative phosphorylation capacity (individuals with type 1 diabetes 101±35 [pmol O2] s-1 mg-1; control individuals 99±23 [pmol O2] s-1 mg-1, p=0.82) did not differ between groups. Both intermyofibrillar (individuals with type 1 diabetes 6.07±2.16%; control individuals 6.01±1.11%; p=0.92) and subsarcolemmal (individuals with type 1 diabetes 18.70±8.16%; control individuals 19.29±7.36%; p=0.83) mitochondrial densities were not different between groups. Mitochondrial respiration normalised by density did not differ between groups. However, individuals with type 1 diabetes and higher HbA1c displayed lower rates of mitochondrial respiration than those with lower HbA1c, whereas those with higher BMI displayed lower mitochondrial densities than those with lower BMI. CONCLUSIONS/INTERPRETATION Collectively, our study demonstrates that when matched for age, sex, BMI andV ˙ O 2max , maximal muscle mitochondrial respiration and morphology in people with type 1 diabetes are not impaired. These findings highlight the importance of habitual exercise, optimal glucose management and a healthy BMI in maintaining mitochondrial health in individuals with type 1 diabetes.
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Affiliation(s)
- Richie P Goulding
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands.
| | - Braeden T Charlton
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands
| | - Ellen A Breedveld
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands
| | - Jelle Y Huijts
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands
| | - Matthijs van der Laan
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands
| | - Anne R Strating
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands
| | - Wendy Noort
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands
| | - Aryna Kolodyazhna
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands
| | - Anita E Grootemaat
- Electron Microscopy Centre Amsterdam, Amsterdam UMC, Location Academic Medical Centre, Amsterdam, the Netherlands
| | - Frank W Bloemers
- Department of Trauma Surgery, Amsterdam Movement Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Nicole N van der Wel
- Electron Microscopy Centre Amsterdam, Amsterdam UMC, Location Academic Medical Centre, Amsterdam, the Netherlands
| | - Rob C I Wüst
- Department of Human Movement Sciences, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, the Netherlands.
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Wang Y, Dou W, Qian X, Chen H, Zhang Y, Yang L, Wu Y, Xu X. Advancements in the study of short-chain fatty acids and their therapeutic effects on atherosclerosis. Life Sci 2025; 369:123528. [PMID: 40049368 DOI: 10.1016/j.lfs.2025.123528] [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: 12/01/2024] [Revised: 02/15/2025] [Accepted: 03/02/2025] [Indexed: 03/09/2025]
Abstract
Atherosclerosis (AS) remains a leading cause of cardiovascular disease and mortality globally. This chronic condition is characterized by inflammation, lipid accumulation, and the deposition of cellular components within arterial walls. Emerging evidence has highlighted the multifaceted therapeutic potential of short-chain fatty acids (SCFAs) in mitigating AS progression. SCFAs have demonstrated anti-inflammatory properties and the ability to regulate immune responses, metabolic pathways, vascular integrity, and intestinal barrier function in animal models of AS. Consequently, SCFAs have garnered significant attention as a promising approach for the prevention and treatment of AS. However, further clinical trials and studies are necessary to fully elucidate the underlying mechanisms and effects of SCFAs. Additionally, different types of SCFAs may exert distinct impacts, necessitating more in-depth investigation into their specific roles and mechanisms. This review provides an overview of the diverse cellular mechanisms contributing to AS formation, as well as a discussion of the significance of SCFAs in AS pathogenesis and their multifaceted therapeutic potential. Nonetheless, additional research is warranted to comprehensively understand and harness the potential of various SCFAs in the context of AS.
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Affiliation(s)
- Yongsen Wang
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China; Department of Hepatobiliary Pancreatic and Splcnic Surgery, Luzhou People's Hospital, Luzhou, Sichuan 646000, PR China; Department of Vascular and Breast Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan 621000, PR China
| | - Wei Dou
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China
| | - Xin Qian
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China
| | - Hao Chen
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China
| | - Yi Zhang
- Department of Vascular and Breast Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan 621000, PR China
| | - Liu Yang
- Department of Hepatobiliary Pancreatic and Splcnic Surgery, Luzhou People's Hospital, Luzhou, Sichuan 646000, PR China
| | - Ya Wu
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China
| | - Xiongfei Xu
- Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Taiping Street 25, Luzhou, Sichuan 646000, PR China.
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14
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Chiu HS, Huang TS, Chen CT, Lin XY, Liao PC, Liou CC, Hsu CC, Somvanshi S, Sumazin P, Hsu PH, Sun CC, Shyu YC. Temporal Regulation of Early-Stage Cytokine Expression in Diabetic Wound Healing Under Negative Pressure Wound Therapy. Int J Mol Sci 2025; 26:4634. [PMID: 40429778 PMCID: PMC12110959 DOI: 10.3390/ijms26104634] [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: 03/04/2025] [Revised: 04/30/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
Negative pressure wound therapy (NPWT) is widely recognized for its efficacy in treating diabetic wounds, but the mechanisms involved in the wound healing process remain unclear. By examining changes in blood cytokine levels as molecular signaling precursors, we aim to provide a comprehensive cytokine profile to support adjunctive therapy research and clinical applications. A diabetic mouse wound model was established to compare cytokine profiles between NPWT-treated and standard dressing groups, identifying key signaling candidates that may facilitate wound healing. By integrating normal mouse data with large-scale cytokine analysis, we developed a time-stratified NPWT approach to track acute-phase cytokine fluctuations in diabetic conditions. NPWT did not significantly enhance coagulation-related cytokine expression but effectively reduced inflammation, albeit with a delayed regulatory effect compared to wild-type mice. A one-sided binomial test revealed that NPWT advanced the cytokine expression peak from 16 to 2 h, partially restoring the early healing pattern seen in normal mice and suggesting its potential role in modulating early-stage wound repair. These findings provide novel insights into early cytokine regulation during wound healing and highlight the potential of NPWT to inform therapeutic strategies. This refined monitoring approach may contribute to improved clinical decision-making and support enhanced wound management in diabetic patients.
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Affiliation(s)
- Hua-Sheng Chiu
- Department of Pediatrics, Texas Children’s Hospital Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; (H.-S.C.); (S.S.)
| | - Ting-Shuo Huang
- Department of General Surgery, Jen Ai Hospital, Taichung 400, Taiwan;
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chien-Tzung Chen
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
- Craniofacial Research Center, Chang Gung University, Taoyuan 333, Taiwan
| | - Xin-Yu Lin
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.)
| | - Po-Cheng Liao
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.)
| | - Cai-Cin Liou
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.)
| | - Chih-Chin Hsu
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (C.-C.H.); (C.-C.S.)
- Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan
| | - Sonal Somvanshi
- Department of Pediatrics, Texas Children’s Hospital Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; (H.-S.C.); (S.S.)
| | - Pavel Sumazin
- Department of Pediatrics, Texas Children’s Hospital Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; (H.-S.C.); (S.S.)
| | - Pang-Hung Hsu
- Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan;
| | - Chi-Chin Sun
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (C.-C.H.); (C.-C.S.)
- Department of Ophthalmology, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan
| | - Yu-Chiau Shyu
- Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan; (X.-Y.L.); (P.-C.L.); (C.-C.L.)
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
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15
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Ling J, Xie Z, Chen X, Ling D, Chen X, Luo X. Inverted U-shaped relationship between HbA1c and diabetic retinopathy in diabetic patients: a cross-sectional study. BMC Ophthalmol 2025; 25:289. [PMID: 40361041 PMCID: PMC12070565 DOI: 10.1186/s12886-025-04079-8] [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: 01/02/2025] [Accepted: 04/16/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Diabetic retinopathy (DR) is a leading cause of blindness among adults with diabetes. Glycated hemoglobin A1C (HbA1C) is a critical biomarker for long-term glycemic control and has been closely associated with the risk of developing DR. However, the relationship between HbA1C and DR remains complex and multifaceted, with limited research exploring the nonlinear aspects of this association. This study aims to investigate the nonlinear relationship between HbA1C and DR, providing insights into their association and informing clinical interventions. OBJECTIVE Many studies have indicated that HbA1C is positively correlated with DR. However, although elevated HbA1C is common in patients with DR, its relationship with DR remains controversial. Our study aimed to investigate the nonlinear relationship between HbA1c and DR, thereby accurately elucidating their association and providing a basis for clinical interventions. METHODS This study is the second analysis based on a cross-sectional studv. A total of 2,001 patients with type 2 Diabetes Mellitus (T2DM) visited the diabetic clinic in the Internal Medicine outpatient departments of two hospitals in southern Taiwan between April 2002 and November 2004 were included in this analysis. Demographic and clinical data were collected, and HbA1c levels were measured. The association between HbA1c and DR was analyzed using multivariate logistic regression, adjusting for potential confounders, and the potential nonlinear correlation was explored with a smooth curve fitting approach. RESULTS The fully-adjusted model showed that HbA1c positively correlated with DR (OR:1.13, 95%CI: 1.05-1.22). However, an inverted U-shaped association between them was observed by applying the smooth curve fitted method. The inflection point of HbA1c (9.4%) was calculated by utilizing the two-piecewise logistic regression model. In the subgroup analysis, the inverted U-shaped nonlinear correlation between HbA1c and DR was also found in age, sex and BMI. CONCLUSIONS HbA1C and DR have an inverted U-shaped relationship, with a peak at an HbA1C of 9.4% in the early phase of DR. After this peak, HbA1C decreases as DR increases. These results have crucial implications for DR patients. The findings also offer insights for public health policy, highlighting the necessity of regular screening and intervention for diabetic patients. Future research should further explore the mechanisms linking HbA1c to DR and consider individualized management strategies for different populations to effectively mitigate the burden of DR.
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Affiliation(s)
- Juan Ling
- Clinical College of Chinese Medicine, Gansu Province, Gansu University of Chinese Medicine, Lanzhou, 730030, China
- Gansu Provincial Hospital, Lanzhou, 730030, China
| | - ZhuoLin Xie
- Gansu Province, Gansu Provincial Hospital of TCM, Lanzhou, 730050, China
| | - XiaoJie Chen
- Clinical College of Chinese Medicine, Gansu Province, Gansu University of Chinese Medicine, Lanzhou, 730030, China
- Gansu Provincial Hospital, Lanzhou, 730030, China
| | - Di Ling
- The Third People's Hospital of Gansu Province, Gansu Province, Lanzhou, 730050, China
| | - XingLin Chen
- Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Epidemiology and Biostatistics, X&Y Solutions Inc, Empower U, Boston, USA
| | - XiangXia Luo
- Gansu Province, Gansu Provincial Hospital of TCM, Lanzhou, 730050, China.
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Cai Y, Liu J, Wang Q, Ren X, Xie J, Yu J, Xiao Y, Zhang Y, Chen X, Hong A. Mechanisms of vascular endothelial cell injury triggered by blood glucose changes in gestational diabetes mellitus. Diabetes Obes Metab 2025. [PMID: 40364503 DOI: 10.1111/dom.16450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 04/26/2025] [Accepted: 04/27/2025] [Indexed: 05/15/2025]
Abstract
AIMS The precise pathogenic mechanism of long-term detrimental effects on mothers and infants resulting from gestational diabetes (GDM) remains unclear. This study aimed to examine the long-term detrimental consequences of GDM on mothers and newborns, particularly the impact of glucose concentration variations on vascular endothelial cells and its possible pathogenic mechanisms. MATERIALS AND METHODS An analysis was conducted on the clinical data of 68 healthy pregnant women and 67 pregnant women diagnosed with GDM. Human umbilical vein endothelial cells (HUVECs) were obtained from six pairs of pregnant women for transcriptomic sequencing and analysis, which were concurrently analysed with existing databases. The study examined the effects of varying glucose concentrations on HUVECs, incorporating relevant biological experimental verifications, and assessed oxidative stress, inflammation, and the TGF-β signalling pathway. RESULTS Clinical data analysis indicated that in patients with gestational diabetes mellitus, early pregnancy hyperglycemia is significantly linked to adverse pregnancy outcomes, even when blood glucose levels are well-controlled. Transcriptomic sequencing revealed significant alterations in the gene expression of HUVECs under GDM conditions, highlighting enrichment in genes associated with metabolism, inflammation, oxidative stress, and diabetes signalling pathways. Cellular experiments indicated that a transition in glucose concentration from elevated to reduced levels can result in damage and dysfunction in HUVECs, elevate ROS levels, and activate the TGF-β signalling pathway. Additionally, injured HUVECs release CTGF through the TGF-β signalling pathway, influencing the extracellular matrix and surrounding cells. CONCLUSIONS The findings demonstrate that alterations in glucose concentration, particularly the shift from high to low levels, can lead to vascular endothelial cell dysfunction, increase ROS levels, and are associated with the TGF β/SMAD3 signalling pathway. Furthermore, compromised HUVECs can influence the microenvironment via their secretions, potentially jeopardising the health of both the mother and foetus.
