1
|
Luo J, Guo X, Zheng Y, Yang Z, Pei SY, Rao RQ, Ai Z, Zou F. Integration of multi-omics data and machine learning to identify antioxidant biomarkers in type 1 diabetes. Free Radic Biol Med 2025; 236:41-56. [PMID: 40339726 DOI: 10.1016/j.freeradbiomed.2025.05.385] [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: 12/29/2024] [Revised: 04/08/2025] [Accepted: 05/05/2025] [Indexed: 05/10/2025]
Abstract
The identification of biomarkers for early diagnosis and monitoring the progression of Type 1 Diabetes (T1DM) is essential for improving disease management. This study integrates multi-omics data with machine learning to identify antioxidant stress proteins in serum as potential biomarkers. Serum samples from mice treated with varying doses of streptozotocin (STZ) and human transcriptomic data from the gene expression omnibus (GEO) database were analyzed using weighted gene co-expression network analysis (WGCNA). Proteomic analysis of 25 T1DM and 25 healthy controls using LC-MS/MS revealed 33 differentially expressed proteins enriched in oxidative stress pathways. Machine learning algorithms, including Random Forest and SVM-RFE, identified five key proteins: GPX3, GSTP1, PRDX6, SOD1, and MSRB2. GPX3 demonstrated the highest diagnostic value, with a significant correlation to clinical parameters such as HbA1c and fasting plasma glucose. Functional validation showed GPX3 overexpression protected pancreatic β-cells from H2O2-induced oxidative damage and alleviated symptoms and pathological changes in T1DM mice. These results suggest that GPX3 is a promising biomarker for diagnosing and tracking T1DM progression, offering new insights into oxidative stress management in T1DM.
Collapse
Affiliation(s)
- Junming Luo
- Department of Respiratory Medicine, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Xin Guo
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Yijing Zheng
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Zhuoyuan Yang
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Si-Ying Pei
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Run-Qing Rao
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - ZhiYing Ai
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China
| | - Fang Zou
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, PR China.
| |
Collapse
|
2
|
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.
Collapse
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
| | | |
Collapse
|
3
|
Khazaei M, Meskaraf-asadabadi M, Ghanbari E, Khazaei AH. Antidiabetic effects of Peganum harmala seed extract on streptozotocin-induced diabetes in rats. AVICENNA JOURNAL OF PHYTOMEDICINE 2025; 15:1193-1203. [PMID: 40365181 PMCID: PMC12068503 DOI: 10.22038/ajp.2024.25241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 08/11/2024] [Indexed: 05/15/2025]
Abstract
Objective Diabetes, a chronic metabolic disease, has many complex complications and an increasing prevalence in various societies. Despite conventional drug treatments and limited surgical and tissue transplant methods, a definitive diabetes treatment remains to be found. Restoring damaged beta cells to insulin production or prompting other pancreatic cells to secrete insulin is an essential goal of diabetes research. The present study investigated the antidiabetic and regenerative effects of Peganum harmala seed extract (PHSE) on streptozotocin (STZ)-induced diabetes in rats. Materials and Methods In this experimental in vivo study, male Wistar rats (200±10 g) were placed in 5 groups: control, untreated diabetic and diabetic groups treated with 100, 200, and 400 mg/kg doses of PHSE. Fasting blood sugar (FBS), C-peptide, insulin, and antioxidant parameters (total antioxidant capacity (TAC) and nitric oxide (NO)) of serum were measured. Pancreatic tissue was used for histologic staining and assessment of the expression of genes related to beta cell regeneration. Results PHSE significantly improved FBS, weight loss, insulin, c-peptide, TAC, NO, and expression of pancreatic genes (insulin, PDX1 and neurogenin-3) (p<0.05). It also increased the number of pancreatic beta cells. Conclusion PHSE has considerable regenerative and antidiabetic effects on changes caused by diabetes in rats' serum and pancreas.
Collapse
Affiliation(s)
- Mozafar Khazaei
- Fertility and Infertility Research Center, Health Technology Research Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammadali Meskaraf-asadabadi
- Fertility and Infertility Research Center, Health Technology Research Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Elham Ghanbari
- Fertility and Infertility Research Center, Health Technology Research Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Department of Tissue Engineering, School of Medicine, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Amir Hossein Khazaei
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
4
|
Velumani K, Rajan PS, Shaik MR, Hussain SA, Shaik B, Guru A, Issac PK. Protective Effect of Artemisinin Against Luperox Induced Oxidative Stress and Insulin Resistance via Pi3k/Akt Pathway in Zebrafish Larvae. Cell Biochem Biophys 2025:10.1007/s12013-025-01747-w. [PMID: 40220071 DOI: 10.1007/s12013-025-01747-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2025] [Indexed: 04/14/2025]
Abstract
Oxidative stress plays a critical role in the development of insulin resistance (IR), a key factor in metabolic disorders such as diabetes. Plant active ingredients play a crucial role in protecting organisms from environmental stressors and have shown promising therapeutic potential against various metabolic disorders. Artemisinin (ART), a sesquiterpenoid with a lactone ring obtained from the herb Artemisia annua, exhibits promising therapeutic properties. This study investigates the potential of ART on Luperox (LUP)-induced oxidative stress and the resulting IR in zebrafish larvae, specifically investigating the involvement of the PI3K/AKT signaling pathway. Zebrafish larvae were chosen due to their high sensitivity to oxidative stress, well-characterized glucose metabolism, and genetic similarity to human metabolic pathways. They were exposed to LUP to induce oxidative stress, followed by treatment with ART. The effects were evaluated through biochemical assays, fluorescence staining and gene expression analysis. ART effectively restored key antioxidant enzymes (SOD, CAT, GSH) and mitigated oxidative stress evidenced by reduction in intercellular ROS and lipid peroxidation, as confirmed through DCFDA and DPPP staining assays. Additionally, ART improved glucose uptake and lowered blood glucose levels. Gene expression analysis further indicated increased levels of PI3K/Akt signalling components and antioxidant-related genes (NRF2, HO-1, GPx, and GSR). Our results indicate that artemisinin significantly alleviates oxidative stress by reducing ROS levels and enhancing antioxidant enzyme activity. Furthermore, artemisinin mitigates IR by restoring glucose metabolism and upregulating PI3K/AKT pathway components. These findings highlight the translational potential of plant active ingredients, particularly artemisinin, for the development of therapies targeting IR and oxidative stress-related metabolic disorders.
Collapse
Affiliation(s)
- Kadhirmathiyan Velumani
- Department of Medical Biotechnology, Institute of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| | - P Sundar Rajan
- Department of Chemical Engineering, Saveetha Engineering College, Chennai, Tamil Nadu, India
| | - Mohammed Rafi Shaik
- Department of Chemistry, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Shaik Althaf Hussain
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Baji Shaik
- School of Chemical Engineering, Yeungnam University, Gyeongsan, Republic of Korea
| | - Ajay Guru
- Department of Cariology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
| | - Praveen Kumar Issac
- Department of Medical Biotechnology, Institute of Biotechnology, Saveetha School of Engineering, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India.
| |
Collapse
|
5
|
Singh A, Khushboo, Pandey M, Mattoo S, Pore SK, Bhattacharyya J. A glucose-responsive alginate-based hydrogel laden with modified GLP-1 and telmisartan ameliorates type 2 diabetes and reduces liver and kidney toxicities. J Mater Chem B 2025; 13:4419-4432. [PMID: 40095672 DOI: 10.1039/d4tb02261k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
The pathophysiology associated with type 2 diabetes mellitus (T2DM) includes insulin resistance, increased oxidative stress, a pro-inflammatory macrophage population, and dysfunction of pancreatic β cells in the islets of Langerhans, along with hepato- and nephro-toxicity. In this study, an injectable glucose-responsive hydrogel (Diabogel) was developed using alginate and 3-aminophenyl boronic acid to deliver modified glucagon-like peptide-1, insulinoma cell-derived extracellular vesicles, and telmisartan. Diabogel demonstrated cytocompatibility, decreased reactive oxygen species, enhanced insulin synthesis, and improved glucose uptake in vitro. In a high-fat diet/streptozotocin-induced murine model of T2DM, Diabogel lowered blood glucose levels, maintained body weight, and increased insulin expression. Furthermore, it promoted an anti-inflammatory microenvironment in the pancreas by regulating macrophage phenotype and the expression of NF-κB, supported cellular proliferation, and restored the pancreatic islets. In addition, Diabogel treatment significantly lowered the serum levels of pro-inflammatory cytokines and enhanced anti-inflammatory cytokines. Interestingly, Diabogel treatment also lowered diabetes-associated hepato- and nephro-toxicity. Taken together, Diabogel may serve as a potential approach for the treatment of T2DM, regulating blood glucose levels, restoring pancreatic β cell function, and reducing hepatic and renal toxicities.
Collapse
Affiliation(s)
- Anjali Singh
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi 110016, India.
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110016, India
| | - Khushboo
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi 110016, India.
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110016, India
| | - Monu Pandey
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi 110016, India.
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110016, India
| | - Shria Mattoo
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
| | - Subrata Kumar Pore
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
| | - Jayanta Bhattacharyya
- Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi 110016, India.
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi, New Delhi 110016, India
| |
Collapse
|
6
|
Ergul Erkec O, Huyut Z, Acikgoz E, Huyut MT. Effects of exogenous ghrelin treatment on oxidative stress, inflammation and histological parameters in a fat-fed streptozotocin rat model. Arch Physiol Biochem 2025; 131:274-284. [PMID: 39324977 DOI: 10.1080/13813455.2024.2407551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/17/2024] [Accepted: 09/16/2024] [Indexed: 09/27/2024]
Abstract
In this study, the anti-inflammatory, antioxidative, and protective effects of ghrelin were investigated in a fat-fed streptozotocin (STZ) rat model and compared with metformin, diabetes and the healthy control groups. Histopathological evaluations were performed on H&E-stained pancreas and brain sections. Biochemical parameters were investigated by enzyme-linked immunosorbent assay. Blood glucose levels were significantly decreased with ghrelin or metformin treatments than the diabetes group. STZ administration increased brain, renal and pancreatic IL-1β, TNF-α and MDA while decreasing GPX, CAT, SOD, and NGF levels. Ghrelin increased renal GPX, CAT, NGF pancreatic GPX, SOD, CAT, NGF and brain SOD, NGF while it decreased renal, pancreatic and brain IL-1β, TNF-α and MDA levels. Ghrelin reduced neuronal loss and degeneration in the cerebral cortex and hippocampus and greatly ameliorated diabetes-related damage in pancreas. In conclusion, the data suggested that ghrelin is an effective candidate as a protectant for reducing the adverse effects of diabetes.