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Affiliation(s)
- Yuling Cai
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
| | - Jia Liu
- The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Qiang Wang
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
- Shanghai Immune Therapy Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiujuan Ren
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
| | - Junye Xie
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
| | - Jialing Yu
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
| | - Yujie Xiao
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
| | - Yibo Zhang
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
| | - Xiaojia Chen
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
- The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - An Hong
- Institute of Biomedicine & Department of Cell Biology, College of Life Science and Technology, Jinan University, Guangzhou, China
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- National Engineering Research Center of Genetic Medicine, Guangzhou, China
- Guangdong Province Key Laboratory of Bioengineering Medicine, Guangzhou, China
- Guangdong Provincial Biotechnology Drug & Engineering Technology Research Center, Guangzhou, China
- The First Affiliated Hospital, Jinan University, Guangzhou, China
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Apostolopoulou M, Lambadiari V, Roden M, Dimitriadis GD. Insulin Resistance in Type 1 Diabetes: Pathophysiological, Clinical, and Therapeutic Relevance. Endocr Rev 2025; 46:317-348. [PMID: 39998445 PMCID: PMC12063105 DOI: 10.1210/endrev/bnae032] [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: 06/23/2024] [Indexed: 02/26/2025]
Abstract
People with type 1 diabetes (T1D) are usually considered to exclusively exhibit β-cell failure, but they frequently also feature insulin resistance. This review discusses the mechanisms, clinical features, and therapeutic relevance of insulin resistance by focusing mainly on human studies using gold-standard techniques (euglycemic-hyperinsulinemic clamp). In T1D, tissue-specific insulin resistance can develop early and sustain throughout disease progression. The underlying pathophysiology is complex, involving both metabolic- and autoimmune-related factors operating synergistically. Insulin treatment may play an important pathogenic role in predisposing individuals with T1D to insulin resistance. However, the established lifestyle-related risk factors and peripheral insulin administration inducing glucolipotoxicity, hyperinsulinemia, hyperglucagonemia, inflammation, mitochondrial abnormalities, and oxidative stress cannot always fully explain insulin resistance in T1D, suggesting a phenotype distinct from type 2 diabetes. The mutual interaction between insulin resistance and impaired endothelial function further contributes to diabetes-related complications. Insulin resistance should therefore be considered a treatment target in T1D. Aside from lifestyle modifications, continuous subcutaneous insulin infusion can ameliorate insulin resistance and hyperinsulinemia, thereby improving glucose toxicity compared with multiple injection insulin treatment. Among other concepts, metformin, pioglitazone, incretin-based drugs such as GLP-1 receptor agonists, sodium-glucose cotransporter inhibitors, and pramlintide can improve insulin resistance, either directly or indirectly. However, considering the current issues of high cost, side effects, limited efficacy, and their off-label status, these agents in people with T1D are not widely used in routine clinical care at present.
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Affiliation(s)
- Maria Apostolopoulou
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - Vaia Lambadiari
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
| | - Michael Roden
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine University, 40225 Düsseldorf, Germany
- Institute for Clinical Diabetology, German Diabetes Center, Leibnitz Center for Diabetes Research at Heinrich-Heine University, 40225 Düsseldorf, Germany
- German Center of Diabetes Research (DZD), Partner Düsseldorf, 85764 München-Neuherberg, Germany
| | - George D Dimitriadis
- 2nd Department of Internal Medicine, Research Institute and Diabetes Center, National and Kapodistrian University of Athens Medical School, 12462 Athens, Greece
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18
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Phochantachinda S, Photcharatinnakorn P, Chatchaisak D, Sakcamduang W, Chansawhang A, Buranasinsup S, Suemanotham N, Chantong B. Plasma-based proteomics analysis of molecular pathways in canine diabetes mellitus after astaxanthin supplementation. PLoS One 2025; 20:e0321509. [PMID: 40333882 PMCID: PMC12057883 DOI: 10.1371/journal.pone.0321509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 03/06/2025] [Indexed: 05/09/2025] Open
Abstract
The hyperglycemic state in diabetes mellitus induces oxidative stress and inflammation, contributing to diabetic tissue damage and associated complications. Astaxanthin, a potent antioxidant carotenoid, has been investigated for its potential to prevent and manage diabetes across various species; however, its effect on client-owned dogs remains poorly studied. This study explored the impact of astaxanthin supplementation on canine diabetes mellitus using a proteomics approach. A total of 18 client-owned dogs were enrolled: 6 dogs with diabetes mellitus and 12 clinically healthy dogs. The diabetic dogs received their standard treatment regimen along with daily oral supplementation of 12 mg of astaxanthin (1.5-2.4 mg/kg) for 90 days. Plasma samples were collected at the beginning and end of the study period for proteomics analysis. After astaxanthin supplementation, significant alterations in the expression of proteins associated with the complement system, coagulation cascade, JAK-STAT signaling, and protein kinase C signaling (all of which contribute to inflammation and oxidative stress) were observed. Astaxanthin exhibited potential for reducing diabetes-associated complications, such as insulin resistance, vascular dysfunction, nephropathy, and cardiac issues, even though it did not affect clinical parameters (hematology, plasma biochemistry, blood glucose, and serum fructosamine). These findings suggest that astaxanthin may be a valuable complementary therapy for managing diabetes-related complications in canines.
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Affiliation(s)
- Sataporn Phochantachinda
- Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | | | - Duangthip Chatchaisak
- Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | - Walasinee Sakcamduang
- Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | - Anchana Chansawhang
- The Center for Veterinary Diagnosis, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | - Shutipen Buranasinsup
- Department of Pre-Clinic and Applied Animal Science, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
| | - Namphung Suemanotham
- Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Boonrat Chantong
- Department of Pre-Clinic and Applied Animal Science, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand
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Qian W, Lingli X, Dexue L, Yangwen C, Yongyan S, Weihua W. Influence of fluctuations in fasting blood glucose on left ventricular function in patients with type 2 diabetes mellitus and coronary microcirculation dysfunction: a prospective cohort study. Acta Diabetol 2025:10.1007/s00592-025-02514-2. [PMID: 40332563 DOI: 10.1007/s00592-025-02514-2] [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: 12/31/2024] [Accepted: 04/16/2025] [Indexed: 05/08/2025]
Abstract
AIMS To examine the effects of fluctuations in fasting blood glucose (FBG) levels on left ventricular function in patients with T2DM and coronary microcirculation dysfunction (CMD). METHODS A total of 290 patients with T2DM who received glucose-lowering therapy during hospitalization and were subsequently followed up for 18 months at the First Affiliated Hospital of Harbin Medical University, were enrolled in this study. 135 were diagnosed with CMD and were assigned to the CMD group, whereas 155 patients without CMD were allocated to the non-CMD group. The fasting blood glucose coefficient of variation (FBG-CV) was calculated for all participants. The CMD group was further stratified into three subgroups based on their FBG-CV values: CMD1 (FBG-CV > 25%), CMD2 (FBG-CV 15% ~ 25%), and CMD3 (FBG-CV < 15%). The left ventricular function, assessed by left ventricular ejection fraction (LVEF) and the E/e' ratio, was compared within each group before and after the follow-up period. This study was registered in the Chinese Clinical Trial Register, ChiCTR-ORC-16009800. RESULTS After the end of follow-up, the E/e' ratio in CMD1 was significantly higher than that in CMD2 and CMD3 (14.35 vs 8.57; p < 0.01; 14.35 vs 6.61; p < 0.01), and the E/e' ratio in CMD2 was significantly higher than that in CMD3 (8.57 vs 6.61; p < 0.01). Compared to the baseline measurements, the E/e' ratio in CMD1 showed a significant increase after an average 17.8 months of follow up (14.35 vs 8.44; p < 0.001). We found elevated E/e' ratio was associated with an increased FBG-CV level (odds ratio [OR]: 2.571; 95% CI 1.819-3.634; p < 0.001). In multivariate logistic analysis, course of diabetes (OR:1.062; 1.016-1.11; P = 0.007) and CMD (OR:2.231; 1.303-3.819; P = 0.003), were significantly associated with elevated E/e' ratio, while oral stains drugs (OR = 0.412 95% CI 0.237-0.715; P = 0.002) and insulin injections (OR = 0.536 95% CI 0.311-0.924; P = 0.025) behaved as a protective factor. CONCLUSIONS Our study clarified the association between FBG-CV levels and the E/e' ratio in a prospective cohort study. In T2DM patients with CMD, FBG-CV > 25% may adversely affect left ventricular diastolic function, whereas an optimal FBG-CV is considered to be less than 15%.
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Affiliation(s)
- Wang Qian
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China
- Department of Endocrinology, Shenzhen Third People's Hospital, Shenzhen, 518112, Guangdong Province, China
| | - Xie Lingli
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China
| | - Lu Dexue
- Department of Endocrinology, Shenzhen Third People's Hospital, Shenzhen, 518112, Guangdong Province, China
| | - Chen Yangwen
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China
| | - Shan Yongyan
- Department of Endocrinology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang Province, China
| | - Wu Weihua
- Department of Endocrinology, Shenzhen Third People's Hospital, Shenzhen, 518112, Guangdong Province, China.
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20
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Li B, Yim MM, Jin YX, Tao BK, Xie JS, Balas M, Khan H, Lam WC, Yan P, Navajas EV. Circulating Cell-Free DNA as an Epigenetic Biomarker for Early Diabetic Retinopathy: A Narrative Review. Diagnostics (Basel) 2025; 15:1161. [PMID: 40361979 PMCID: PMC12071738 DOI: 10.3390/diagnostics15091161] [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: 04/02/2025] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 05/15/2025] Open
Abstract
Diabetic retinopathy (DR), a complication of type 2 diabetes mellitus (T2DM), is typically asymptomatic in its early stages. Diagnosis typically relies on routine fundoscopy for the clinical detection of microvascular abnormalities. However, permanent retinal damage may occur well before clinical signs are appreciable. In the early stages of DR, the retina undergoes distinct epigenetic changes, including DNA methylation and histone modifications. Recent evidence supports unique epigenetic 'signatures' in patients with DR compared to non-diabetic controls. These DNA 'signature' sequences may be specific to the retina and may circulate in peripheral blood in the form of cell-free DNA (cfDNA). In this review, we explore the literature and clinical application of cfDNA sampling as an early, non-invasive, accessible assessment tool for early DR detection. First, we summarize the known epigenetic signatures of DR. Next, we review current sequencing technologies used for cfDNA detection, such as magnetic bead-based enrichment, next-generation sequencing, and bisulfite sequencing. Finally, we outline the current research limitations and emerging areas of study which aim to improve the clinical utility of cfDNA for DR evaluation.
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Affiliation(s)
- Boaz Li
- Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada; (B.L.); (M.M.Y.); (Y.X.J.)
| | - Megan M. Yim
- Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada; (B.L.); (M.M.Y.); (Y.X.J.)
| | - Yu Xuan Jin
- Faculty of Medicine, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada; (B.L.); (M.M.Y.); (Y.X.J.)
| | - Brendan K. Tao
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada (P.Y.)
| | - Jim S. Xie
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada (P.Y.)
| | - Michael Balas
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada (P.Y.)
| | - Haaris Khan
- Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada; (H.K.)
| | - Wai-Ching Lam
- Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada; (H.K.)
| | - Peng Yan
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5S 2L9, Canada (P.Y.)
| | - Eduardo V. Navajas
- Department of Ophthalmology and Visual Sciences, The University of British Columbia, Vancouver, BC V5Z 3N9, Canada; (H.K.)
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21
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Dar MI, Gulya A, Abass S, Dev K, Parveen R, Ahmad S, Qureshi MI. Hallmarks of diabetes mellitus and insights into the therapeutic potential of synergy-based combinations of phytochemicals in reducing oxidative stress-induced diabetic complications. Nat Prod Res 2025; 39:2929-2943. [PMID: 39290074 DOI: 10.1080/14786419.2024.2402461] [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: 02/21/2024] [Revised: 08/03/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024]
Abstract
Diabetes mellitus (DM) is a serious health issue and is still one of the major causes of mortality around the globe. Natural products have progressively integrated into modern, advanced medical practices. Phytoconstituents from some medicinal plants have demonstrated therapeutic activity in treating different metabolic disorders and have been used to treat DM and its severe complications. The present review provides details of the major anti-diabetic targets identified in the literature and also provides comprehensive information regarding the therapeutic role of a synergy-based combination of phytoconstituents that functions by controlling specific molecular pathways synchronously by inhibiting certain key regulators involved in the development and progression of DM. The review also implicated the role of oxidative stress in diabetic complications and presented scientific validations of phytochemicals and their synergy-based combination using in vitro and or in vivo approaches.
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Affiliation(s)
- Mohammad Irfan Dar
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
- School of Pharmaceutical Education and Research, Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), and Bioactive Natural Product Laboratory, New Delhi, India
| | - Anu Gulya
- All India Institute of Medical Science, New Delhi, India
| | - Sageer Abass
- School of Pharmaceutical Education and Research, Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), and Bioactive Natural Product Laboratory, New Delhi, India
- School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Kapil Dev
- Department of Biotechnology, Jamia Millia Islamia, New Delhi, India
| | - Rabea Parveen
- School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Sayeed Ahmad
- School of Pharmaceutical Education and Research, Centre of Excellence in Unani Medicine (Pharmacognosy & Pharmacology), and Bioactive Natural Product Laboratory, New Delhi, India
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22
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Iwasaki H, Yagyu H, Shimano H. A Comprehensive Analysis of Diabetic Complications and Advances in Management Strategies. J Atheroscler Thromb 2025; 32:550-559. [PMID: 39805627 PMCID: PMC12055507 DOI: 10.5551/jat.65551] [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: 11/26/2024] [Accepted: 12/11/2024] [Indexed: 01/16/2025] Open
Abstract
Diabetes mellitus, particularly type 2 diabetes mellitus (T2DM), is a pervasive chronic disease that affects millions of people worldwide. It predisposes individuals to a range of severe microvascular and macrovascular complications, which drastically impact the patient's quality of life and increase mortality rates owing to various comorbidities. This extensive review explores the intricate pathophysiology underlying diabetic complications, focusing on key mechanisms, such as atherosclerosis, insulin resistance, chronic inflammation, and endothelial dysfunction. It also highlights recent therapeutic advancements, including the introduction of SGLT2 inhibitors and GLP-1 receptor agonists, which provide benefits beyond glycemic control and offer cardiovascular and renal protection. Furthermore, the future position of SGLT2 inhibitors and GLP-1 receptor agonists in terms of the prevention of diabetes and macrovascular diseases will be discussed. Considering the differences in insulin secretion capacity between Western and Asian patients, including Japanese patients, we propose a treatment strategy for high-quality diabetes in Japan.
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Affiliation(s)
- Hitoshi Iwasaki
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Hiroaki Yagyu
- Department of Endocrinology and Metabolism, Tsukuba University Hospital Mito Clinical Education and Training Center, Mito Kyodo General Hospital, Ibaraki, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki, Japan
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23
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Pan K, Gao Y, Zong H, Zhang Y, Qi Y, Wang H, Chen W, Zhou T, Zhao J, Yin T, Guo H, Wang M, Wang H, Pang T, Zang Y, Li J. Neuronal CCL2 responds to hyperglycaemia and contributes to anxiety disorders in the context of diabetes. Nat Metab 2025; 7:1052-1072. [PMID: 40329008 DOI: 10.1038/s42255-025-01281-2] [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: 10/10/2023] [Accepted: 03/17/2025] [Indexed: 05/08/2025]
Abstract
Anxiety disorders are frequently observed in patients with diabetes and can be associated with several diabetes-related factors. Here we determine that hyperglycaemia is a major cause for the development of anxiety disorders through a C-C motif chemokine ligand 2 (CCL2)-dependent mechanism. By adopting complementary strategies, we demonstrate that neuron-specific (not peripheral) CCL2 mediates anxiety-like behaviours in streptozotocin-induced diabetic mice. Mechanistically, high glucose levels induce Tonicity-responsive enhancer-binding protein (TonEBP)-dependent CCL2 expression in neurons, leading to microglial activation in a paracrine manner. Similar phenotypes are also observed in high-fat diet-induced diabetic mice, independent of insulin signalling. Furthermore, we reveal that neuronal CCL2 in the medial prefrontal cortex and ventral hippocampus synergistically induces anxiety-like behaviours, indicating brain region-specific effects on diabetic mice. Finally, we confirm that the neuronal TonEBP-CCL2 axis and inflammatory pathways are both upregulated in patients with diabetes. Conclusively, neuronal CCL2 is specifically increased by hyperglycaemia and contributes to anxiety disorders, providing additional insights into the link between diabetes and mental health disorders.
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Affiliation(s)
- Kaijun Pan
- Metabolic Disease Research Center, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yanan Gao
- Metabolic Disease Research Center, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Haichao Zong
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yongmei Zhang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Yingbei Qi
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Hanlin Wang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Wengang Chen
- Metabolic Disease Research Center, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Ting Zhou
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Jinwen Zhao
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Tao Yin
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Haoran Guo
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Min Wang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Hanmin Wang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Tao Pang
- Metabolic Disease Research Center, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China
| | - Yi Zang
- Lingang Laboratory, Shanghai, China.
| | - Jia Li
- Metabolic Disease Research Center, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
- University of Chinese Academy of Sciences, Beijing, China.
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24
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Jansook P, Sigurdsson HH, Loftsson T. A look to the future: cyclodextrins and cyclodextrin-based drug delivery to the retina. Expert Opin Drug Deliv 2025; 22:693-710. [PMID: 40105773 DOI: 10.1080/17425247.2025.2482049] [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: 12/15/2024] [Revised: 03/06/2025] [Accepted: 03/17/2025] [Indexed: 03/20/2025]
Abstract
INTRODUCTION Retinal diseases are a leading cause of vision loss, affecting millions of people worldwide. Current treatment options are based on invasive methods such as intravitreal injections. Therefore, there is a need for alternative therapeutic strategies that are both effective and more patient-friendly. AREAS COVERED Topical drug delivery has gained attention as a preferred noninvasive approach, although it is hindered by several ocular barriers. Cyclodextrin (CD)-based nanoparticles have emerged as a promising strategy to overcome these limitations by enhancing drug permeability in the posterior segment of the eye. This review discusses the potential of CDs as enabling pharmaceutical excipients, their role in improving ocular drug bioavailability, and provides examples of CD-based eye drop formulations currently under development or undergoing clinical trials. Also, the role of CDs as active pharmaceutical agents in ophthalmology is discussed. EXPERT OPINION CD-based nanoparticle eye drops present a promising solution and have shown clinical success. CDs are approved pharmaceutical excipients for eye drop formulations and can act as active pharmaceutical ingredients for the treatment of inherent retinal diseases. Future innovations in hybrid CD-based delivery systems and integration of novel therapeutic compounds could provide more efficient and targeted treatment options for retinal diseases.
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Affiliation(s)
- Phatsawee Jansook
- Faculty of Pharmaceutical Sciences, Chulalongkorn University, Pathumwan, Bangkok, Thailand
- Cyclodextrin Application and Nanotechnology-Based Delivery Systems Research Unit, Chulalongkorn University, Pathumwan, Bangkok, Thailand
| | - Hákon H Sigurdsson
- Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland
| | - Thorsteinn Loftsson
- Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland
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25
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Arrigo A, Cremona O, Aragona E, Casoni F, Consalez G, Dogru RM, Hauck SM, Antropoli A, Bianco L, Parodi MB, Bandello F, Grosche A. Müller cells trophism and pathology as the next therapeutic targets for retinal diseases. Prog Retin Eye Res 2025; 106:101357. [PMID: 40254246 DOI: 10.1016/j.preteyeres.2025.101357] [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: 02/20/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 04/22/2025]
Abstract
Müller cells are a crucial retinal cell type involved in multiple regulatory processes and functions that are essential for retinal health and functionality. Acting as structural and functional support for retinal neurons and photoreceptors, Müller cells produce growth factors, regulate ion and fluid homeostasis, and facilitate neuronal signaling. They play a pivotal role in retinal morphogenesis and cell differentiation, significantly contributing to macular development. Due to their radial morphology and unique cytoskeletal organization, Müller cells act as optical fibers, efficiently channeling photons directly to the photoreceptors. In response to retinal damage, Müller cells undergo specific gene expression and functional changes that serve as a first line of defense for neurons, but can also lead to unwarranted cell dysfunction, contributing to cell death and neurodegeneration. In some species, Müller cells can reactivate their developmental program, promoting retinal regeneration and plasticity-a remarkable ability that holds promising therapeutic potential if harnessed in mammals. The crucial and multifaceted roles of Müller cells-that we propose to collectively call "Müller cells trophism"-highlight the necessity of maintaining their functionality. Dysfunction of Müller cells, termed "Müller cells pathology," has been associated with a plethora of retinal diseases, including age-related macular degeneration, diabetic retinopathy, vitreomacular disorders, macular telangiectasia, and inherited retinal dystrophies. In this review, we outline how even subtle disruptions in Müller cells trophism can drive the pathological cascade of Müller cells pathology, emphasizing the need for targeted therapies to preserve retinal health and prevent disease progression.
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Affiliation(s)
- Alessandro Arrigo
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Eye Repair Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Ottavio Cremona
- Vita-Salute San Raffaele University, Milan, Italy; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Emanuela Aragona
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Filippo Casoni
- Vita-Salute San Raffaele University, Milan, Italy; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giacomo Consalez
- Vita-Salute San Raffaele University, Milan, Italy; Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rüya Merve Dogru
- Department of Physiological Genomics, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Stefanie M Hauck
- Metabolomics and Proteomics Core, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, 80939, Germany
| | - Alessio Antropoli
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Lorenzo Bianco
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | | | - Francesco Bandello
- Ophthalmology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Antje Grosche
- Department of Physiological Genomics, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
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Brock R, Kornfehl A, Oppenauer J, Eibensteiner F, Neymayer M, Veigl C, Cuhaj C, Erbes O, Wirth S, Perkmann T, Haslacher H, Müller M, Schlager O, Wolf P, Schnaubelt S. Associations of Thyroid and Parathyroid Hormones with Arterial Stiffness in Emergency Department Patients: A Prospective Cross-Sectional Study. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:812. [PMID: 40428770 PMCID: PMC12113468 DOI: 10.3390/medicina61050812] [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: 03/10/2025] [Revised: 04/22/2025] [Accepted: 04/24/2025] [Indexed: 05/29/2025]
Abstract
Background and Objectives: Cardiovascular diseases are prevalent entities, especially in emergency patients. Arterial stiffness is a known predictor of cardiovascular risk and mortality and is quantified by carotid-femoral pulse wave velocity (cfPWV). It is caused in part by vascular calcification, but exact details of the underlying mechanisms are yet to be elucidated, and current data suggest endocrine influences. This study thus aimed to assess the associations of endocrine parameters, particularly thyroid and parathyroid hormones, calcium, inorganic phosphate, and vitamin D, with cfPWV as a surrogate for arterial stiffness. Materials and Methods: Adults presenting to a single tertiary care emergency department in Vienna between 2018 and 2023 were prospectively enrolled. CfPWV was measured non-invasively, and levels of thyroid and parathyroid hormones and 25-hydroxyvitamin D, calcium, and inorganic phosphate were assessed. Results: In total, data from 827 patients, predominantly male (57%) and around 60 (47-72) years of age, were assessed. We observed a significant worsening of cfPWV with increasing parathyroid hormone levels (p < 0.001) and TSH levels (p = 0.03). No significant influences of calcium, inorganic phosphate, or 25-hydroxyvitamin D were observed. Conclusions: Thyroid and parathyroid hormone levels are associated with arterial stiffness in emergency department patients, suggesting a need for a comprehensive workup in patients at risk because of comorbidities and age. Additional prospective studies are needed to further elucidate the role of endocrinology in arterial stiffness and the subsequent relevance in emergency medicine.
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Affiliation(s)
- Roman Brock
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Andrea Kornfehl
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Julia Oppenauer
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Felix Eibensteiner
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Marco Neymayer
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Christoph Veigl
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Carina Cuhaj
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Oliver Erbes
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Sophia Wirth
- Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Thomas Perkmann
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Helmuth Haslacher
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Markus Müller
- Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria
| | - Oliver Schlager
- Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria
| | - Peter Wolf
- Division of Endocrinology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Sebastian Schnaubelt
- Department of Emergency Medicine, Medical University of Vienna, 1090 Vienna, Austria
- Emergency Medical Service Vienna, 1030 Vienna, Austria
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Yang Y, Zhao B, Wang Y, Lan H, Liu X, Hu Y, Cao P. Diabetic neuropathy: cutting-edge research and future directions. Signal Transduct Target Ther 2025; 10:132. [PMID: 40274830 PMCID: PMC12022100 DOI: 10.1038/s41392-025-02175-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/12/2024] [Accepted: 02/08/2025] [Indexed: 04/26/2025] Open
Abstract
Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.