Collapse
Affiliation(s)
- Ozlem Ergul Erkec
- Department of Physiology, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey
| | - Zubeyir Huyut
- Department of Biochemistry, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey
| | - Eda Acikgoz
- Department of Histology and Embryology, Faculty of Medicine, Van Yuzuncu Yil University, Van, Turkey
| | - Mehmet Tahir Huyut
- Department of Biostatistics, Faculty of Medicine, Erzincan Binali Yıldırım University, Erzincan, Turkey
| |
Collapse
|
7
|
Nigi L, Pedace E, Dotta F, Sebastiani G. Neutrophils in Type 1 Diabetes: Untangling the Intricate Web of Pathways and Hypothesis. Biomolecules 2025; 15:505. [PMID: 40305198 PMCID: PMC12025241 DOI: 10.3390/biom15040505] [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: 03/03/2025] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 05/02/2025] Open
Abstract
Neutrophils are increasingly recognized as key contributors to the pathogenesis of Type 1 Diabetes (T1D), yet their precise mechanistic role in disease onset and progression remains incompletely understood. While these innate immune cells reside in pancreatic tissue and support tissue homeostasis under physiological conditions, they can also drive tissue damage by triggering innate immune responses and modulating inflammation. Within the inflammatory milieu, neutrophils establish complex, bidirectional interactions with various immune cells, including macrophages, dendritic cells, natural killer cells, and lymphocytes. Once activated, they may enhance the innate immune response through direct or indirect crosstalk with immune cells, antigen presentation, and β-cell destruction or dysfunction. These mechanisms underscore the multifaceted and dynamic role of neutrophils in T1D, shaped by their intricate immunological interactions. Further research into the diverse functional capabilities of neutrophils is crucial for uncovering novel aspects of their involvement in T1D, potentially revealing new therapeutic targets to modulate disease progression.
Collapse
Affiliation(s)
- Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (L.N.); (E.P.); (G.S.)
- Fondazione Umberto Di Mario ONLUS, Toscana Life Sciences, 53100 Siena, Italy
| | - Erika Pedace
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (L.N.); (E.P.); (G.S.)
- Fondazione Umberto Di Mario ONLUS, Toscana Life Sciences, 53100 Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (L.N.); (E.P.); (G.S.)
- Fondazione Umberto Di Mario ONLUS, Toscana Life Sciences, 53100 Siena, Italy
- Tuscany Centre for Precision Medicine, 53100 Siena, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy; (L.N.); (E.P.); (G.S.)
- Fondazione Umberto Di Mario ONLUS, Toscana Life Sciences, 53100 Siena, Italy
| |
Collapse
|
8
|
Xiao S, Rao L, Yan C, Nie L, Wang L, Zhao Y, Zhang S, Zhan W, Qin D, Zhuang M. Aptamer Functionalized Liposomes Co-Loaded with Exenatide-4 and Coenzyme Q10 Ameliorate Type 2 Diabetes Mellitus by Improving Pancreatic β Cell Function. Int J Nanomedicine 2025; 20:3363-3378. [PMID: 40125440 PMCID: PMC11928442 DOI: 10.2147/ijn.s510240] [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: 12/04/2024] [Accepted: 02/11/2025] [Indexed: 03/25/2025] Open
Abstract
Introduction Oxidative stress has been shown to disrupt β-cell function and promote the development of type 2 diabetes mellitus (T2DM). Exenatide-4 (Ext-4) is a widely used anti-glycemic drug but cannot restore pancreatic β-cells' structure and function. Coenzyme Q10 (CoQ10) has great antioxidant activities but shows suboptimal therapeutic effects because of its poor solubility and poor bioavailability. To further enhance the therapeutic efficacy of the drugs, a pancreas-targeting liposomal co-delivery system encapsulating Ext-4 and CoQ10 ((E+Q)-Lip-Apt) was designed, using the aptamers as the targeting ligands. Methods (E+Q)-Lip-Apt was prepared by thin film dispersion method and its optimal formulation was obtained through single-factor experiments and orthogonal experiments. The pancreatic β-cell protecting effect of (E+Q)-Lip-Apt was investigated both in vitro and in vivo. Results (E+Q)-Lip-Apt exhibited uniform size, good dispersion, and high encapsulation efficiency (EE) for both Ext-4 and CoQ10. The in vitro results showed that (E+Q)-Lip-Apt manifested superior capacity in scavenging ROS, enhancing mitochondrial membrane potential, and reducing malondialdehyde (MDA) content compared to Ext-4 in MIN6 cells. In vivo investigations demonstrated that (E+Q)-Lip-Apt significantly improved glucose tolerance, insulin sensitivity, hepatic lipid metabolism, oxidative stress, and enhanced antioxidant enzyme activity in diabetic mice. Moreover, Hematoxylin-eosin staining (H&E) and Immunohistochemistry (IHC) results indicated that (E+Q)-Lip-Apt could improve liver and pancreatic lesions, restoring the structure and function of β-cells in diabetic mice. Conclusion (E+Q)-Lip-Apt could improve oxidative stress, thereby restoring pancreatic β-cell function, and alleviating diabetes.
Collapse
Affiliation(s)
- Shangying Xiao
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| | - Lei Rao
- Medical College, Shaoguan University, Shaoguan, People’s Republic of China
| | - Canying Yan
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| | - Ling Nie
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| | - Leiqi Wang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| | - Yingyin Zhao
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| | - Shihao Zhang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| | - WeiMao Zhan
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| | - Dongyun Qin
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| | - Manjiao Zhuang
- Guangdong Provincial Key Laboratory of Research and Development of Natural Drugs, and School of Pharmacy, Guangdong Medical University, Dongguan, People’s Republic of China
| |
Collapse
|
9
|
Anghel L, Ciubară A, Patraș D, Ciubară AB. Chronic Obstructive Pulmonary Disease and Type 2 Diabetes Mellitus: Complex Interactions and Clinical Implications. J Clin Med 2025; 14:1809. [PMID: 40142617 PMCID: PMC11942939 DOI: 10.3390/jcm14061809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 03/01/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Chronic obstructive pulmonary disease (COPD) and type 2 diabetes mellitus (T2DM) are highly prevalent chronic conditions, frequently coexisting due to their shared pathophysiological mechanisms and risk factors. Epidemiological studies estimate that up to 30% of COPD patients have comorbid T2DM, contributing to worsened disease progression, more hospitalizations, and higher mortality rates. Systemic inflammation in COPD contributes to insulin resistance by increasing pro-inflammatory cytokines (TNF-α, IL-6, and CRP), which impair glucose metabolism and beta-cell function. Conversely, hyperglycemia in T2DM exacerbates oxidative stress, leading to endothelial dysfunction, reduced lung function, and impaired pulmonary repair mechanisms. A comprehensive narrative review was conducted to evaluate the interplay between COPD and T2DM, examining shared pathophysiological mechanisms, clinical consequences, and management strategies. The co-occurrence of COPD and T2DM accelerates disease development, elevates hospitalization rates, and deteriorates overall prognosis. Pharmacological interactions complicate illness treatment, requiring a multidisciplinary therapy strategy. Recent data underscore the need to integrate palliative care, facilitate shared decision-making, and provide psychological support to enhance patient outcomes. Efficient therapy of COPD-T2DM comorbidity necessitates a customized, interdisciplinary strategy that targets both respiratory and metabolic health. Preliminary prognostic dialogues, palliative care, and holistic lifestyle modifications can improve patient quality of life and clinical results.
Collapse
Affiliation(s)
- Lucreția Anghel
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania; (L.A.); (D.P.)
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania;
| | - Anamaria Ciubară
- Faculty of Medicine and Pharmacy, Dunarea de Jos University of Galati, 35 AI Cuza St., 800010 Galati, Romania;
| | - Diana Patraș
- Saint Apostle Andrew Emergency County Clinical Hospital, 177 Brailei St., 800578 Galati, Romania; (L.A.); (D.P.)
- Doctoral School Biomedicine Science, University Galati, 800008 Galati, Romania
| | | |
Collapse
|
10
|
Chaudhary RK, Ali O, Kumar A, Kumar A, Pervez A. Double Diabetes: A Converging Metabolic and Autoimmune Disorder Redefining the Classification and Management of Diabetes. Cureus 2025; 17:e80495. [PMID: 40225541 PMCID: PMC11992394 DOI: 10.7759/cureus.80495] [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: 03/12/2025] [Indexed: 04/15/2025] Open
Abstract
This review explores the pathophysiology, clinical implications, and management of double diabetes. The increasing prevalence of obesity, sedentary lifestyles, and genetic predisposition has blurred the difference between type 1 and type 2 diabetes, leading to diagnostic and therapeutic challenges. Double diabetes presents with overlapping symptoms from both diabetes types, making accurate diagnosis crucial. Biomarkers, such as C-peptide levels, autoantibody testing, and insulin resistance markers, help differentiate double diabetes from classic diabetes subtypes. Early intervention is necessary because of the condition's elevated risk of microvascular and macrovascular consequences, such as retinopathy, nephropathy, and cardiovascular disease. Effective management integrates pharmacological and lifestyle approaches. Metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin therapy adjustments all boost glycemic control and metabolic results. Additionally, structured exercise, dietary modifications, and weight management are essential for reducing insulin resistance and preserving beta-cell activity. The potential of precision medicine, artificial intelligence (AI)-driven healthcare, and continuous glucose monitoring (CGM) offers promising advancements for personalized treatment strategies. Future research should focus on targeted immunotherapies, genetic profiling, and refined clinical guidelines to improve early detection and individualized treatment, with long-term outcomes. The review emphasizes the need for a multidisciplinary approach in managing double diabetes, ensuring early diagnosis, optimized treatment, and improved metabolic health to mitigate long-term complications.