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Affiliation(s)
- Yang Yang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Bing Zhao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanzhe Wang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongli Lan
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinyu Liu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Hu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Cao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
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Juricic S, Klac J, Stojkovic S, Tesic M, Jovanovic I, Aleksandric S, Dobric M, Zivkovic S, Maricic B, Simeunovic D, Lasica R, Dikic M, Banovic M, Beleslin B. Molecular and Pathophysiological Mechanisms Leading to Ischemic Heart Disease in Patients with Diabetes Mellitus. Int J Mol Sci 2025; 26:3924. [PMID: 40362167 PMCID: PMC12071796 DOI: 10.3390/ijms26093924] [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] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/07/2025] [Accepted: 04/10/2025] [Indexed: 05/15/2025] Open
Abstract
Coronary atherosclerosis in patients with diabetes mellitus is the most significant pathophysiological mechanism responsible for ischemic heart disease. Atherosclerosis in diabetes is premature, more diffuse, and more progressive, and it affects more coronary blood vessels compared to non-diabetics. Atherosclerosis begins with endothelial dysfunction, continues with the formation of fatty streaks in the intima of coronary arteries, and ends with the appearance of an atherosclerotic plaque that expands centrifugally and remodels the coronary artery. If the atherosclerotic plaque is injured, a thrombus forms at the site of the damage, which can lead to vessel occlusion and potentially fatal consequences. Diabetes mellitus and atherosclerosis are connected through several pathological pathways. Among the most significant factors that lead to atherosclerosis in diabetics are hyperglycemia, insulin resistance, oxidative stress, dyslipidemia, and chronic inflammation. Chronic inflammation is currently considered one of the most important factors in the development of atherosclerosis. However, to date, no adequate anti-inflammatory therapeutic measures have been found to prevent the progression of the atherosclerotic process, and they remain a subject of ongoing research. In this review, we summarize the most significant pathophysiological mechanisms that link atherosclerosis and diabetes mellitus.
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Affiliation(s)
- Stefan Juricic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
| | - Jovana Klac
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (J.K.); (R.L.)
| | - Sinisa Stojkovic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Milorad Tesic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Ivana Jovanovic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
| | - Srdjan Aleksandric
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Milan Dobric
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
- Dedinje Cardiovascular Institute, 11000 Belgrade, Serbia;
| | | | - Bojan Maricic
- Clinic of Cardiology, University Clinical Center Nis, 18000 Nis, Serbia;
| | - Dejan Simeunovic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Ratko Lasica
- Department of Cardiology, Emergency Center, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (J.K.); (R.L.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Miodrag Dikic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
| | - Marko Banovic
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
| | - Branko Beleslin
- Clinic for Cardiology, University Clinical Center of Serbia, 11000 Belgrade, Serbia; (S.S.); (M.T.); (I.J.); (S.A.); (D.S.); (M.D.); (M.B.)
- School of Medicine, University of Belgrade, 11000 Belgrade, Serbia;
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Xu Y, Dong B, Tang Y, Jiang Y, Huang T, Jiang F, Xing W, Chen J, Zhu F. Association between thyroid stimulating hormone levels and nonproliferative diabetic retinopathy: a cross-sectional study. BMC Endocr Disord 2025; 25:106. [PMID: 40259281 PMCID: PMC12010677 DOI: 10.1186/s12902-025-01928-x] [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: 01/14/2024] [Accepted: 04/08/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND The association between thyroid-stimulating hormone (TSH) and type 2 diabetes mellitus (T2DM) is well known. However, whether TSH is related to nonproliferative diabetic retinopathy (NPDR) has not been studied. This study aimed to explore the relationship between TSH and NPDR in Chinese patients with T2DM. METHODS In this cross-sectional study, 427 patients with T2DM were enrolled. The individuals were classified into two groups according to the fundus oculi examination: the non-diabetic retinopathy (NDR) group (n = 224) and the non-proliferative diabetic retinopathy (NPDR) group (n = 203). The individuals' demographic and clinical data were collected by reviewing medical records and direct interviews. The demographic data and biochemical parameters were compared between groups using the Student's t - test or the Mann‒Whitney U test, anthropometric measurements, thyroid function, and NPDR were evaluated, and the associations between TSH and NPDR were assessed using logistic regression models. RESULTS No significant differences in age, sex, body mass index (BMI), incidence of alcohol consumption, and duration of diabetes were found between these two groups. The systolic blood pressure (SBP), incidence of smoking, TSH, blood urea nitrogen (BUN), and urinary micro-albumin (mALB) were significantly higher in the NPDR group than in the NDR group (P < 0.05). Individuals in the NDR group had higher levels of thyroxine (T4), glutamic pyruvic transaminase (ALT), fasting C-peptide (FCP), and 2-hour C-peptide (2hCP) than individuals in the NPDR group (P < 0.05). Spearman's correlation analysis revealed that the serum TSH levels were negatively associated with the HbA1c levels in all patients (r=-0.11, P < 0.05). Serum TSH levels were negatively correlated with HbA1c levels (r = -0.19, P < 0.01) and positively correlated with diabetes duration (r = 0.14, P < 0.05) in the NPDR group. Multivariate logistic regression analysis revealed that high TSH levels, sex, diabetes duration, high-density lipoprotein cholesterol (HDL-C), glycosylated hemoglobin (HbA1c), FCP, and SBP were associated with NPDR [odds ratio (OR) > 1, P < 0.05]. Receiver operating characteristic curve analysis revealed that the optimal cutoff point of TSH for predicting NPDR was 2.235 mIU/L. CONCLUSION The TSH level is independently associated with NPDR in the Chinese population with T2DM. A high serum TSH level may be a potential risk factor for NPDR and an indicator for screening for diabetic microangiopathy. TRIAL REGISTRATION This study is registered with the Chinese Clinical Trial Registry (02/21/2025 ChiCTR2500097614).
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Affiliation(s)
- Yiqi Xu
- Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China
| | - Biwu Dong
- Department of Cardiology, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China
| | - Youyun Tang
- Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China
| | - Yan Jiang
- Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China
| | - Tingting Huang
- Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China
| | - Feng Jiang
- Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China
| | - Wei Xing
- Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China
| | - Junsheng Chen
- Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China
| | - Fengping Zhu
- Department of Endocrinology and Genetic Metabolism, The First Affiliated Hospital of Anhui Health College (the Second People's Hospital of Chizhou), Chizhou, Anhui, China.
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Liang X, Lai K, Li X, Ren D, Gui S, Xing Z, Li Y. Association between estimated glucose disposal rate and future cardiovascular disease risk across glucose metabolism status: a prospective cohort study. Diabetol Metab Syndr 2025; 17:131. [PMID: 40251696 PMCID: PMC12007373 DOI: 10.1186/s13098-025-01697-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 04/08/2025] [Indexed: 04/20/2025] Open
Abstract
BACKGROUND Cardiovascular disease (CVD) remains a major global health challenge, particularly affected by glucose metabolism status. However, the relationship between estimated glucose disposal rate (eGDR) and future CVD risk across different glucose metabolism status remains unclear. METHODS We analyzed data from the China Health and Retirement Longitudinal Study (2011-2020) of participants aged ≥ 45 years. The eGDR was calculated using waist circumference, hypertension status, and HbA1c levels. CVD events (stroke or cardiac events) were the outcome. Participants were categorized by glucose metabolism status (normoglycemia, prediabetes, diabetes). Cox proportional hazards models and restricted cubic splines were used to assess associations and potential non-linear relationships. RESULTS Among 7,828 participants (52.84% male, mean age 59.01 ± 9.21 years) followed for an average of 8.29 years, 1,944 participants (24.83%) developed CVD. Higher eGDR was inversely associated with CVD risk across all glucose metabolism states. Below the inflection points (11.77, 11.15, and 11.56 mg/kg/min for normoglycemia, prediabetes, and diabetes, respectively), each 1-unit increase in eGDR reduced CVD risk by 14% (HR = 0.86, 95%CI: 0.83-0.89), 10% (HR = 0.90, 95%CI: 0.86-0.93), and 14% (HR = 0.86, 95%CI: 0.81-0.91), respectively. CONCLUSION The eGDR demonstrates a potentially non-linear inverse association with future CVD risk across different glucose metabolism states.
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Affiliation(s)
- Xiaomin Liang
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Kai Lai
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Xiaohong Li
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Di Ren
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Shuiqing Gui
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
| | - Zemao Xing
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
| | - Ying Li
- Department of Critical Care Medicine, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China.
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Ding J, Li J, Cai X, Zhang K, Yu S, Liu K, Huang M. The relationship between the triglyceride-glucose (TyG) index and all-cause mortality in ICU patients with primary hypertension: a retrospective study. Sci Rep 2025; 15:12071. [PMID: 40199939 PMCID: PMC11978879 DOI: 10.1038/s41598-025-96202-4] [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: 09/18/2024] [Accepted: 03/26/2025] [Indexed: 04/10/2025] Open
Abstract
Primary hypertension is the most common type of hypertension, with a complex and not fully understood pathogenesis. Insulin resistance (IR) is a metabolic abnormality that has been shown to be quite prevalent among patients with hypertension in existing literature. The triglyceride-glucose (TyG) index is a reliable indicator for assessing insulin resistance (IR). This study aims to evaluate the relationship between the TyG index at admission and all-cause mortality (ACM) in patients with severe primary hypertension, and to explore its role in predicting the future all-cause mortality risk in primary hypertension patients. This study employs a retrospective design to categorize all patients into four quartiles based on the TyG index. The Kaplan-Meier (K-M) method was utilized to estimate the survival curves for each group and to compare the survival outcomes across different quartiles. To assess the nonlinear relationship between the TyG index and prognosis, Cox proportional hazards regression models and restricted cubic splines (RCS) were applied, adjusting for potential confounders. Additionally, subgroup analyses were performed to conduct stratified analyses and interaction tests. Kaplan-Meier survival curve analysis showed that patients with higher TyG index levels had higher all-cause mortality rates at 30 days, 60 days, and 90 days post-admission. This indicates that a higher TyG index is associated with an increased risk of death in the short term. Additionally, multivariate Cox proportional hazards regression analysis revealed that an increased TyG index was significantly associated with all-cause mortality at 30 days, 60 days, and 90 days. Meanwhile, RCS analysis indicates that as the TyG index level increases, the hazard ratio (HR) shows a significant upward trend, suggesting a gradual increase in the risk of all-cause mortality. In summary, among patients with primary hypertension in the intensive care unit, elevated TyG levels are associated with an increased risk of short-term mortality.
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Affiliation(s)
- Jiacheng Ding
- Second Affiliated Hospital of Jilin University, Changchun, China
| | - Jingqian Li
- Second Affiliated Hospital of Jilin University, Changchun, China
| | - Xinyu Cai
- Second Affiliated Hospital of Jilin University, Changchun, China
| | - Kai Zhang
- Second Affiliated Hospital of Jilin University, Changchun, China
| | - Shi Yu
- Second Affiliated Hospital of Jilin University, Changchun, China
| | - Keyan Liu
- Second Affiliated Hospital of Jilin University, Changchun, China
| | - Maoxun Huang
- Second Affiliated Hospital of Jilin University, Changchun, China.