Collapse
Affiliation(s)
- Raj K Chaudhary
- Department of Medicine, Jawaharlal Nehru Medical College, Bhagalpur, IND
| | - Obaid Ali
- Department of Medicine, Jawaharlal Nehru Medical College, Bhagalpur, IND
| | - Amrendra Kumar
- Department of Medicine, Jawaharlal Nehru Medical College, Bhagalpur, IND
| | - Abilesh Kumar
- Department of Medicine, Jawaharlal Nehru Medical College, Bhagalpur, IND
| | - Anjum Pervez
- Department of Medicine, Jawaharlal Nehru Medical College, Bhagalpur, IND
| |
Collapse
|
11
|
Mladenov M, Sazdova I, Hadzi-Petrushev N, Konakchieva R, Gagov H. The Role of Reductive Stress in the Pathogenesis of Endocrine-Related Metabolic Diseases and Cancer. Int J Mol Sci 2025; 26:1910. [PMID: 40076537 PMCID: PMC11899626 DOI: 10.3390/ijms26051910] [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: 01/14/2025] [Revised: 02/14/2025] [Accepted: 02/21/2025] [Indexed: 03/14/2025] Open
Abstract
Reductive stress (RS), characterized by excessive accumulation of reducing equivalents such as NADH and NADPH, is emerging as a key factor in metabolic disorders and cancer. While oxidative stress (OS) has been widely studied, RS and its complex interplay with endocrine regulation remain less understood. This review explores molecular circuits of bidirectional crosstalk between metabolic hormones and RS, focusing on their role in diabetes, obesity, cardiovascular diseases, and cancer. RS disrupts insulin secretion and signaling, exacerbates metabolic inflammation, and contributes to adipose tissue dysfunction, ultimately promoting insulin resistance. In cardiovascular diseases, RS alters vascular smooth muscle cell function and myocardial metabolism, influencing ischemia-reperfusion injury outcomes. In cancer, RS plays a dual role: it enhances tumor survival by buffering OS and promoting metabolic reprogramming, yet excessive RS can trigger proteotoxicity and mitochondrial dysfunction, leading to apoptosis. Recent studies have identified RS-targeting strategies, including redox-modulating therapies, nanomedicine, and drug repurposing, offering potential for novel treatments. However, challenges remain, particularly in distinguishing physiological RS from pathological conditions and in overcoming therapy-induced resistance. Future research should focus on developing selective RS biomarkers, optimizing therapeutic interventions, and exploring the role of RS in immune and endocrine regulation.
Collapse
Affiliation(s)
- Mitko Mladenov
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (M.M.); (N.H.-P.)
- Department of Fundamental and Applied Physiology, Russian States Medical University, 117997 Moscow, Russia
| | - Iliyana Sazdova
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1164 Sofia, Bulgaria;
| | - Nikola Hadzi-Petrushev
- Institute of Biology, Faculty of Natural Sciences and Mathematics, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (M.M.); (N.H.-P.)
| | - Rossitza Konakchieva
- Department of Cell and Developmental Biology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1164 Sofia, Bulgaria;
| | - Hristo Gagov
- Department of Animal and Human Physiology, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 1164 Sofia, Bulgaria;
| |
Collapse
|
12
|
Damasceno ROS, Pinheiro JLS, da Silva LD, Rodrigues LHM, Emídio JJ, Lima TC, de Sousa DP. Phytochemistry and Anti-Inflammatory and Antioxidant Activities of Cinnamomum osmophloeum and Its Bioactive Constituents: A Review. PLANTS (BASEL, SWITZERLAND) 2025; 14:562. [PMID: 40006821 PMCID: PMC11859615 DOI: 10.3390/plants14040562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 01/31/2025] [Accepted: 02/08/2025] [Indexed: 02/27/2025]
Abstract
Cinnamomum osmophloeum, commonly known as indigenous cinnamon, is a tree species native to Taiwan's hardwood forests. It has been extensively investigated for its chemical composition and bioactivities. Several reports have shown that C. osmophloeum leaves are rich in aromatic oils, which are grouped into various chemotypes based on their major constituents. Components of the volatile oils included phenylpropanoids, monoterpenoids, sesquiterpenoids, phenols, coumarins, and other miscellaneous compounds. In addition, other secondary metabolites previously identified in this species included flavonol glycosides, phenolic acids, lignans, proanthocyanidins, and cyclopropanoids. C. osmophloeum is widely recognized for its medicinal and industrial applications, particularly its essential oils. In general, essential oils exhibit remarkable anti-inflammatory and antioxidant actions, enabling them to modulate key inflammatory mediators and neutralize free radicals. This review explored the phytochemical composition of the essential oils and extracts from C. osmophloeum as well as therapeutic potential of this species, focusing on the action mechanisms and clinical potential. We hope that this review will contribute to a better understanding of the biological effects of this plant and its potential applications in the management of conditions associated with inflammation and oxidative stress.
Collapse
Affiliation(s)
- Renan Oliveira Silva Damasceno
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (J.L.S.P.); (L.D.d.S.); (L.H.M.R.)
| | - João Lucas Silva Pinheiro
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (J.L.S.P.); (L.D.d.S.); (L.H.M.R.)
| | - Lorena Duarte da Silva
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (J.L.S.P.); (L.D.d.S.); (L.H.M.R.)
| | - Lucas Henrique Marques Rodrigues
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife 50670-901, Pernambuco, Brazil; (J.L.S.P.); (L.D.d.S.); (L.H.M.R.)
| | - Jeremias Justo Emídio
- Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa 58051-970, Paraíba, Brazil;
| | - Tamires Cardoso Lima
- Department of Pharmacy, Federal University of Sergipe, São Cristóvão 49100-000, Sergipe, Brazil;
| | - Damião Pergentino de Sousa
- Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa 58051-970, Paraíba, Brazil;
| |
Collapse
|
13
|
Dai L, Wang Q. Targeting ferroptosis: opportunities and challenges of mesenchymal stem cell therapy for type 1 diabetes mellitus. Stem Cell Res Ther 2025; 16:47. [PMID: 39901210 PMCID: PMC11792594 DOI: 10.1186/s13287-025-04188-7] [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: 10/09/2024] [Accepted: 01/24/2025] [Indexed: 02/05/2025] Open
Abstract
Type 1 diabetes mellitus (T1DM) is characterized by progressive β-cell death, leading to β-cell loss and insufficient insulin secretion. Mesenchymal stem cells (MSCs) transplantation is currently one of the most promising methods for β-cell replacement therapy. However, recent studies have shown that ferroptosis is not only one of the key mechanisms of β-cell death, but also one of the reasons for extensive cell death within a short period of time after MSCs transplantation. Ferroptosis is a new type of regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides. Due to the weak antioxidant capacity of β-cells, they are susceptible to cytotoxic stimuli such as oxidative stress (OS), and are therefore susceptible to ferroptosis. Transplanted MSCs are also extremely susceptible to perturbations in their microenvironment, especially OS, which can weaken their antioxidant capacity and induce MSCs death through ferroptosis. In the pathophysiological process of T1DM, a large amount of reactive oxygen species (ROS) are produced, causing OS. Therefore, targeting ferroptosis may be a key way to protect β-cells and improve the therapeutic effect of MSCs transplantation. This review reviews the research related to ferroptosis of β-cells and MSCs, and summarizes the currently developed strategies that help inhibit cell ferroptosis. This study aims to help understand the ferroptosis mechanism of β-cell death and MSCs death after transplantation, emphasize the importance of targeting ferroptosis for protecting β-cells and improving the survival and function of transplanted MSCs, and provide a new research direction for stem cells transplantation therapy of T1DM in the future.
Collapse
Affiliation(s)
- Le Dai
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, 126 Xiantai Avenue, Changchun City, Jilin Province, China
| | - Qing Wang
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, 126 Xiantai Avenue, Changchun City, Jilin Province, China.
| |
Collapse
|
14
|
Singh A, Shadangi S, Gupta PK, Rana S. Type 2 Diabetes Mellitus: A Comprehensive Review of Pathophysiology, Comorbidities, and Emerging Therapies. Compr Physiol 2025; 15:e70003. [PMID: 39980164 DOI: 10.1002/cph4.70003] [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: 12/19/2024] [Revised: 02/03/2025] [Accepted: 02/07/2025] [Indexed: 02/22/2025]
Abstract
Humans are perhaps evolutionarily engineered to get deeply addicted to sugar, as it not only provides energy but also helps in storing fats, which helps in survival during starvation. Additionally, sugars (glucose and fructose) stimulate the feel-good factor, as they trigger the secretion of serotonin and dopamine in the brain, associated with the reward sensation, uplifting the mood in general. However, when consumed in excess, it contributes to energy imbalance, weight gain, and obesity, leading to the onset of a complex metabolic disorder, generally referred to as diabetes. Type 2 diabetes mellitus (T2DM) is one of the most prevalent forms of diabetes, nearly affecting all age groups. T2DM is clinically diagnosed with a cardinal sign of chronic hyperglycemia (excessive sugar in the blood). Chronic hyperglycemia, coupled with dysfunctions of pancreatic β-cells, insulin resistance, and immune inflammation, further exacerbate the pathology of T2DM. Uncontrolled T2DM, a major public health concern, also contributes significantly toward the onset and progression of several micro- and macrovascular diseases, such as diabetic retinopathy, nephropathy, neuropathy, atherosclerosis, and cardiovascular diseases, including cancer. The current review discusses the epidemiology, causative factors, pathophysiology, and associated comorbidities, including the existing and emerging therapies related to T2DM. It also provides a future roadmap for alternative drug discovery for the management of T2DM.