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Hazer Rosberg DB, Mahlapuu M, Perez R, Dahlin LB. Lactoferrin-derived peptide PXL01 impacts nerve regeneration after sciatic nerve reconstruction in healthy and diabetic rats. Front Cell Dev Biol 2025; 13:1565285. [PMID: 40260416 PMCID: PMC12009942 DOI: 10.3389/fcell.2025.1565285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 03/18/2025] [Indexed: 04/23/2025] Open
Abstract
Introduction Although advanced surgical techniques are available, satisfactory functional outcomes after peripheral nerve injuries are uncommon. Hence, immune-modulating factors such as PXL01, a lactoferrin-derived peptide that improves axonal outgrowth in injured human digital nerves, have gained attention. We previously reported a short-term immunosuppressive effect of PXL01 after the repair of transected rat sciatic nerves, but it had no effect on nerve regeneration. Here, we investigated the potential of PXL01 to improve nerve regeneration in healthy rats and in a rat model of type 2 diabetes (Goto-Kakizaki [GK] rats). Methods A 10-mm sciatic nerve defect was created in healthy (n = 14) and diabetic GK rats (n = 14) and reconstructed using nerve autografts. Immediately after surgery, PXL01 or sodium chloride (control, placebo) (n = 7 for each treatment) was administered around the autograft. On day 8, immunohistochemical staining of the sciatic nerve and dorsal root ganglia (DRGs) was performed to analyze axonal outgrowth (neurofilament staining); inflammation (CD68 and CD206 macrophage staining in nerve); Schwann cell and sensory neuron activation (transcription factor ATF3 staining in nerve and DRGs) and apoptosis (cleaved caspase 3 staining in nerve); and neuroprotection (heat shock protein [HSP27] staining in nerve and DRGs). Results PXL01 had no impact on the macrophage response in the autografts but increased axonal outgrowth and HSP27 expression in the DRGs of healthy and diabetic rats, despite a lower number of activated Schwann cells in the autograft. Diabetes affected axonal outgrowth, Schwann cell and macrophage responses, and HSP27 expression. These effects were observed in the sciatic nerve as well as the DRG. Discussion Application of PXL01, despite having no impact on macrophages, may improve axonal outgrowth and affects Schwann cell activation in autograft-reconstructed sciatic nerves, as well as conveys neuroprotection (HSP27 expression) in the DRGs of healthy and diabetic GK rats. Diabetes influenced nerve regeneration in such autografts. Therefore, PXL01 is a promising candidate to improve nerve regeneration.
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Affiliation(s)
- Derya Burcu Hazer Rosberg
- Department of Translational Medicine – Hand Surgery, Lund University, Malmö, Sweden
- Department of Hand Surgery, Skåne University Hospital, Malmö, Sweden
| | - Margit Mahlapuu
- Department of Chemistry and Molecular Biology, Göteborg University, Göteborg, Sweden
| | - Raquel Perez
- Department of Translational Medicine – Hand Surgery, Lund University, Malmö, Sweden
- Unit for Social Epidemiology, Department of Clinical Sciences (Malmö), Lund University, Malmö, Sweden
| | - Lars B. Dahlin
- Department of Translational Medicine – Hand Surgery, Lund University, Malmö, Sweden
- Department of Hand Surgery, Skåne University Hospital, Malmö, Sweden
- Department of Biomedical & Clinical Sciences, Linköping University, Linköping, Sweden
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Li Q, Shang J, Inagi R. Control of Mitochondrial Quality: A Promising Target for Diabetic Kidney Disease Treatment. Kidney Int Rep 2025; 10:994-1010. [PMID: 40303215 PMCID: PMC12034889 DOI: 10.1016/j.ekir.2024.12.029] [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: 07/29/2024] [Revised: 12/05/2024] [Accepted: 12/23/2024] [Indexed: 05/02/2025] Open
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), affecting over 40% of patients with diabetes. DKD progression involves fibrosis and damage to glomerular and tubulointerstitial regions, with mitochondrial dysfunction playing a critical role. Impaired mitochondria lead to reduced adenosine triphosphate (ATP) production, damaged mitochondria accumulation, and increased reactive oxygen species (ROS), contributing to renal deterioration. Maintaining mitochondrial quality control (MQC) is essential for preventing cell death, tissue injury, and kidney failure. Recent clinical trials show that enhancing MQC can alleviate DKD. However, current treatments cannot halt kidney function decline, underscoring the need for new therapeutic strategies. Mitochondrial-targeted drugs show potential; however, challenges remain because of adverse effects and unclear mechanisms. Future research should aim to comprehensively explore therapeutic potential of MQC in DKD. This review highlights the significance of MQC in DKD treatment, emphasizing the need to maintain mitochondrial quality for developing new therapies.
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Affiliation(s)
- Qi Li
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
| | - Jin Shang
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
- The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Reiko Inagi
- Division of Chronic Kidney Disease Pathophysiology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan
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Zhang F, Zhou R, Bai Y, Huang L, Li J, Zhong Y. Hemoglobin glycation index and rapid kidney function decline in diabetes patients: Insights from CHARLS. Diabetes Res Clin Pract 2025; 222:112054. [PMID: 39986657 DOI: 10.1016/j.diabres.2025.112054] [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: 01/06/2025] [Revised: 02/05/2025] [Accepted: 02/17/2025] [Indexed: 02/24/2025]
Abstract
AIMS This study aimed to assess the relationship between hemoglobin glycation index (HGI) and risk of rapid kidney function decline (RKFD) in diabetic patients. METHODS HGI was calculated as actual measured HbA1c minus predicted HbA1c. RKFD was defined as a 30 % decline in estimated glomerular filtration rate during follow-up. Participants were categorized into three groups based on HGI levels: lower (HGI ≤ -0.55), medium (-0.55 < HGI ≤ 0.22) and higher (HGI > 0.23). To understand the association between HGI and risk of RKFD in diabetic patients, directed acyclic graph were drawn and multivariate Cox proportional hazards models were used to adjust for covariates. RESULTS During a median follow-up of 4.0 years, RKFD occurred in 43 patients (6.3 %) with diabetes. After adjusting for potential confounders, Compared to the lower-HGI group, the hazard ratios for RKFD were 1.75 (95 % confidence interval [95 % CI]: 0.72, 4.25) and 2.64 (95 % CI: 1.12, 6.21) in the medium- and higher-HGI groups, respectively. HGI showed a linearly associated with RKFD (Pfor nonlinear = 0.383). The magnitude of associations was not materially altered in all sensitivity analyses, but with none significantly. CONCLUSION Higher HGI may be associated with an increased risk of RKFD in diabetic patients.
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Affiliation(s)
- Fan Zhang
- Department of Nephrology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Rui Zhou
- Department of Nephrology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yan Bai
- Department of Endocrinology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liuyan Huang
- Department of Nephrology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiao Li
- Department of Nephrology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Yifei Zhong
- Department of Nephrology, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Ryu HE, Heo SJ, Lee JH, Park B, Han T, Kwon YJ. Data-driven cluster analysis of lipids, inflammation, and aging in relation to new-onset type 2 diabetes mellitus. Endocrine 2025; 88:151-161. [PMID: 39743640 DOI: 10.1007/s12020-024-04154-y] [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: 10/19/2024] [Accepted: 12/27/2024] [Indexed: 01/04/2025]
Abstract
PURPOSE Early detection and intervention are vital for managing type 2 diabetes mellitus (T2DM) effectively. However, it's still unclear which risk factors for T2DM onset are most significant. This study aimed to use cluster analysis to categorize individuals based on six known risk factors, helping to identify high-risk groups requiring early intervention to prevent T2DM onset. METHODS This study comprised 7402 Korean Genome and Epidemiology Study individuals aged 40 to 69 years. The hybrid hierarchical k-means clustering algorithm was employed on six variables normalized by Z-score-age, triglycerides, total cholesterol, non-high-density lipoprotein cholesterol, high-density lipoprotein cholesterol and C-reactive protein. Multivariable Cox proportional hazard regression analyses were conducted to assess T2DM incidence. RESULTS Four distinct clusters with significantly different characteristics and varying risks of new-onset T2DM were identified. Cluster 4 (insulin resistance) had the highest T2DM incidence, followed by Cluster 3 (inflammation and aging). Clusters 3 and 4 exhibited significantly higher T2DM incidence rates compared to Clusters 1 (healthy metabolism) and 2 (young age), even after adjusting for covariates. However, no significant difference was found between Clusters 3 and 4 after covariate adjustment. CONCLUSION Clusters 3 and 4 showed notably higher T2DM incidence rates, emphasizing the distinct risks associated with insulin resistance and inflammation-aging clusters.
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Affiliation(s)
- Ha-Eun Ryu
- Department of Family Medicine, Yongin Severance Hospital, Gyeonggi-do, Republic of Korea
- Department of Family Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seok-Jae Heo
- Division of Biostatistics, Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jong Hee Lee
- Department of Family Medicine, Yongin Severance Hospital, Gyeonggi-do, Republic of Korea
- Department of Family Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Byoungjin Park
- Department of Family Medicine, Yongin Severance Hospital, Gyeonggi-do, Republic of Korea
- Department of Family Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Taehwa Han
- Integrative Research Center for Cerebrovascular and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yu-Jin Kwon
- Department of Family Medicine, Yongin Severance Hospital, Gyeonggi-do, Republic of Korea.
- Department of Family Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
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Thabet EH, Khalil NA, Essawy MM, Harby SA, Solaiman AA, El Gazaerly HM, Khalifa YH. MiRNA-21-loaded chitosan nanoparticles ameliorate pancreatic apoptosis and oxidative stress in diabetic rats. Life Sci 2025; 366-367:123471. [PMID: 39956187 DOI: 10.1016/j.lfs.2025.123471] [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: 08/26/2024] [Revised: 02/09/2025] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
BACKGROUND Accelerated Pancreatic β-cell apoptosis and oxidative stress are the mainstays of type-1 diabetes. MicroRNA-21's (miRNA-21) role in regulating pancreatic β-cell function remains indefinable. MATERIAL AND METHODS Five groups of rats were used in this study (healthy controls (Ia), controls that received only chitosan (CS) nanoparticles (NPs)(Ib), streptozotocin (STZ)-induced diabetics rats (II),STZ-induced diabetic rats that received only CS-NPs(III), and STZ-induced diabetic rats treated with mi-RNA-21-CS-NPs(IV). Sera were collected for measurement of fasting blood glucose levels (FBG), insulin, oxidative stress, and intraperitoneal glucose intolerance tests. Pancreatic tissue was collected after sacrifice partly for histological examination and for oxidative stress assessment and evaluation of PTEN/ AKT using qRT-PCR. KEY FINDINGS We showed over-expression of cleaved-caspase-3 indicating accelerated apoptosis in the β-cell of STZ-induced diabetic rats. Apoptosis was significantly ameliorated by miRNA-21-CS. MiRNA-21-CS-NPs faithfully restored serum fasting insulin, and FBG, and reduced serum and pancreatic oxidative stress markers while enhancing the total antioxidant capacity. Histological examination revealed that miRNA-21 restored healthy β-cell architecture, decreased cleaved-caspase-3, and increased insulin secretion. Transmission electron microscopy revealed increased mitochondrial circularity that significantly correlated with an exaggerated oxidative stress profile as shown by high serum and pancreatic malondialdehyde (MDA), low glutathione peroxidase, and total antioxidant capacity in STZ-induced diabetes. This oxidative profile was reversed using miRNA-21-CS-NPs. Mi-RNA-21 therapy downregulated PTEN but increased AKT and pAKT expression. Altogether, we show that miRNA-21 restored normal islet β-cell structure and insulin secretion through PTEN inhibition. SIGNIFICANCE miRNA-21- CS-NPs are promising targeted therapeutics that may effectively decrease the global burden of diabetes.
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Affiliation(s)
- Eman H Thabet
- Department of Medical Physiology, Faculty of Medicine, University of Alexandria, 21500 Alexandria, Egypt; Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
| | - Nehal A Khalil
- Department of Medical Biochemistry, Faculty of Medicine, University of Alexandria, 21500 Alexandria, Egypt; Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry, Alexandria University, 21500 Alexandria, Egypt; Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Sahar A Harby
- Department of Clinical Pharmacology, Faculty of Medicine, University of Alexandria, 21500 Alexandria, Egypt
| | - Amany A Solaiman
- Department of Histology and Cell Biology, Faculty of Medicine, University of Alexandria, 21500 Alexandria, Egypt
| | - Hanaa M El Gazaerly
- Department of Oral Pathology, Faculty of Dentistry, Tanta University, Tanta 31527, Egypt
| | - Yassmin H Khalifa
- Department of Histology and Cell Biology, Faculty of Medicine, University of Alexandria, 21500 Alexandria, Egypt
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Pan SY, Weng CH, Tsai SF, Lin HJ, Lin JF, Lin CH, Wang IJ, Chou CC. Use of SGLT2 Inhibitors Versus DPP-4 Inhibitors and Age-Related Macular Degeneration in Patients WithType 2 Diabetes: A Multinational Cohort Study. Invest Ophthalmol Vis Sci 2025; 66:58. [PMID: 40257783 PMCID: PMC12020956 DOI: 10.1167/iovs.66.4.58] [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: 02/06/2025] [Accepted: 03/26/2025] [Indexed: 04/22/2025] Open
Abstract
Purpose To compare the impact of sodium-glucose cotransporter 2 (SGLT2) and dipeptidyl peptidase 4 (DPP-4) inhibitors on age-related macular degeneration (AMD) risk among patients with type 2 diabetes mellitus (T2DM). Methods This multinational, retrospective cohort study used electronic medical records from healthcare institutions across 21 countries. Adults 50 years or older with T2DM who had a prior prescription of metformin and initiated SGLT2 or DPP-4 inhibitors from 2013 to 2023 were included. The SGLT2 and DPP-4 inhibitor groups were propensity score matched in a 1:1 ratio to balance baseline characteristics and were followed for up to 5 years to observe the occurrence of AMD. Statistical analysis was performed using the Cox proportional hazards model and Kaplan-Meier analysis. Results Our final analysis included 20,966 T2DM patients prescribed SGLT2 inhibitors and 20,966 prescribed DPP-4 inhibitors. Compared to the DPP-4 inhibitor group, the SGLT2 inhibitor group was associated with significantly lower risks of AMD (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.58-0.85) and dry AMD (HR, 0.61; 95% CI, 0.46-0.80) but not wet AMD (HR, 0.74; 95% CI, 0.48-1.16). SGLT2 inhibitors compared with DPP-4 inhibitors were linked to a reduced risk of AMD in the White population, patients prescribed empagliflozin or dapagliflozin, and individuals with glycated hemoglobin < 8.5%, estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2, hypertension, or dyslipidemia, regardless of body mass index level. Conclusions In patients with T2DM, those prescribed SGLT2 inhibitors may experience lower risks of AMD and dry AMD compared to those prescribed DPP-4 inhibitors.
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Affiliation(s)
- Ssu-Yu Pan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chien-Hsiang Weng
- Department of Family Medicine, Brown University Warren Alpert Medical School, Providence, Rhode Island, United States
- Brown University Health, Providence, Rhode Island, United States
| | - Shang-Feng Tsai
- Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Life Science, Tunghai University, Taichung, Taiwan
| | - Hui-Ju Lin
- Eye Center, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Jun-Fu Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Ching-Heng Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan
- Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - I-Jong Wang
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chien-Chih Chou
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Ophthalmology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan
- Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
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Kowluru RA, Kumar J, Malaviya P. DNA methylation of long noncoding RNA cytochrome B in diabetic retinopathy. Noncoding RNA Res 2025; 11:141-149. [PMID: 39811245 PMCID: PMC11732211 DOI: 10.1016/j.ncrna.2024.12.007] [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: 10/07/2024] [Revised: 12/03/2024] [Accepted: 12/15/2024] [Indexed: 01/16/2025] Open
Abstract
Diabetic retinopathy, a microvascular complication of diabetes, is the leading cause of blindness in adults, but the molecular mechanism of its development remains unclear. Retinal mitochondrial DNA is damaged and hypermethylated, and mtDNA-encoded genes are downregulated. Expression of a long noncoding RNA (larger than 200 nucleotides, which does not translate into proteins), encoded by mtDNA, cytochrome B (LncCytB), is also downregulated. This study aims to investigate the role of DNA methylation in the downregulation of LncCytB in diabetic retinopathy. Human retinal endothelial cells, incubated in 5 mM (normal) or 20 mM (high) D-glucose, in the presence/absence of Azacytidine (a DNA methyl transferase inhibitor) were analyzed for LncCytB DNA methylation by immunoprecipitation and methylation specific PCR techniques, and LncCytB transcripts by strand-specific PCR and RNA-FISH. Mitochondrial genomic stability was evaluated by quantifying protective mtDNA nucleoids by SYBR green staining and by flow cytometry, and functional stability by oxygen consumption rate using Seahorse analyzer. Results were confirmed in an in vivo model using retina from diabetic rat. While high glucose elevated 5 mC and the ratio of methylated to unmethylated amplicons at LncCytB and downregulated its transcripts, azacytidine prevented LncCytB DNA hypermethylation and decrease in its expression. Azacytidine also ameliorated decrease in nucleoids and oxygen consumption rate. Similarly, azacytidine prevented increase in retinal LncCytB DNA methylation and decrease in its expression in diabetic rats. Thus, DNA hypermethylation plays a major role in the downregulation of retinal LncCytB in diabetes, resulting in impaired mitochondrial homeostasis, and culminating in the development of diabetic retinopathy.
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Affiliation(s)
- Renu A. Kowluru
- Kresge Eye Institute, Wayne State University, Detroit, MI, USA
| | - Jay Kumar
- Kresge Eye Institute, Wayne State University, Detroit, MI, USA
| | - Pooja Malaviya
- Kresge Eye Institute, Wayne State University, Detroit, MI, USA
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Zhao J, Massoudian SD, Stray-Gundersen S, Wojan F, Lalande S. Short bouts of hypoxia improve insulin sensitivity in adults with type 2 diabetes. J Appl Physiol (1985) 2025; 138:873-880. [PMID: 40013508 DOI: 10.1152/japplphysiol.00932.2024] [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: 11/27/2024] [Revised: 12/28/2024] [Accepted: 02/20/2025] [Indexed: 02/28/2025] Open
Abstract
Hypoxia stimulates glucose uptake independently from the action of insulin. The purpose of this study was to determine the effect of intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and room air, on glucose concentration, insulin concentration, and insulin sensitivity during an oral glucose tolerance test in adults with type 2 diabetes and adults with normal glycemic control. Nine adults with type 2 diabetes (2 women, HbA1c: 7.3 ± 1.5%, age: 52 ± 13 yr) and nine adults with normal glycemic control (4 women, HbA1c: 5.4 ± 0.1%, age: 24 ± 4 yr) performed a 2-h oral glucose tolerance test on two separate visits to the laboratory. Following ingestion of the glucose drink, participants were exposed to either an intermittent hypoxia protocol, consisting of eight 4-min hypoxic cycles at a targeted oxygen saturation of 80% interspersed with breathing room air to resaturation, or a sham protocol consisting of eight 4-min normoxic cycles interspersed with breathing room air. Intermittent hypoxia did not attenuate the increase in glucose concentration but attenuated the increase in insulin concentration in response to an oral glucose tolerance test in comparison with the sham protocol in adults with type 2 diabetes. Insulin sensitivity was greater during intermittent hypoxia in comparison with the sham protocol in adults with type 2 diabetes (0.043 ± 0.036 vs. 0.032 ± 0.046 μmol/kg/min/pmol, P = 0.01), but did not change in the control group (0.122 ± 0.015 vs. 0.128 ± 0.008 μmol/kg/min/pmol, P = 0.12). In conclusion, intermittent hypoxia improved insulin sensitivity in adults with type 2 diabetes.NEW & NOTEWORTHY The aim of this study was to determine the effect of short bouts of hypoxia, which stimulates glucose uptake, on glucose concentration, insulin concentration, and insulin sensitivity during an oral glucose tolerance test in adults with type 2 diabetes and adults with normal glycemic control. Intermittent hypoxia acutely improved insulin sensitivity in adults with type 2 diabetes.
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Affiliation(s)
- Jiahui Zhao
- Department of Kinesiology and Health EducationThe University of Texas at Austin, Austin, Texas, United States
| | - Sahar D Massoudian
- Department of Kinesiology and Health EducationThe University of Texas at Austin, Austin, Texas, United States
| | - Sten Stray-Gundersen
- Department of Kinesiology and Health EducationThe University of Texas at Austin, Austin, Texas, United States
| | - Frank Wojan
- Department of Kinesiology and Health EducationThe University of Texas at Austin, Austin, Texas, United States
| | - Sophie Lalande
- Department of Kinesiology and Health EducationThe University of Texas at Austin, Austin, Texas, United States
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Chen X, Wang W, Hu Y, Sun J, Zhang L, Chen Y, Liu J, Yu Y, Li J, Ge S. In Situ Assembled Metal-Phenolic Nanozyme Biointerfaces Revitalize Stem Cells and Optimize Diabetic Implant Osseointegration. Adv Healthc Mater 2025; 14:e2404804. [PMID: 39935069 DOI: 10.1002/adhm.202404804] [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: 11/30/2024] [Revised: 01/29/2025] [Indexed: 02/13/2025]
Abstract
The hyperglycemic microenvironment of diabetes inevitably leads to the accumulated reactive oxygen species (ROS) and impairs the function of stem cells, thereby impeding the process of osseointegration after implant placement. In this study, a self-assembled metal-phenolic nanozyme coating is presented for alleviating diabetic oxidative stress and improving osseointegration at implant interfaces. The antioxidant-like enzyme activity is induced by phenolic ligand-metal charge transfer (LMCT) during the coordination of epigallocatechin-3-gallate (EGCG) with copper phosphate nanosheets (Cu NS). The metal-phenolic nanozyme biointerfaces exhibits scavenging activity against a range of free radicals and facilitated the adhesion, migration, and osteogenic differentiation of stem cells, thereby enhancing the osseointegration of implants in diabetic rats. Additionally, the nanozyme coating strategy inhibits bacterial invasion and supports the adhesion of soft tissue cells. This study provides a prospective approach for surface modification to safeguard and enhance the osseointegration of implants in diabetic subjects.
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Affiliation(s)
- Xinxiao Chen
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Weijia Wang
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Yuhan Hu
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Jiao Sun
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Liguo Zhang
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Yi Chen
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Jin Liu
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Yang Yu
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Jianhua Li
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
| | - Shaohua Ge
- Department of Periodontology/Biomaterials, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, 250012, China
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Kawamoto R, Kikuchi A, Ninomiya D, Kumagi T, Abe M. Excessively Low Insulin Resistance May Increase the Risk of All-Cause Mortality Among Community-Dwelling Individuals Without Diabetes. Cureus 2025; 17:e81773. [PMID: 40330410 PMCID: PMC12052468 DOI: 10.7759/cureus.81773] [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] [Accepted: 01/07/2025] [Indexed: 05/08/2025] Open
Abstract
Background Epidemiological evidence has indicated that insulin resistance (IR), as measured by a homeostatic model assessment for IR (HOMA-IR), is strongly correlated with body mass index (BMI). However, there is a paucity of studies assessing the complex interaction between BMI and HOMA-IR with respect to all-cause mortality, particularly among Asian individuals without diabetes. Materials and methods The research centered on individuals diagnosed without diabetes, comprising 881 men with a mean age of 62 years (± standard deviation (SD): 14) and 1,159 women with a mean age of 64 years (± 11). The participants were drawn from the Nomura cohort study, consisting of two cohorts: one initiated in 2002 and the other in 2014. To assess the risk of all-cause mortality up to the end of the follow-up period, we applied a Cox proportional hazards model, adjusting for a range of covariates to calculate the hazard ratios (HRs). Results Participants were followed for a median duration of 7,691 days (interquartile range: 4,235-7,761 days). Over the course of the follow-up period, a total of 672 deaths were documented, comprising 338 deaths among men and 334 among women. The interaction between BMI and HOMA-IR (HR: 1.05; 95% confidence interval (CI): 1.02-1.09) was significantly associated with all-cause mortality, along with gender, age, BMI, history of cardiovascular disease, hyperuricemia, and HOMA-IR. Moreover, the HRs for all-cause mortality were examined for each BMI group by dividing the HOMA-IR by one SD. In the BMI < 22.0 kg/m² group, using the third HOMA-IR as the reference, significant HR (J curve) increases were observed in the first, second, and fourth HOMA-IR. In the BMI ≥ 22.0 kg/m² group, using the first HOMA-IR as the reference, a significant increase in HR was observed only in the fourth HOMA-IR. An interaction between BMI and HOMA-IR was identified for all-cause mortality (p = 0.005). Conclusions BMI confounds the association between IR, as measured by HOMA-IR, and the risk of all-cause mortality among Japanese individuals.