Collapse
Affiliation(s)
- Aditi Singh
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India
| | - Sucharita Shadangi
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India
| | - Pulkit Kr Gupta
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India
| | - Soumendra Rana
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha, India
| |
Collapse
|
15
|
Qin M, Chao L, Liu S. Comparative efficacy and safety of sitagliptin or gliclazide combined with metformin in treatment-naive patients with type 2 diabetes: A single-center, prospective, randomized, controlled, noninferiority study with genetic polymorphism analysis. Medicine (Baltimore) 2025; 104:e41061. [PMID: 39792745 PMCID: PMC11730665 DOI: 10.1097/md.0000000000041061] [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: 06/21/2024] [Accepted: 12/05/2024] [Indexed: 01/12/2025] Open
Abstract
BACKGROUND This study evaluates the efficacy and safety of sitagliptin versus gliclazide, combined with metformin, in treatment-naive patients with type 2 diabetes mellitus (T2DM) and glucotoxicity. METHODS In this single-center, randomized, controlled noninferiority trial, 129 treatment-naive patients with T2DM with glucotoxicity (fasting plasma glucose [FPG] ≥ 200 mg/dL and glycated hemoglobin ≥ 9.0%) were randomized to receive sitagliptin plus metformin (n = 66) or gliclazide plus metformin (n = 63) for 12 weeks. Sitagliptin and gliclazide were given for the first 4 weeks, followed by metformin monotherapy for 8 weeks. Efficacy end points included changes in glycemic control, body weight, and β-cell function at baseline, 4 weeks, and 12 weeks. RESULTS After 12 weeks, mean glycated hemoglobin reductions were 4.03% in the sitagliptin group and 4.13% in the gliclazide group, with a mean difference of -0.097 (95% confidence interval, -0.648 to 0.453), confirming noninferiority. Both groups showed significant FPG reductions at 4 weeks (P < .05). The sitagliptin group achieved faster glycemic targets, greater FPG and body weight reductions, and higher rates of FPG < 6.1 mmol/L (26.2% vs 5.7%; P = .012). No significant differences were observed in β-cell function or hypoglycemia incidence (P > .05). Genetic analysis showed specific single-nucleotide polymorphisms affected drug efficacy: dipeptidyl peptidase-4 rs2909451 TT and rs4664443 GG genotypes showed lower efficacy with sitagliptin, while GLP1R rs3765467 AG and KCNJ11 rs2285676 CC genotypes responded better to sitagliptin. CONCLUSION Sitagliptin combined with metformin is noninferior to gliclazide combined with metformin in treatment-naive patients with T2DM with glucotoxicity. Genetic polymorphisms significantly affect drug efficacy, highlighting the importance of personalized medicine. The sitagliptin group achieved glycemic targets more quickly and had greater weight reductions without increased adverse effects.
Collapse
Affiliation(s)
- Min Qin
- Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lingxi Chao
- The First Clinical Medical School, Southern Medical University, Guangzhou, China
| | - Shiqun Liu
- Department of Endocrinology and Metabolism, Nanfang Hospital, Southern Medical University, Guangzhou, China
| |
Collapse
|
16
|
Wang Z, Wei J, Zhang X, Ji H, Fu S, Gao Z, Li H. Nitration of Tyr37 alters the aggregation pathway of hIAPP and enhances its cytotoxicity. Int J Biol Macromol 2025; 286:138367. [PMID: 39643176 DOI: 10.1016/j.ijbiomac.2024.138367] [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: 08/31/2024] [Revised: 11/29/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024]
Abstract
The amyloid aggregation of hIAPP and the increased level of oxidative stress are closely related to the occurrence and development of type 2 diabetes (T2D). Protein tyrosine nitration is a common post-translational modification under oxidative stress conditions. We previously found that tyrosine nitrated hIAPP (3-NT-hIAPP) has higher cytotoxicity than wild type hIAPP. In order to further elucidate the mechanism by which tyrosine nitration enhances the toxicity of hIAPP, we systematically studied the effect of tyrosine nitration on hIAPP aggregation and its impact on INS-1 cells. Collective experimental data from ThT, RLS, DLS, zeta potentials, Bis-ANS, 1H NMR, TEM, dye leakage and hemolysis confirmed that tyrosine nitration accelerates hIAPP aggregation, consistent with tyrosine nitration reducing hIAPP zeta potential, but 3-NT-hIAPP mainly undergoes an off-pathway aggregation to form amorphous aggregates, even in the presence of POPC/POPG LUVs. Further, our results confirmed that the most toxic species are the small amorphous aggregates formed by 3-NT-hIAPP, which is more stable and toxic than hIAPP oligomers. Collectively, these data suggest that tyrosine nitration can increase cytotoxicity of hIAPP by modulating its amyloidogenicity. This study provides new support for the fact that oxidative stress promotes the development of T2D from the view of nitrative stress.
Collapse
Affiliation(s)
- Zhilong Wang
- Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Jingjing Wei
- Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Xuan Zhang
- Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Haoran Ji
- Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Shitao Fu
- Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan, 430074, PR China
| | - Zhonghong Gao
- Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan, 430074, PR China.
| | - Hailing Li
- Hubei Key Laboratory of Bioinorganic Chemistry & Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science & Technology, Wuhan, 430074, PR China.
| |
Collapse
|
17
|
Kaur A, Singh S, Mujwar S, Singh TG. Molecular Mechanisms Underlying the Therapeutic Potential of Plant-Based α-Amylase Inhibitors for Hyperglycemic Control in Diabetes. Curr Diabetes Rev 2025; 21:e020724231486. [PMID: 38956911 DOI: 10.2174/0115733998304373240611110224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 05/14/2024] [Accepted: 05/30/2024] [Indexed: 07/04/2024]
Abstract
BACKGROUND Diabetes mellitus (DM), arising from pancreatic β-cell dysfunction and disrupted alpha-amylase secretion, manifests as hyperglycemia. Synthetic inhibitors of alphaamylase like acarbose manage glucose but pose adverse effects, prompting interest in plantderived alternatives rich in antioxidants and anti-inflammatory properties. OBJECTIVE The current review investigates plant-based alpha-amylase inhibitors, exploring their potential therapeutic roles in managing DM. Focusing on their ability to modulate postprandial hyperglycemia by regulating alpha-amylase secretion, it assesses their efficacy, health benefits, and implications for diabetes treatment. METHODS This review examines plant-derived alpha-amylase inhibitors as prospective diabetic mellitus treatments using PubMed, Google Scholar, and Scopus data. RESULTS Plant-derived inhibitors, including A. deliciosa, B. egyptiaca, and N. nucifera, exhibit anti-inflammatory and antioxidant properties, effectively reducing alpha-amylase levels in diabetic conditions. Such alpha-amylase inhibitors showed promising alternative treatment in managing diabetes with reduced adverse effects. CONCLUSION The current literature concludes that plant-derived alpha-amylase inhibitors present viable therapeutic avenues for diabetes management by modulating alpha-amylase secretion by regulating inflammatory, oxidative stress, and apoptotic mechanisms involved in the pathogenesis of diabetes. Further investigation into their formulations and clinical efficacy may reveal their more comprehensive diabetes therapeutic significance, emphasizing their potential impact on glucose regulation and overall health.
Collapse
Affiliation(s)
- Amritpal Kaur
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Shareen Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Somdutt Mujwar
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, 140401, Punjab, India
| |
Collapse
|
18
|
Grieve LM, Rani A, ZeRuth GT. Downregulation of Glis3 in INS1 cells exposed to chronically elevated glucose contributes to glucotoxicity-associated β cell dysfunction. Islets 2024; 16:2344622. [PMID: 38652652 PMCID: PMC11042057 DOI: 10.1080/19382014.2024.2344622] [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: 12/06/2023] [Revised: 04/05/2024] [Accepted: 04/15/2024] [Indexed: 04/25/2024] Open
Abstract
Chronically elevated levels of glucose are deleterious to pancreatic β cells and contribute to β cell dysfunction, which is characterized by decreased insulin production and a loss of β cell identity. The Krüppel-like transcription factor, Glis3 has previously been shown to positively regulate insulin transcription and mutations within the Glis3 locus have been associated with the development of several pathologies including type 2 diabetes mellitus. In this report, we show that Glis3 is significantly downregulated at the transcriptional level in INS1 832/13 cells within hours of being subjected to high glucose concentrations and that diminished expression of Glis3 is at least partly attributable to increased oxidative stress. CRISPR/Cas9-mediated knockdown of Glis3 indicated that the transcription factor was required to maintain normal levels of both insulin and MafA expression and reduced Glis3 expression was concomitant with an upregulation of β cell disallowed genes. We provide evidence that Glis3 acts similarly to a pioneer factor at the insulin promoter where it permissively remodels the chromatin to allow access to a transcriptional regulatory complex including Pdx1 and MafA. Finally, evidence is presented that Glis3 can positively regulate MafA transcription through its pancreas-specific promoter and that MafA reciprocally regulates Glis3 expression. Collectively, these results suggest that decreased Glis3 expression in β cells exposed to chronic hyperglycemia may contribute significantly to reduced insulin transcription and a loss of β cell identity.
Collapse
Affiliation(s)
- LilyAnne M. Grieve
- Department of Biological Sciences, Murray State University, Murray, KY, USA
| | - Abhya Rani
- Department of Biological Sciences, Murray State University, Murray, KY, USA
| | - Gary T. ZeRuth
- Department of Biological Sciences, Murray State University, Murray, KY, USA
| |
Collapse
|
19
|
Ren Y, Hu X, Qi M, Zhu W, Li J, Yang S, Dai C. Tangningtongluo Tablet ameliorates pancreatic damage in diabetic mice by inducing autophagy and inhibiting the PI3K/Akt/mTOR signaling pathway. Int Immunopharmacol 2024; 142:113032. [PMID: 39236456 DOI: 10.1016/j.intimp.2024.113032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/20/2024] [Accepted: 08/25/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND Diabetes is a metabolic disease characterized by hyperglycaemia. Tangningtongluo Tablet (TNTL) is an inpatient formula extensively utilized to treat diabetes mellitus (DM), but the protective mechanism is not clear. This study aimed to investigate the relevant mechanisms by which TNTL affects pancreatic damage in diabetic mice and autophagy. METHODS The impact of TNTL on pancreatic damage in diabetic mice in vitro and in vivo was investigated via glucose and lipid metabolism analyses, HE staining, CCK-8, TUNEL staining, Annexin V/PI, and Western blotting. Molecular docking and Western blotting were used to verify the results of network pharmacological analysis, which was carried out to explore the mechanism by which TNTL affects DM. The autophagosome levels were visualized via RFP-GFP-LC3 and transmission electron microscopy, and lysosomal function was evaluated via Lysotracker red staining. Western blot, immunohistochemistry and immunofluorescence staining were used to detect the expression of the autophagy proteins LC3, p62 and LAMP2. RESULTS Compared with the model group, TNTL protected pancreas from oxidative stress, decreased the level of MDA, increased the levels of SOD and GSH-px, induced the occurrence of autophagy and decreased the levels of apoptotic factors. Moreover, TNTL inhibited the protein expression of p-PI3K, p-Akt and p-mTOR, increased the levels of LC3 and LAMP2 and decreased the level of p62, and the autophagy inhibitor CQ blocked the protective effect of TNTL on pancreatic damage in diabetic mice. CONCLUSION These results demonstrated that TNTL ameliorated pancreatic damage in diabetic mice by inhibiting the PI3K/Akt/mTOR signaling and regulating autophagy.