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Affiliation(s)
- Ryuichi Kawamoto
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, JPN
| | - Asuka Kikuchi
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, JPN
| | - Daisuke Ninomiya
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, JPN
| | - Teru Kumagi
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, JPN
| | - Masanori Abe
- Department of Community Medicine, Ehime University Graduate School of Medicine, Toon, JPN
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Li C, Du L, Xiao Y, Fan L, Li Q, Cao CY. Multi-active phlorotannins boost antimicrobial peptide LL-37 to promote periodontal tissue regeneration in diabetic periodontitis. Mater Today Bio 2025; 31:101535. [PMID: 39990735 PMCID: PMC11847560 DOI: 10.1016/j.mtbio.2025.101535] [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: 07/05/2024] [Revised: 12/23/2024] [Accepted: 01/30/2025] [Indexed: 02/25/2025] Open
Abstract
The bidirectional correlation between diabetes and periodontitis positions the latter as the most prevalent complication of the former. Rehabilitation of the periodontal tissues damaged by diabetic periodontitis presents a significant clinical challenge. The multifaceted nature of the pathogenesis of diabetic periodontitis necessitates a comprehensive approach in its treatment to mitigate its adverse effects. To address this, a temperature-sensitive hydrogel containing phlorotannins (PL) and antimicrobial peptide LL-37 was developed to shift the microenvironment of diabetic periodontitis from an exacerbated high-glycemic inflammatory state to a regenerative one. The addition of PL significantly enhanced the antimicrobial properties, stability, and safety of LL-37. Vitro experiments confirmed that PL/LL-37 had good biocompatibility and promoted osteogenic differentiation of bone. PL/LL-37 demonstrated antioxidant properties by scavenging DPPH free radicals and inhibiting NO production. Furthermore, PL/LL-37 effectively modulated macrophage polarization from a M1 phenotype to an M2 phenotype through NF-κB P-p65 inflammatory pathway, thereby reducing the release of pro-inflammatory cytokines and promoting the secretion of anti-inflammatory cytokines. Interestingly, it could downregulate the AGE-RAGE signaling pathway, exerting a protective effect against diabetes. In addition, PL/LL-37 could attenuate inflammation levels, inhibit osteoclast production, promote bone regeneration, inhibit apoptosis and decrease RAGE levels in a rat model of diabetic periodontitis. These combined features synergistically accelerate diabetic periodontal bone regeneration. Consequently, PL/LL-37 emerges as a promising candidate for clinical treatment of diabetic periodontitis.
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Affiliation(s)
- Cancan Li
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Luowen Du
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Yingying Xiao
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Lei Fan
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
| | - Quanli Li
- Institute of Oral Science, Department of Stomatology, Longgang Otorhinolaryngology Hospital of Shenzhen, Shenzhen, 518172, China
| | - Chris Ying Cao
- College & Hospital of Stomatology, Anhui Medical University, Key Lab. of Oral Diseases Research of Anhui Province, Hefei, 230032, China
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Fang C, He D, Shen M, Chen R, Shen X. Association between stress hyperglycemia ratio and neovascular glaucoma in patients with proliferative diabetic retinopathy. BMC Ophthalmol 2025; 25:163. [PMID: 40170000 PMCID: PMC11963471 DOI: 10.1186/s12886-025-03982-4] [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: 12/28/2024] [Accepted: 03/17/2025] [Indexed: 04/03/2025] Open
Abstract
OBJECTIVE The purpose of this study was to investigate the association between the stress hyperglycemia ratio (SHR) and the occurrence of neovascular glaucoma (NVG) in patients with proliferative diabetic retinopathy (PDR). We aimed to explore the potential role of SHR as a biomarker for NVG risk and to identify demographic and clinical modifiers of this association. METHODS We conducted a retrospective cohort study using electronic health records from our hospital over a 10-year period from 2010 to 2020. Patients diagnosed with PDR were included, with exclusions for those without diabetes-related NVG or incomplete SHR data. The SHR was calculated using admission blood glucose and HbA1c levels. Logistic regression and Cox proportional hazards modeling were used to assess the association between SHR and NVG, adjusting for potential confounders. RESULTS A total of 1,245 patients were identified, of which 378 (30.3%) had PDR with NVG. The mean SHR for the entire cohort was 2.9, with a higher mean SHR observed in the PDR with NVG group (3.2 vs. 2.7, p < 0.001). Multivariate logistic regression analysis revealed a significant association between SHR and NVG (OR 2.5, 95% CI 1.9 to 3.3, p < 0.001). Subgroup analysis showed a stronger association between SHR and NVG risk in males (HR 1.4, 95% CI 1.1 to 1.7, p = 0.01) and patients over 65 years old (HR 1.5, 95% CI 1.2 to 1.9, p = 0.001). The association was also more pronounced in patients with a diabetes duration exceeding 15 years (HR 1.4, 95% CI 1.1 to 1.8, p = 0.01). CONCLUSION Our study demonstrated a significant association between SHR and NVG with PDR patients, with certain subgroups showing a stronger association. These findings suggest that glycemic variability, as measured by SHR, may play a critical role in the development of NVG and could inform tailored clinical strategies for the prevention and management of NVG in high-risk patients.
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Affiliation(s)
- Chuankai Fang
- Department of Ophthalmology, Tongxiang First People's Hospital, No. 1918, East Xuechang Road, Tongxiang City, Jiaxing City, Zhejiang Province, China
| | - Di He
- Department of Otorhinolaryngology, Tongxiang First People's Hospital, Tongxiang, 314500, Zhejiang, China
| | - Minghai Shen
- Department of Ophthalmology, Tongxiang First People's Hospital, No. 1918, East Xuechang Road, Tongxiang City, Jiaxing City, Zhejiang Province, China
| | - Runan Chen
- Department of Ophthalmology, Tongxiang First People's Hospital, No. 1918, East Xuechang Road, Tongxiang City, Jiaxing City, Zhejiang Province, China
| | - Xiaomei Shen
- Department of Ophthalmology, Tongxiang First People's Hospital, No. 1918, East Xuechang Road, Tongxiang City, Jiaxing City, Zhejiang Province, China.
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Tu J, Zhang C, Qiu Y, Zhang H, Zheng J, Xie S, He J. Rotigotine safety in real-world settings: a pharmacovigilance study using FAERS data. BMC Pharmacol Toxicol 2025; 26:72. [PMID: 40165303 PMCID: PMC11956487 DOI: 10.1186/s40360-025-00911-5] [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] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 03/24/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND This pharmacovigilance study aims to assess adverse reactions to rotigotine based on spontaneous reports in the FDA Adverse Event Reporting System (FAERS) database, providing insights for clinical dosing. METHODS We conducted a retrospective analysis using FAERS data from Q2 2007 to Q2 2024, employing four disproportionality analysis methods: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multinomial Gamma Poisson Shrinkage (MGPS). These methods were utilized to detect and evaluate adverse events (AEs) associated with rotigotine. RESULTS The dataset retrieved from the FAERS, encompassing 17,522,075 reports, a subset of 7,570 AE reports specifically implicated rotigotine. Upon analysis, 172 preferred terms (PTs) exhibited significant disproportionality and were consistently identified by the four employed algorithms. Particularly, product adhesion issue(N = 1,336, ROR 115,28 [108.94-121.98], PRR 108.46 [135850.43], EBGM 103.57 [98.79], IC (5.03) [5.03]) emerged as the predominant AE. Serious and unexpected AEs, such as drug ineffectiveness(N = 651, ROR 1.32 [ 1.22-1.43], PRR 1.31 [50.04], EBGM 1.31 [1.23], IC 0.39 [-1.27]), fall incidents(N = 361, ROR 2.93 [2.64-3.25 ], PRR 2.9 [451.76], EBGM 2.9 [2.66], IC 1.54 [-0.13]), and Parkinson's disease(N = 345, ROR 51.57 [46.31-57.42], PRR 50.79 [16476.71], EBGM 49.7 [45.43], IC 5.64 [3.97], were also recorded.The majority of these AEs were reported within the initial 30 days of therapy (n = 298, 22.1%), whereas a significant number were noted after 360 days of treatment (n = 507, 36.2%). The median time to the onset of AEs was 213 days. CONCLUSION Our findings, which align with the established safety profile of rotigotine, reveal the presence of unexpected serious AEs and emphasize the importance of continued vigilance in post-marketing surveillance.
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Affiliation(s)
- Jiakuan Tu
- The First Department of Orthopedics, Jiangxi Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Nanchang, 33003, China
- Jiangxi University of Traditional Chinese Medicine, Nanchang, 33004, China
| | - Chaoxiang Zhang
- The First Department of Orthopedics, Jiangxi Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Nanchang, 33003, China
- Jiangxi University of Traditional Chinese Medicine, Nanchang, 33004, China
| | - Yichun Qiu
- The First Department of Orthopedics, Jiangxi Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Nanchang, 33003, China
- Jiangxi University of Traditional Chinese Medicine, Nanchang, 33004, China
| | - Hao Zhang
- The First Department of Orthopedics, Jiangxi Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Nanchang, 33003, China
| | - Jiaxin Zheng
- The First Department of Orthopedics, Jiangxi Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Nanchang, 33003, China
- Jiangxi University of Traditional Chinese Medicine, Nanchang, 33004, China
| | - Shuihua Xie
- The First Department of Orthopedics, Jiangxi Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Nanchang, 33003, China.
| | - Jianhua He
- The First Department of Orthopedics, Jiangxi Provincial Hospital of Integrated Traditional Chinese and Western Medicine, Nanchang, 33003, China.
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Cappellani F, Foti R, Malaguarnera G, D’Esposito F, Musumeci C, Rapisarda L, Tognetto D, Gagliano C, Zeppieri M. Nutrients and Natural Substances for Hypoglycemic Effects and Management in Diabetic Retinopathy. Nutrients 2025; 17:1207. [PMID: 40218965 PMCID: PMC11990073 DOI: 10.3390/nu17071207] [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] [Subscribe] [Scholar Register] [Received: 03/14/2025] [Revised: 03/26/2025] [Accepted: 03/26/2025] [Indexed: 04/14/2025] Open
Abstract
UNLABELLED Diabetic retinopathy (DR) is a significant microvascular consequence of diabetes mellitus (DM), resulting in visual impairment and blindness. Controlling hyperglycemia is essential for avoiding and alleviating diabetic retinopathy. Nutrients and natural compounds possessing hypoglycemic characteristics present promising supplementary approaches to conventional therapies. This review assesses the influence of nutrients and natural substances on glycemic regulation and their possible effects on diabetic retinopathy. GOAL To investigate and consolidate knowledge about nutrients and natural compounds exhibiting hypoglycemic properties and their processes in the prevention and management of diabetic retinopathy. APPROACHES Extensive reviews were conducted on pertinent studies from databases including PubMed, Scopus, and Web of Science. Selection criteria encompassed papers that examined natural substances, nutrients, or dietary supplements exhibiting effects on blood glucose levels and pathways associated to diabetic retinopathy. Principal findings were encapsulated according to their mechanisms, efficacy, and safety. OUTCOMES Numerous foods, including omega-3 fatty acids, vitamin D, and polyphenols (e.g., curcumin, resveratrol), have hypoglycemic properties by improving insulin sensitivity and diminishing oxidative stress. Natural substances like berberine, quercetin, and flavonoids demonstrate analogous effects, influencing pathways associated with inflammation, advanced glycation end products (AGEs), and angiogenesis, which are critical factors in the evolution of diabetic retinopathy (DR). The synergistic benefits of integrating natural medicines with conventional antidiabetic medications may enhance glycemic control and reduce retinal damage. The safety profiles of these therapies are predominantly positive; nonetheless, clinical trials are still constrained in both breadth and scale. CONCLUSIONS Nutrients and natural compounds are promising supplementary approaches for glycemic regulation and the therapy of diabetic retinopathy. Additional research, encompassing extensive clinical studies, is required to substantiate their efficacy, determine optimal dose, and verify long-term safety. The use of these natural substances into clinical practice may improve comprehensive management of diabetes and associated consequences.
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Affiliation(s)
- Francesco Cappellani
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (F.C.)
| | - Roberta Foti
- Division of Rheumatology, A.O.U. “Policlinico San Marco”, 95123 Catania, Italy
| | - Giulia Malaguarnera
- Department of Human Sciences and Quality of Life Promotion, San Raffaele Roma Open University, 00166 Rome, Italy
| | - Fabiana D’Esposito
- Imperial College Ophthalmic Research Group (ICORG) Unit, Imperial College, 153-173 Marylebone Rd., London NW1 5QH, UK
- Department of Neurosciences, Reproductive Sciences and Dentistry, University of Naples Federico II, Via Pansini 5, 80131 Napoli, Italy
| | - Carlo Musumeci
- Department of Ophthalmology, University of Catania, 95123 Catania, Italy; (F.C.)
| | - Lorenzo Rapisarda
- Department of Medicine and Surgery, University of Enna “Kore”, Piazza dell’Università, 94100 Enna, Italy
| | - Daniele Tognetto
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy
| | - Caterina Gagliano
- Department of Medicine and Surgery, University of Enna “Kore”, Piazza dell’Università, 94100 Enna, Italy
- Mediterranean Foundation “G.B. Morgagni”, 95125 Catania, Italy
| | - Marco Zeppieri
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy
- Department of Ophthalmology, University Hospital of Udine, 33100 Udine, Italy
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Thal SC, Shityakov S, Salvador E, Förster CY. Heart Rate Variability, Microvascular Dysfunction, and Inflammation: Exploring the Potential of taVNS in Managing Heart Failure in Type 2 Diabetes Mellitus. Biomolecules 2025; 15:499. [PMID: 40305215 PMCID: PMC12024555 DOI: 10.3390/biom15040499] [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: 02/10/2025] [Revised: 03/19/2025] [Accepted: 03/27/2025] [Indexed: 05/02/2025] Open
Abstract
Patients with type 2 diabetes mellitus (T2DM) predominantly experience mortality due to cardiovascular diseases (CVD), particularly in low- and middle-income nations. Among these, heart failure (HF) is the most severe cardiovascular complication in terms of prognosis and management. Despite advancements in individualized glycemic control and cardiovascular risk management, including the development of novel glucose- and lipid-lowering agents, the prevalence of HF in T2DM patients remains persistently high. This indicates that factors beyond hyperglycemia significantly contribute to the heightened risk of HF associated with T2DM. This review examines critical factors influencing CVD risk in T2DM, particularly the roles of reduced heart rate variability (HRV), a marker of autonomic dysfunction, and chronic inflammation, both of which play pivotal roles in HF pathogenesis. Recent evidence highlights the potential of vagus nerve activation to modulate these risk factors, underscoring its capacity to reduce T2DM-related cardiovascular complications. Specifically, we discuss the therapeutic promise of transcutaneous auricular vagus nerve stimulation (taVNS) as a non-invasive intervention to enhance vagal tone, decrease systemic inflammation, and improve cardiovascular outcomes in T2DM. By addressing the interplay among HRV, microvascular disease, and inflammation, this review provides a comprehensive perspective on the potential utility of taVNS in managing HF in T2DM.
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Affiliation(s)
- Serge C. Thal
- Department of Anesthesiology, Helios University Hospital, Witten/Herdecke University, 42283 Wuppertal, Germany;
| | - Sergey Shityakov
- Laboratory of Chemoinformatics, Infochemistry Scientific Center, ITMO University, 197101 Saint-Petersburg, Russia;
| | - Ellaine Salvador
- Section Experimental Neurosurgery, Department of Neurosurgery, University Hospital Würzburg, 97080 Würzburg, Germany;
| | - Carola Y. Förster
- Department of Anesthesiology, Intensive Care, Emergency and Pain Medicine, Section Cerebrovascular Sciences and Neuromodulation, University Hospital Würzburg, 97080 Würzburg, Germany
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Che PY, Zuo CJ, Tian J. Global trends in esophageal cancer and metabolic syndrome research: bibliometric analysis and visualization from 1995 to 2024. Discov Oncol 2025; 16:398. [PMID: 40138022 PMCID: PMC11947393 DOI: 10.1007/s12672-025-02181-3] [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: 01/11/2025] [Accepted: 03/18/2025] [Indexed: 03/29/2025] Open
Abstract
PURPOSE Metabolic syndrome (MetS) plays a key role in the progression of esophageal cancer (EC), yet few studies have comprehensively explored research trends on this topic. To fill this gap, this study analyzes global research developments, hotspots, and collaborations related to MetS and EC. METHODS A total of 1008 publications from 1995 to 2024 were analyzed using bibliometric tools like VOSviewer, CiteSpace, and the R package 'bibliometrix', drawing from the Web of Science Core Collection. RESULTS The analysis includes contributions from 5,183 researchers at 1500 institutions across 85 countries, with publications appearing in 411 journals. The United States, China, and the United Kingdom are leading in both publication volume and research impact. Karolinska Institutet emerged as a prominent contributor to this body of work. Key journals include the Diseases of the Esophagus and Gastroenterology. Main areas cover metabolic factors, metabolic surgery, adipokines, lifestyle risk factors, cirrhosis & portal hypertension. Emerging trends focus on "metabolic syndrome and EC risk", "inflammation and adipokines", "bariatric surgery and EC prevention", "post-surgical outcomes", "early detection strategies". CONCLUSION As the first comprehensive bibliometric study on MetS and EC, this research highlights metabolism-related factors driving EC progression. Future research should focus on clarifying MetS-EC mechanisms and developing prevention and treatment strategies.
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Affiliation(s)
- Peng-Yu Che
- Department of Cardiothoracic Surgery, The People's Hospital of Chongqing Hechuan, Chongqing, 401520, China.
| | - Chun-Jian Zuo
- Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China
| | - Jie Tian
- Department of Thoracic Surgery, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Wuhou District, Chengdu, 610041, Sichuan, China.
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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Hubayni RA, Qedair J, Bukhari ZM, Alsudais AS, Badghaish OS, Bawazir RO, AlQahtani AS, Almarzouki H. Intravitreal Bevacizumab Alone Vs Combined With Topical Timolol-Dorzolamide or Dorzolamide for Diabetic Macular Edema: A Systematic Review and Meta-Analysis. Clin Ophthalmol 2025; 19:1007-1019. [PMID: 40151418 PMCID: PMC11947024 DOI: 10.2147/opth.s509136] [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: 12/04/2024] [Accepted: 02/10/2025] [Indexed: 03/29/2025] Open
Abstract
Purpose Diabetic macular edema (DME) is a major cause of vision loss in diabetes. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of intravitreal bevacizumab (IVB) combined with topical timolol-dorzolamide versus dorzolamide alone in DME patients. Patients and Methods A literature search was conducted across multiple databases until March 2024. Randomized controlled trials (RCTs) comparing IVB (1.25 mg, monthly) with topical dorzolamide-timolol (twice daily) or dorzolamide alone (twice daily) were included. Primary outcomes assessed were best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) at various intervals. Results Four RCTs involving 98 patients (150 eyes) were analyzed, with a mean age of 57.9 years and a female predominance (55.1%). The subgroup meta-analysis indicated a weighted mean difference (WMD) in BCVA of -0.125 [95% CI: -0.21 to -0.041]. The IVB+D group showed no significant difference in WMD compared to the IVB and IVB+TD groups. IOP measurements revealed a WMD of -1.244 mmHg [95% CI: -2.548 mmHg to 0.06 mmHg], with a significant increase in the IVB group compared to the IVB+D and IVB+TD groups. CMT analysis showed a WMD of -78.875 μm [95% CI: -118.606 μm to -39.145 μm], with no significant differences among groups. Conclusion Concurrent IVB with topical timolol-dorzolamide or dorzolamide alone demonstrated similar efficacy in improving BCVA and CMT in DME patients. However, the IVB+TD combination resulted in a more significant reduction in IOP compared to IVB alone.
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Affiliation(s)
- Rahaf A Hubayni
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Jumanah Qedair
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Ziad M Bukhari
- Ophthalmology Department, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Ali S Alsudais
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Orjwan Salah Badghaish
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Razan Osama Bawazir
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Abdullah S AlQahtani
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- Ophthalmology Department, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Hashem Almarzouki
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
- King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
- Ophthalmology Department, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
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49
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Gaur A, Maity R, Dhali A, Biswas J. Impact of poorly controlled type II diabetes mellitus on chemoresistance in colorectal cancer. World J Gastroenterol 2025; 31:104065. [PMID: 40124270 PMCID: PMC11924008 DOI: 10.3748/wjg.v31.i11.104065] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 01/16/2025] [Accepted: 02/17/2025] [Indexed: 03/13/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) significantly elevates the risk of colorectal cancer (CRC) and complicates its treatment by promoting chemoresistance. Poor glycemic control has been linked to exacerbated CRC progression and diminished chemotherapy efficacy, impacting patient outcomes through various mechanisms such as oxidative stress, activation of metabolic pathways, and altered protein modifications that hinder apoptosis and enhance tumor survival. Clinical evidence shows that T2DM patients experience higher rates of chemoresistance and reduced disease-free survival and overall survival compared to non-diabetic patients. Specifically, those with poor glycemic control exhibit increased chemoresistance and poorer survival metrics. Antidiabetic treatments, including metformin, acarbose, and gliclazide, show promise in improving chemotherapy response and glycemic management, potentially enhancing patient outcomes. Addressing this challenge requires a comprehensive, multidisciplinary approach involving oncologists, endocrinologists, and surgeons to optimize patient care. Integrated strategies that prioritize glycemic control are essential for reducing chemoresistance and improving survival in CRC patients with T2DM.
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Affiliation(s)
- Aditya Gaur
- Foundation Training Program, Somerset NHS Foundation Trust, Yeovil BA20 2BX, Somerset, United Kingdom
| | - Rick Maity
- General Medicine, Institute of Post Graduate Medical Education and Research, Kolkata 700020, India
| | - Arkadeep Dhali
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Sheffield S10 2JF, United Kingdom
- School of Medicine and Population Health, University of Sheffield, Sheffield S10 2HQ, United Kingdom
- Deanery of Clinical Sciences, University of Edinburgh, Edinburgh EH16 4SB, United Kingdom
- School of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom
| | - Jyotirmoy Biswas
- General Medicine, College of Medicine and Sagore Dutta Hospital, Kolkata 700058, India
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50
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Li X, Ye X, Xu L, Chen H. Association between endocrine disrupting chemicals exposure and diabetic kidney disease in adults: A national cross-sectional NHANES study. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 293:118044. [PMID: 40101590 DOI: 10.1016/j.ecoenv.2025.118044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 03/09/2025] [Accepted: 03/10/2025] [Indexed: 03/20/2025]
Abstract
BACKGROUND Diabetic kidney disease (DKD) is a global public health concern. Environmental factors are increasingly recognized as significant risk factors that cannot be overlooked, and certain environmental pollutants exhibit endocrine-disrupting properties. Previous research on the association between endocrine-disrupting chemicals (EDCs) and DKD has been notably limited. METHODS This study investigated the association between exposure to 25 EDC metabolites and DKD in 1421 U.S. adults from the 2015-2018 National Health and Nutrition Examination Survey (NHANES). We used logistic regression, restricted cubic spline regression, weighted quantile sum (WQS) regression, and bayesian kernel machine regression (BKMR) models to assess the association between individual and co-exposure to multiple EDCs and DKD. Subgroup analyses and interaction tests were performed to investigate whether this association was stable across the population. Additionally, mediation analysis was used to explore the mediating role of serum globulins in the association between Pb exposure and DKD. RESULTS In logistic regression models, N-Acetyl-S-(2-hydroxypropyl)-L-cysteine (2HPMA), N-Acetyl-S-(4-hydroxy-2-butenyl)-L-cysteine (MHBMA3), Phenylglyoxylic acid (PGA), and lead (Pb) were significantly positively associated with diabetes. Restricted cubic spline (RCS) analyses also revealed significant non-linear positive associations between 2HPMA, MHBMA3, and DKD. Perfluorohexane sulfonic acid (PFHxS), n-perfluorooctanoic acid (n-PFOA), n-perfluorooctane sulfonic acid (n-PFOS), and Perfluoromethylheptane sulfonic acid isomers (Sm-PFOS) were significantly negatively associated with DKD. Furthermore, co-exposure to metals and metalloid was positively associated with DKD in both the WQS regression and the BKMR models, with Pb as the primary contributing factor. Mediation analysis showed that globulin mediated the association between Pb exposure and DKD, with a mediation proportion of 7.25 % (P = 0.046). Co-exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) was negatively correlated with DKD, and subgroup analyses revealed that this correlation was more pronounced in the obese group (BMI ≥30 kg/m²). The BKMR analysis revealed potential interactions among various chemical compounds, such as N-Acetyl-S-(2-hydroxypropyl)-L-cysteine (2HPMA), 2-Methylhippuric acid (2MHA), N-Acetyl-S-(4-hydroxy-2-methyl-2-butenyl)-L-cysteine (IPM3), mercury (Hg), and cadmium (Cd), in a model simulating co-exposure to metals and metalloid, as well as to volatile organic compound metabolites (mVOCs). CONCLUSION The findings suggest an association between individual or co-exposure to EDC metabolites and DKD, providing valid evidence for DKD prevention from the perspective of EDCs exposure. However, more prospective studies are needed to elucidate the potential mechanisms underlying these findings.
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Affiliation(s)
- Xinru Li
- Hangzhou Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China
| | - Xiaoang Ye
- The Second Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China
| | - Luhuan Xu
- Department of Nephrology, Lishui People's Hospital, Lishui, Zhejiang, PR China
| | - Hongyu Chen
- Department of Nephrology, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR China.
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