Collapse
Affiliation(s)
- Ying Ren
- College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Xiangka Hu
- Institute of Materia Medica, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Mushuang Qi
- College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Wanjun Zhu
- College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Jin Li
- The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, China; School of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Shuyu Yang
- The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, China; School of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
| | - Chunmei Dai
- Institute of Materia Medica, Jinzhou Medical University, Jinzhou, Liaoning 121001, China.
| |
Collapse
|
20
|
Malik MZ, Dashti M, Jangid A, Channanath A, Elsa John S, Singh RKB, Al-Mulla F, Alphonse Thanaraj T. Complex p53 dynamics regulated by miR-125b in cellular responses to reactive oxidative stress and DNA damage. Brief Bioinform 2024; 26:bbae706. [PMID: 39820247 PMCID: PMC11736902 DOI: 10.1093/bib/bbae706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Revised: 10/27/2024] [Accepted: 12/28/2024] [Indexed: 01/19/2025] Open
Abstract
In response to distinct cellular stresses, the p53 exhibits distinct dynamics. These p53 dynamics subsequently control cell fate. However, different stresses can generate the same p53 dynamics with different cell fate outcomes, suggesting that the integration of dynamic information from other pathways is important for cell fate regulation. The interactions between miRNA-125b, p53, and reactive oxygen species (ROS) are significant in the context of cellular stress responses and apoptosis. However, the regulating mechanism of miR-125b with p53 is not fully studied. The dynamics of p53 and its response to the miR-125b regulation are still open questions. In the present study, we try to answer some of these fundamental questions based on basic model built from available experimental reports. The miR-125b-p53 regulatory network is modeled using a set of 11 molecular species variables. The biochemical network of miR-125b-p53, described by 22 reaction channels, is represented by coupled ordinary differential equations (ODEs) using the mass action law of chemical kinetics. These ODEs are solved numerically using the standard fourth-order Runge-Kutta method to analyze the dynamical behavior of the system. The biochemical network model we designed is based on both experimental and theoretical reported data. The p53 dynamics driven by miR-125b exhibit five distinct dynamical states: first and second stable states, first and second dynamical states, and a sustained oscillation state. These different p53 dynamical states may correspond to various cellular conditions. If the stress induced by miR-125b is weak, the system will be weakly activated, favoring a return to normal functioning. However, if the stress is significantly strong, the system will move to an active state. To sustain this active state, which is far from equilibrium with little scope for returning to normal conditions, the system may transition to an apoptotic state by crossing through other intermediate states, as it is unlikely to regain normal functioning. The p53 dynamical states show a multifractal nature, contributed by both short- and long-range correlations. The networks illustrated from these dynamical states follow hierarchical scale-free features, exhibiting an assortative nature with an absence of the centrality-lethality rule. Furthermore, the active dynamical state is generally closer to hierarchical characteristics and is self-organized. Our research study reveals that significant activity of miR-125b on the p53 regulatory network and its dynamics can only be observed when the system is slightly activated by ROS. However, this process does not necessarily require the direct study of ROS activity. These findings elucidate the mechanisms by which cells integrate signaling pathways with distinct temporal activity patterns to encode stress specificity and direct diverse cell fate decisions.
Collapse
Affiliation(s)
- Md Zubbair Malik
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait City, Kuwait
| | - Mohammed Dashti
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait City, Kuwait
| | - Amit Jangid
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Arshad Channanath
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait City, Kuwait
| | - Sumi Elsa John
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait City, Kuwait
| | - R K Brojen Singh
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Fahd Al-Mulla
- Department of Translational Research, Dasman Diabetes Institute, Dasman 15462, Kuwait City, Kuwait
| | | |
Collapse
|
21
|
Bentoumi H, Bouzina A, Amira A, Sekiou O, Chohra D, Ferchichi L, Zerrouki R, Aouf NE. Theoretical investigations of some isolated compounds from Calophyllum flavoramulum as potential antioxidant agents and inhibitors of AGEs. J Biomol Struct Dyn 2024:1-27. [PMID: 39568387 DOI: 10.1080/07391102.2024.2428375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Accepted: 06/01/2024] [Indexed: 11/22/2024]
Abstract
In this paper, we have attempted a theoretical calculation of some plant-isolated compounds as potential inhibitors of oxidative stress and Advanced Glycation Endproducts (AGEs). Herein, theoretical reactivity indices based on the CDFT theory were computed to explore the reactivity of five isolated products from Calophyllum flavoramulum. Global reactivity indices based on HOMO and LUMO energy such as electronic chemical potential, hardness, electrophilicity and the local reactivity descriptors Parr function, molecular electrostatic potentials(MEP), electrostatic potential (ESP) and thermodynamic parameters for the studied compounds are computed and discussed using DFT method and two functionals B3LYP and CAM-B3LYP with 6-31 G(d,p) basis set. The free radical scavenging activity mechanisms (HAT, SET-PT, and SPLET) of some of the isolated products with DPPH are also presented in this work. SET-PT mechanism of the antiradical activity is found to be thermodynamically favorable. Furthermore, a molecular docking study with RAGE receptor and AtGSTF2 enzyme was conducted, in which flavonoids 4 and 5 show a low binding affinity with -8.42 and -10.49 kcal/mol for RAGE, -8.67 and -9.00 kcal/mol for AtGSTF2. After the encouraging outcomes from the molecular docking study, the 4-AtGSTF2 and 5-RAGE complex were subjected to 200 ns molecular dynamics simulation using Desmond, where both studied systems exhibited remarkable stability throughout the 200 ns simulations. Also, the MM-GBSA method was measured by calculating the binding free energy using the individual energy components. Finally, the ADMET predictions were assessed to anticipate the behavior of a drug candidate within the human body.
Collapse
Affiliation(s)
- Houria Bentoumi
- Laboratory of Applied Organic Chemistry (LAOC), Bioorganic Chemistry Group, Sciences Faculty, Chemistry Department, Badji Mokhtar-Annaba University, Annaba, Algeria
| | - Abdeslem Bouzina
- Laboratory of Applied Organic Chemistry (LAOC), Bioorganic Chemistry Group, Sciences Faculty, Chemistry Department, Badji Mokhtar-Annaba University, Annaba, Algeria
| | - Aïcha Amira
- Laboratory of Applied Organic Chemistry (LAOC), Bioorganic Chemistry Group, Sciences Faculty, Chemistry Department, Badji Mokhtar-Annaba University, Annaba, Algeria
- National Higher School of Technology and Engineering, Annaba, Algeria
| | - Omar Sekiou
- Environmental Research Center (CRE), Annaba, Algeria
| | - Djawhara Chohra
- Laboratory of Applied Organic Chemistry (LAOC), Bioorganic Chemistry Group, Sciences Faculty, Chemistry Department, Badji Mokhtar-Annaba University, Annaba, Algeria
| | - Loubna Ferchichi
- Laboratory of Synthesis and Organic Biocatalysis (LSOB), Phytochemistry Group, Sciences Faculty, Chemistry Department, Badji Mokhtar-Annaba University, Annaba, Algeria
| | - Rachida Zerrouki
- Laboratory of Agroresources, Biomolecules and Chemistry for Health Innovation (LABCiS), Faculty of Science and Technology, University of Limoges, Limoges, France
| | - Nour-Eddine Aouf
- Laboratory of Applied Organic Chemistry (LAOC), Bioorganic Chemistry Group, Sciences Faculty, Chemistry Department, Badji Mokhtar-Annaba University, Annaba, Algeria
| |
Collapse
|
22
|
Tiselko AV, Misharina EV, Yarmolinskaya MI, Milyutina YP, Zalozniaia IV, Korenevsky AV. Evaluation of folliculogenesis and oxidative stress parameters in type 1 diabetes mellitus women with different glycemic profiles. Endocrine 2024; 85:1131-1140. [PMID: 38842765 DOI: 10.1007/s12020-024-03805-4] [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: 01/09/2024] [Accepted: 03/26/2024] [Indexed: 06/07/2024]
Abstract
BACKGROUND Despite enormous advances in diabetes treatment, women with type 1 diabetes mellitus (DM) still experience delayed menarche, menstrual irregularities, fewer pregnancies, and a higher rate of stillbirths compared to women without the disease. Due to the fact that type 1 DM occurs at a young age, the preservation of reproductive health is one of the most important goals of treatment. AIMS The aim of this study was to evaluate the relationship between different glycemic profiles and changes in the pro-oxidant-antioxidant balance and ovarian follicular apparatus in reproductive-age patients with type 1 DM. METHODS We examined 50 reproductive-age (19-38 years) women with type 1 DM with a disease duration of at least ten years. Carbohydrate metabolism was assessed with the continuous glucose monitoring (CGM) system and glycated hemoglobin (HbA1c) concentration measurement. CGM was performed using the FreeStyle Libre flash glucose monitoring system (Abbott Diabetes Care, Witney, UK). In each patient, malondialdehyde level, catalase activity and 3-nitrotyrosine level in the blood serum were determined. To assess the ovarian function, we measured the ovarian volume, the antral follicle count, and the serum levels of anti-Müllerian hormone and follicle-stimulating hormone. All patients were divided into four groups (glucotypes) based on the CGM results. Group 1 included type 1 DM patients with satisfactory compensation of carbohydrate metabolism; group 2 consisted of patients with frequent hypoglycemic conditions and pathological glucose variability; group 3 included individuals with prolonged hyperglycemic conditions and maximum HbA1c levels; and group 4 comprised patients with the glycemic profile characterized by all the presented types of dysglycemia (intermittent glycemia). RESULTS We revealed a negative correlation between serum catalase activity and time of hypoglycemic conditions in patients with type 1 DM based on the CGM results (rs = -0.47, p < 0.01). In group 4 (intermittent glycemia), patients demonstrated the lowest serum catalase activity and increased serum 3-nitrotyrosine level, while in group 3, women with chronic hyperglycemia (HbA1c 8.4 [8.1; 9.9]%; 68 [65; 85] mmol/mol) had a moderate change in antioxidant defense and oxidative stress parameters. Correlation analysis of ovarian volume, the antral follicle count, and the serum anti-Müllerian hormone level in type 1 DM women with different glycemic profiles established a negative relationship (rs = -0.82, p < 0.05) between the antral follicle count and glucose variability in group 1, a positive relationship (rs = 0.68, p < 0.05) between ovarian volume and glucose variability in group 2, and a positive relationship (rs = 0.88, p < 0.05) between ovarian volume and time of hypoglycemic conditions, which, according to the CGM results, amounted to a critical value of 57.5 [40.0; 82.0]%. CONCLUSIONS The data obtained indicate the relationship between the ovarian volume, serum anti-Müllerian hormone level, the antral follicle count and oxidative stress parameters not only in patients with hyperglycemia, but also in those with hypoglycemic conditions, as well as with pathological glucose variability.
Collapse
Affiliation(s)
- A V Tiselko
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, Russia.
| | - E V Misharina
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, Russia
| | - M I Yarmolinskaya
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, Russia
| | - Y P Milyutina
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, Russia
| | - I V Zalozniaia
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, Russia
| | - A V Korenevsky
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductive Medicine, St. Petersburg, Russia
| |
Collapse
|
23
|
Nagayach A, Bhaskar R, Ghosh S, Singh KK, Han SS, Sinha JK. Advancing the understanding of diabetic encephalopathy through unravelling pathogenesis and exploring future treatment perspectives. Ageing Res Rev 2024; 100:102450. [PMID: 39134179 DOI: 10.1016/j.arr.2024.102450] [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: 06/03/2024] [Revised: 07/31/2024] [Accepted: 08/05/2024] [Indexed: 08/25/2024]
Abstract
Diabetic encephalopathy (DE), a significant micro-complication of diabetes, manifests as neurochemical, structural, behavioral, and cognitive alterations. This condition is especially dangerous for the elderly because aging raises the risk of neurodegenerative disorders and cognitive impairment, both of which can be made worse by diabetes. Despite its severity, diagnosis of this disease is challenging, and there is a paucity of information on its pathogenesis. The pivotal roles of various cellular pathways, activated or influenced by hyperglycemia, insulin sensitivity, amyloid accumulation, tau hyperphosphorylation, brain vasculopathy, neuroinflammation, and oxidative stress, are widely recognized for contributing to the potential causes of diabetic encephalopathy. We also reviewed current pharmacological strategies for DE encompassing a comprehensive approach targeting metabolic dysregulations and neurological manifestations. Antioxidant-based therapies hold promise in mitigating oxidative stress-induced neuronal damage, while anti-diabetic drugs offer neuroprotective effects through diverse mechanisms, including modulation of insulin signaling pathways and neuroinflammation. Additionally, tissue engineering and nanomedicine-based approaches present innovative strategies for targeted drug delivery and regenerative therapies for DE. Despite significant progress, challenges remain in translating these therapeutic interventions into clinical practice, including long-term safety, scalability, and regulatory approval. Further research is warranted to optimize these approaches and address remaining gaps in the management of DE and associated neurodegenerative disorders.
Collapse
Affiliation(s)
- Aarti Nagayach
- Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Rakesh Bhaskar
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, South Korea
| | - Shampa Ghosh
- GloNeuro, Sector 107, Vishwakarma Road, Noida, Uttar Pradesh 201301 India
| | - Krishna Kumar Singh
- Symbiosis Centre for Information Technology, Symbiosis International (Deemed University), Rajiv Gandhi InfoTech Park, Hinjawadi, Pune, Maharashtra 411057, India
| | - Sung Soo Han
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, South Korea; Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, South Korea.
| | | |
Collapse
|
24
|
Gouaref I, Otmane A, Makrelouf M, Abderrhmane SA, Haddam AEM, Koceir EA. Crucial Interactions between Altered Plasma Trace Elements and Fatty Acids Unbalance Ratio to Management of Systemic Arterial Hypertension in Diabetic Patients: Focus on Endothelial Dysfunction. Int J Mol Sci 2024; 25:9288. [PMID: 39273236 PMCID: PMC11395650 DOI: 10.3390/ijms25179288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
The coexistence of SAH with T2DM is a common comorbidity. In this study, we investigated the link between altered plasma antioxidant trace elements (ATE: manganese, selenium, zinc, and copper) and fatty acids ratio (FAR: polyunsaturated/saturated) imbalance as transition biomarkers between vascular pathology (SAH) to metabolic pathology (T2DM). Our data revealed strong correlation between plasma ATE and FAR profile, which is modified during SAH-T2DM association compared to the healthy group. This relationship is mediated by lipotoxicity (simultaneously prominent visceral adipose tissue lipolysis, significant flow of non-esterified free fatty acids release, TG-Chol-dyslipidemia, high association of total SFA, palmitic acid, arachidonic acid, and PUFA ω6/PUFA ω3; drop in tandem of PUFA/SFA and EPA + DHA); oxidative stress (lipid peroxidation confirmed by TAS depletion and MDA rise, concurrent drop of Zn/Cu-SOD, GPx, GSH, Se, Zn, Se/Mn, Zn/Cu; concomitant enhancement of Cu, Mn, and Fe); endothelial dysfunction (endotheline-1 increase); athero-thrombogenesis risk (concomitant rise of ApoB100/ApoA1, Ox-LDL, tHcy, and Lp(a)), and inflammation (higher of Hs-CRP, fibrinogen and ferritin). Our study opens to new therapeutic targets and to better dietary management, such as to establishing dietary ATE and PUFA ω6/PUFA ω3 or PUFA/SFA reference values for atherosclerotic risk prevention in hypertensive/diabetic patients.
Collapse
Affiliation(s)
- Ines Gouaref
- Bioenergetics and Intermediary Metabolism Team, Laboratory of Biology and Organism Physiology, Biological Sciences Faculty, Nutrition and Pathologies Post Graduate School, Houari Boumediene University of Sciences and Technology (USTHB), Bab Ezzouar, Algiers 16123, Algeria
- Tamayouz Laboratory, Centre de Recherche en Biotechnologie (CRBT), Ali Mendjli Nouvelle Ville UV 03 BP E73, Constantine 25000, Algeria
| | - Amel Otmane
- Biochemistry and Genetics Laboratory, University Hospital Center, Mohamed Lamine Debaghine, Bab El Oued, Algiers 16000, Algeria
| | - Mohamed Makrelouf
- Biochemistry and Genetics Laboratory, University Hospital Center, Mohamed Lamine Debaghine, Bab El Oued, Algiers 16000, Algeria
| | - Samir Ait Abderrhmane
- Diabetology Unit, University Hospital Center, Mohamed Seghir Nekkache (ex. HCA de Aïn Naâdja), Algiers 16208, Algeria
| | - Ali El Mahdi Haddam
- Diabetology Unit, University Hospital Center, Mohamed Lamine Debaghine, Algiers I-University, Bab El Oued, Algiers 16000, Algeria
| | - Elhadj-Ahmed Koceir
- Bioenergetics and Intermediary Metabolism Team, Laboratory of Biology and Organism Physiology, Biological Sciences Faculty, Nutrition and Pathologies Post Graduate School, Houari Boumediene University of Sciences and Technology (USTHB), Bab Ezzouar, Algiers 16123, Algeria
- Tamayouz Laboratory, Centre de Recherche en Biotechnologie (CRBT), Ali Mendjli Nouvelle Ville UV 03 BP E73, Constantine 25000, Algeria
| |
Collapse
|
25
|
Ramadan H, Moustafa N, Ahmed RR, El-Shahawy AA, Eldin ZE, Al-Jameel SS, Amin KA, Ahmed OM, Abdul-Hamid M. Therapeutic effect of oral insulin-chitosan nanobeads pectin-dextrin shell on streptozotocin-diabetic male albino rats. Heliyon 2024; 10:e35636. [PMID: 39170289 PMCID: PMC11336891 DOI: 10.1016/j.heliyon.2024.e35636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 08/09/2024] Open
Abstract
The current study inspects the therapeutic effects of orally ingested insulin-loaded chitosan nanobeads (INS-CsNBs) with a pectin-dextrin (PD) coating on streptozotocin (STZ)-induced diabetes in Wistar rats. The study also assessed antioxidant effects in pancreatic tissue homogenate, insulin, C-peptide, and inflammatory markers interleukin-1 beta and interleukin-6 (IL-1β and IL-6) in serum. Additionally, histopathological and immunohistochemical examination of insulin granules, oxidative stress, nuclear factor kappa B (NF-κB P65), and sirtuin-1 (SIRT-1) protein detection, as well as gene expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), B-cell lymphoma 2 (Bcl2), and Bcl-2-associated X protein (Bax) in pancreatic tissue were investigated. After induction of diabetes with STZ, rats were allocated into 6 groups: the normal control (C), the diabetic control (D), and the diabetic groups treated with INS-CsNBs coated with PD shell (50 IU/kg) (NF), free oral insulin (10 IU/kg) (FO), CsNBs-PD shell (50 IU/kg) (NB), and subcutaneous insulin (10 IU/kg) (Sc). The rats were treated daily for four weeks. Treatment of diabetic rats with INS-CsNBs coated with PD shell resulted in a significant improvement in blood glucose levels, elevated antioxidant activities, decreased NF-κB P65, IL-1β, and IL-6 levels, upregulated Nrf-2 and HO-1, in addition to a marked improvement in the histological architecture and integrity compared to the diabetic group. The effects of oral INS-CsNBs administration were comparable to those of subcutaneous insulin. In conclusion, oral administration of INS-loaded Cs-NBs with a pectin-dextrin shell demonstrated an ameliorative effect on STZ-induced diabetes, avoiding the drawbacks of subcutaneous insulin.
Collapse
Affiliation(s)
- Hanaa Ramadan
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Nadia Moustafa
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Rasha Rashad Ahmed
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Ahmed A.G. El-Shahawy
- Materials Science and Nanotechnology Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, 62521 Beni-Suef 12827, Egypt
| | - Zienab E. Eldin
- Materials Science and Nanotechnology Department, Faculty of Postgraduate Studies for Advanced Sciences (PSAS), Beni-Suef University, 62521 Beni-Suef 12827, Egypt
| | - Suhailah S. Al-Jameel
- Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
- Basic and Applied Scientific Research Center, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Kamal Adel Amin
- Department of Chemistry, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
- Basic and Applied Scientific Research Center, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Osama M. Ahmed
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Manal Abdul-Hamid
- Cell Biology, Histology and Genetics Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| |
Collapse
|
26
|
Dinić S, Arambašić Jovanović J, Uskoković A, Jovanović A, Grdović N, Rajić J, Đorđević M, Sarić A, Bugarski B, Vidaković M, Mihailović M. Liposome Encapsulation Enhances the Antidiabetic Efficacy of Silibinin. Pharmaceutics 2024; 16:801. [PMID: 38931922 PMCID: PMC11207473 DOI: 10.3390/pharmaceutics16060801] [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: 05/15/2024] [Revised: 06/05/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Silibinin has considerable therapeutic potential for the treatment of diabetes through anti-inflammatory, antioxidant, and immunomodulatory properties. However, the therapeutic application of silibinin is quite limited due to its poor bioavailability. In the present study, an attempt was made to improve the antidiabetic efficacy of silibinin by its encapsulation in liposomal vesicles. The liposomes with a high encapsulation efficiency of silibinin (96%) and a zeta potential of -26.2 ± 0.6 mV were developed and studied using nicotinamide/streptozotocin-induced diabetic rats. Administration of silibinin-loaded liposomes to diabetic rats lowered glucose levels, increased insulin levels, and improved pancreatic islet architecture. The anti-inflammatory effect of silibinin-loaded liposomes was demonstrated by a decrease in serum C-reactive protein (CRP) levels and a reduced deposition of collagen fibers in the islets of diabetic rats. Furthermore, silibinin-loaded liposomes were more efficient in lowering glucose, alanine transaminase, triglyceride, and creatinine levels in diabetic rats than pure silibinin. In addition, silibinin-loaded liposomes had a significantly better effect on beta-cell mass and Glut2 glucose receptor distribution in diabetic islets than pure silibinin. The present results clearly show that liposome encapsulation of silibinin enhances its antidiabetic efficacy, which may contribute to the therapeutic benefit of silibinin in the treatment of diabetes and its complications.
Collapse
Affiliation(s)
- Svetlana Dinić
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Jelena Arambašić Jovanović
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Aleksandra Uskoković
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Aleksandra Jovanović
- Institute for the Application of Nuclear Energy INEP, University of Belgrade, 11080 Belgrade, Serbia;
| | - Nevena Grdović
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Jovana Rajić
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Marija Đorđević
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Ana Sarić
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Branko Bugarski
- Faculty of Technology and Metallurgy, University of Belgrade, 11000 Belgrade, Serbia;
| | - Melita Vidaković
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| | - Mirjana Mihailović
- Department of Molecular Biology, Institute for Biological Research “Siniša Stanković”—National Institute of the Republic of Serbia, University of Belgrade, 11108 Belgrade, Serbia; (J.A.J.); (A.U.); (N.G.); (J.R.); (M.Đ.); (A.S.); (M.V.); (M.M.)
| |
Collapse
|
27
|
Biedrzycki G, Wolszczak-Biedrzycka B, Dorf J, Michalak D, Żendzian-Piotrowska M, Zalewska A, Maciejczyk M. The antiglycation potential of H1 receptor antagonists - in vitro studies in bovine serum albumin model and in silico molecular docking analyses. Biomed Pharmacother 2024; 175:116632. [PMID: 38663107 DOI: 10.1016/j.biopha.2024.116632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 04/17/2024] [Indexed: 06/03/2024] Open
Abstract
The H1 receptor belongs to the family of rhodopsin-like G-protein-coupled receptors activated by the biogenic amine histamine. H1 receptor antagonists are widely used in the treatment of allergies. However, these drugs could have a much broader spectrum of activity, including hypoglycemic effects, which can broaden the spectrum of their use. The aim of the study was to evaluate the antiglycation potential of twelve H1 receptor antagonists (diphenhydramine, antazoline, promethazine, ketotifen, clemastine, pheniramine, cetirizine, levocetirizine, bilastine, fexofenadine, desloratadine, and loratadine). Bovine serum albumin (BSA) was glycated with sugars (glucose, fructose, galactose, and ribose) and aldehydes (glyoxal and methylglyoxal) in the presence of H1 blockers. The tested substances did not induce a significant decrease in the content of albumin glycation end-products, and the inhibition rate of glycoxidation was not influenced by the chemical structure or generation of H1 blockers. None of the tested H1 receptor antagonists exhibited strong antiglycation activity. Antiglycemic potential of H1 blockers could be attributed to their antioxidant and anti-inflammatory activity, as well as their effects on carbohydrate metabolism/metabolic balance at the systemic level.
Collapse
Affiliation(s)
| | - Blanka Wolszczak-Biedrzycka
- Department of Psychology and Sociology of Health and Public Health, University of Warmia and Mazury in Olsztyn, Poland
| | - Justyna Dorf
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland
| | - Daniel Michalak
- "Biochemistry of Civilization Diseases" Student Scientific Club at the Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Poland
| | | | - Anna Zalewska
- Experimental Dentistry Laboratory, Medical University of Bialystok, ul. M. Sklodowskiej-Curie 24a, Bialystok 15-274, Poland
| | - Mateusz Maciejczyk
- Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, Poland.
| |
Collapse
|
28
|
Liu X, Wang N, Gu S, He Z. Changes of RNA m 6A/m 5C Modification Regulatory Molecules in Ferroptosis of T2DM Rat Pancreas. Cell Biochem Biophys 2024; 82:1279-1289. [PMID: 38709441 DOI: 10.1007/s12013-024-01282-0] [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] [Accepted: 04/17/2024] [Indexed: 05/07/2024]
Abstract
N6-methyladenine (m6A) and 5-methylcytosine (m5C) are two common forms of RNA methylation that play an important role in the epigenetics of type 2 diabetes mellitus (T2DM). One type of cell death, ferroptosis, has been implicated in islet β-cell damage in T2DM. Notably, RNA methylation, an upstream regulatory mechanism of mRNAs, can regulate the expression of ferroptosis signaling molecules, thereby affecting cell proliferation and death. Here, we found that the ferroptosis signaling pathway was activated in pancreas of T2DM rats, followed by significant changes in m6A/m5C modification regulatory molecules. These detection data together with the prediction results that m6A and m5C exist in the mRNAs of ferroptosis molecules, we speculate that m6A and m5C are probably involved in pancreatic cell damage by modifying of ferroptosis signaling molecules. In short, our findings provide a new research idea for future studies on the molecular mechanisms of pancreatic cell damage and point to a new direction for exploring the mechanisms of ferroptosis from the perspective of RNA methylation modification.
Collapse
Affiliation(s)
- Xiaoyu Liu
- Institute of Preventive Medicine, School of Public Health, Dali University, Dali, Yunnan, China
| | - Nan Wang
- Institute of Preventive Medicine, School of Public Health, Dali University, Dali, Yunnan, China
| | - Shiyan Gu
- Institute of Preventive Medicine, School of Public Health, Dali University, Dali, Yunnan, China.
| | - Zuoshun He
- Institute of Preventive Medicine, School of Public Health, Dali University, Dali, Yunnan, China.
| |
Collapse
|
29
|
Li S, Niu W, Wang C, Zhao J, Zhang N, Yin Y, Jia M, Cui L. Exploring Anthracycline-Induced Cardiotoxicity from the Perspective of Protein Quality Control. Rev Cardiovasc Med 2024; 25:213. [PMID: 39076322 PMCID: PMC11270093 DOI: 10.31083/j.rcm2506213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/26/2023] [Accepted: 01/15/2024] [Indexed: 07/31/2024] Open
Abstract
Anthracyclines are effective anticancer drugs; however, their use is restricted because of their dose-dependent, time-dependent and irreversible myocardial toxicity. The mechanism of anthracycline cardiotoxicity has been widely studied but remains unclear. Protein quality control is crucial to the stability of the intracellular environment and, ultimately, to the heart because cardiomyocytes are terminally differentiated. Two evolutionarily conserved mechanisms, autophagy, and the ubiquitin-proteasome system, synergistically degrade misfolded proteins and remove defective organelles. Recent studies demonstrated the importance of these mechanisms. Further studies will reveal the detailed metabolic pathway and metabolic control of the protein quality control mechanism integrated into anthracycline-induced cardiotoxicity. This review provides theoretical support for clinicians in the application and management of anthracyclines.
Collapse
Affiliation(s)
- Shanshan Li
- Department of Laboratory Medicine, Peking University Third Hospital, 100191 Beijing, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Peking University Third Hospital, 100191 Beijing, China
- Department of Clinical Laboratory, Peking University People’s Hospital, 100041 Beijing, China
| | - Weihua Niu
- Department of Clinical Laboratory, Peking University People’s Hospital, 100041 Beijing, China
| | - Chunyan Wang
- Department of Clinical Laboratory, Peking University People’s Hospital, 100041 Beijing, China
| | - Jie Zhao
- Department of Clinical Laboratory, Peking University People’s Hospital, 100041 Beijing, China
| | - Na Zhang
- Department of Clinical Laboratory, Peking University People’s Hospital, 100041 Beijing, China
| | - Yue Yin
- Department of Clinical Laboratory, Peking University People’s Hospital, 100041 Beijing, China
| | - Mei Jia
- Department of Clinical Laboratory, Peking University People’s Hospital, 100041 Beijing, China
| | - Liyan Cui
- Department of Laboratory Medicine, Peking University Third Hospital, 100191 Beijing, China
- Core Unit of National Clinical Research Center for Laboratory Medicine, Peking University Third Hospital, 100191 Beijing, China
| |
Collapse
|
30
|
Dagli Gul AS, Boyuk Ozcan G, Arihan O. Silibinin as a promising treatment for diabetes: Insights into behavioral and metabolic changes in an animal model. Food Sci Nutr 2024; 12:3336-3345. [PMID: 38726421 PMCID: PMC11077243 DOI: 10.1002/fsn3.3999] [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: 10/02/2023] [Revised: 12/25/2023] [Accepted: 01/17/2024] [Indexed: 05/12/2024] Open
Abstract
Diabetes mellitus is causing serious health problems in the chronic period. Silibinin is a flavonoid obtained from the milk thistle (Silybum marianum), which is among the herbal ethnopharmacological administrations. In studies with silibinin, it has been reported that it increases the activity of pancreatic beta cells and insulin sensitivity and has a hyperglycemia-reducing effect. However, behavioral parameters have not been evaluated together with insulin levels and liver function tests. Our aim in this study was to examine the effects of silibinin on insulin secretion, anxiety-like behaviors, and learning in a streptozotocin (STZ)-induced rat diabetes model. Wistar albino rats weighing 200-250 g were divided into 4 groups. Control: Saline solution, Diabetes: STZ 45 mg/kg, S 100: STZ 45 mg/kg + Silibinin 100 mg/kg, S 200: STZ 45 mg/kg + Silibinin 200 mg/kg. Administrations were continued for 21 days. On the 21st day, open field and elevated plus maze as unconditional anxiety tests; Barnes maze for learning and memory; and rotarod test for locomotor activity were conducted. Following behavioral tests, blood samples were taken under anesthesia. Blood glucose levels and ALT values were measured. Insulin levels were measured with an ELISA plate reader. Silibinin shortened the time to find the correct hole. Silibinin prevented the decrease in insulin due to STZ, exhibited a hyperglycemia-reducing effect and decreased the elevation of ALT.
Collapse
Affiliation(s)
- Asli San Dagli Gul
- Department of Physiology, Faculty of MedicineHacettepe UniversityAnkaraTurkey
| | - Gulbahar Boyuk Ozcan
- Department of Physiology, Faculty of MedicineAnkara Medipol UniversityAnkaraTurkey
| | - Okan Arihan
- Department of Physiology, Faculty of MedicineHacettepe UniversityAnkaraTurkey
| |
Collapse
|
31
|
Villaca CBP, Mastracci TL. Pancreatic Crosstalk in the Disease Setting: Understanding the Impact of Exocrine Disease on Endocrine Function. Compr Physiol 2024; 14:5371-5387. [PMID: 39109973 PMCID: PMC11425433 DOI: 10.1002/cphy.c230008] [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] [Indexed: 08/15/2024]
Abstract
The exocrine and endocrine are functionally distinct compartments of the pancreas that have traditionally been studied as separate entities. However, studies of embryonic development, adult physiology, and disease pathogenesis suggest there may be critical communication between exocrine and endocrine cells. In fact, the incidence of the endocrine disease diabetes secondary to exocrine disease/dysfunction ranges from 25% to 80%, depending on the type and severity of the exocrine pathology. Therefore, it is necessary to investigate how exocrine-endocrine "crosstalk" may impact pancreatic function. In this article, we discuss common exocrine diseases, including cystic fibrosis, acute, hereditary, and chronic pancreatitis, and the impact of these exocrine diseases on endocrine function. Additionally, we review how obesity and fatty pancreas influence exocrine function and the impact on cellular communication between the exocrine and endocrine compartments. Interestingly, in all pathologies, there is evidence that signals from the exocrine disease contribute to endocrine dysfunction and the progression to diabetes. Continued research efforts to identify the mechanisms that underlie the crosstalk between various cell types in the pancreas are critical to understanding normal pancreatic physiology as well as disease states. © 2024 American Physiological Society. Compr Physiol 14:5371-5387, 2024.
Collapse
Affiliation(s)
| | - Teresa L Mastracci
- Department of Biology, Indiana University Indianapolis, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA
| |
Collapse
|
32
|
Lu Y, Tian H, Peng H, Wang Q, Bunnell BA, Bazan NG, Hong S. Novel lipid mediator 7 S,14 R-docosahexaenoic acid: biogenesis and harnessing mesenchymal stem cells to ameliorate diabetic mellitus and retinal pericyte loss. Front Cell Dev Biol 2024; 12:1380059. [PMID: 38533089 PMCID: PMC10963555 DOI: 10.3389/fcell.2024.1380059] [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: 01/31/2024] [Accepted: 02/29/2024] [Indexed: 03/28/2024] Open
Abstract
Introduction: Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7S,14R-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid (7S,14R-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7S,14R-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic db/db mice. Methods: MSCs treated with 7S,14R-diHDHA were delivered into db/db mice i.v. every 5 days for 35 days. Results: Blood glucose levels in diabetic mice were lowered by 7S,14R-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7S,14R-diHDHA-treated MSCs increased insulin+ β-cell ratio and decreased glucogan+ α-cell ratio in islets, as well as reduced macrophages in pancreas. 7S,14R-diHDHA induced MSC functions in promoting MIN6 β-cell viability and insulin secretion. 7S,14R-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7S,14R-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in db/db mice. Discussion: Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7S,14R-diHDHA-primed MSCs.
Collapse
Affiliation(s)
- Yan Lu
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| | - Haibin Tian
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Tongji University, Shanghai, China
| | - Hongying Peng
- Biostatistics, Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Quansheng Wang
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Bruce A. Bunnell
- Tulane University School of Medicine, Center for Stem Cell Research and Regenerative Medicine, New Orleans, LA, United States
| | - Nicolas G. Bazan
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Department of Ophthalmology, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| | - Song Hong
- Neuroscience Center of Excellence, School of Medicine, L.S.U. Health, New Orleans, LA, United States
- Department of Ophthalmology, School of Medicine, L.S.U. Health, New Orleans, LA, United States
| |
Collapse
|
33
|
González I, Lindner C, Schneider I, Diaz E, Morales MA, Rojas A. Emerging and multifaceted potential contributions of polyphenols in the management of type 2 diabetes mellitus. World J Diabetes 2024; 15:154-169. [PMID: 38464365 PMCID: PMC10921170 DOI: 10.4239/wjd.v15.i2.154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 12/16/2023] [Accepted: 01/19/2024] [Indexed: 02/04/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is recognized as a serious public health concern with a considerable impact on human life, long-term health expenditures, and substantial health losses. In this context, the use of dietary polyphenols to prevent and manage T2DM is widely documented. These dietary compounds exert their beneficial effects through several actions, including the protection of pancreatic islet β-cell, the antioxidant capacities of these molecules, their effects on insulin secretion and actions, the regulation of intestinal microbiota, and their contribution to ameliorate diabetic complications, particularly those of vascular origin. In the present review, we intend to highlight these multifaceted actions and the molecular mechanisms by which these plant-derived secondary metabolites exert their beneficial effects on type 2 diabetes patients.
Collapse
Affiliation(s)
- Ileana González
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile
| | - Cristian Lindner
- Department of Radiology, Faculty of Medicine, University of Concepción, Concepción 4030000, Chile
| | - Ivan Schneider
- Centre of Primary Attention, South Metropolitan Health Service, Santiago 3830000, Chile
| | - Erik Diaz
- Faculty of Medicine, Catholic University of Maule, Talca 3460000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
| | - Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile
| |
Collapse
|
34
|
Farrim MI, Gomes A, Milenkovic D, Menezes R. Gene expression analysis reveals diabetes-related gene signatures. Hum Genomics 2024; 18:16. [PMID: 38326874 PMCID: PMC10851551 DOI: 10.1186/s40246-024-00582-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 02/01/2024] [Indexed: 02/09/2024] Open
Abstract
BACKGROUND Diabetes is a spectrum of metabolic diseases affecting millions of people worldwide. The loss of pancreatic β-cell mass by either autoimmune destruction or apoptosis, in type 1-diabetes (T1D) and type 2-diabetes (T2D), respectively, represents a pathophysiological process leading to insulin deficiency. Therefore, therapeutic strategies focusing on restoring β-cell mass and β-cell insulin secretory capacity may impact disease management. This study took advantage of powerful integrative bioinformatic tools to scrutinize publicly available diabetes-associated gene expression data to unveil novel potential molecular targets associated with β-cell dysfunction. METHODS A comprehensive literature search for human studies on gene expression alterations in the pancreas associated with T1D and T2D was performed. A total of 6 studies were selected for data extraction and for bioinformatic analysis. Pathway enrichment analyses of differentially expressed genes (DEGs) were conducted, together with protein-protein interaction networks and the identification of potential transcription factors (TFs). For noncoding differentially expressed RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which exert regulatory activities associated with diabetes, identifying target genes and pathways regulated by these RNAs is fundamental for establishing a robust regulatory network. RESULTS Comparisons of DEGs among the 6 studies showed 59 genes in common among 4 or more studies. Besides alterations in mRNA, it was possible to identify differentially expressed miRNA and lncRNA. Among the top transcription factors (TFs), HIPK2, KLF5, STAT1 and STAT3 emerged as potential regulators of the altered gene expression. Integrated analysis of protein-coding genes, miRNAs, and lncRNAs pointed out several pathways involved in metabolism, cell signaling, the immune system, cell adhesion, and interactions. Interestingly, the GABAergic synapse pathway emerged as the only common pathway to all datasets. CONCLUSIONS This study demonstrated the power of bioinformatics tools in scrutinizing publicly available gene expression data, thereby revealing potential therapeutic targets like the GABAergic synapse pathway, which holds promise in modulating α-cells transdifferentiation into β-cells.
Collapse
Affiliation(s)
- M I Farrim
- CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Universidade Lusófona, Lisbon, Portugal
- Universidad de Alcalá, Escuela de Doctorado, Madrid, Spain
| | - A Gomes
- CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Universidade Lusófona, Lisbon, Portugal
| | - D Milenkovic
- Department of Nutrition, University of California Davis, Davis, USA
| | - R Menezes
- CBIOS, Universidade Lusófona's Research Center for Biosciences & Health Technologies, Universidade Lusófona, Lisbon, Portugal.
| |
Collapse
|
35
|
Chen Z, Shi N, Xing C, Zou Y, Zhang Y, Chen Z, Wu F, Jin H, Chen R, Dai M. A novel clinical model for risk prediction and stratification of new-onset diabetes mellitus after distal pancreatectomy. Hepatobiliary Surg Nutr 2023; 12:868-881. [PMID: 38115946 PMCID: PMC10727825 DOI: 10.21037/hbsn-22-382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 12/21/2022] [Indexed: 12/21/2023]
Abstract
Background The incidence of new-onset diabetes mellitus (NODM) after distal pancreatectomy (DP) remains high. Few studies have focused on NODM in patients with pancreatic benign or low-grade malignant lesions (PBLML). This study aimed to develop and validate an effective clinical model for risk prediction and stratification of NODM after DP in patients with PBLML. Methods A follow-up survey was conducted to investigate NODM in patients without preoperative DM who underwent DP. Four hundred and forty-eight patients from Peking Union Medical College Hospital (PUMCH) and 178 from Guangdong Provincial People's Hospital (GDPH) met the inclusion criteria. They constituted the training cohort and the validation cohort, respectively. Univariate and multivariate Cox regression, as well as least absolute shrinkage and selection operator (LASSO) analyses, were used to identify the independent risk factors. The nomogram was constructed and verified. Concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curves, and decision curve analysis (DCA) were applied to assess its predictive performance and clinical utility. Accordingly, the optimal cut-off point was determined by maximally selected rank statistics method, and the cumulative risk curves for the high- and low-risk populations were plotted to evaluate the discrimination ability of the nomogram. Results The median follow-up duration was 42.8 months in the PUMCH cohort and 42.9 months in the GDPH cohort. The postoperative cumulative 5-year incidences of DM were 29.1% and 22.1%, respectively. Age, body mass index (BMI), length of pancreatic resection, intraoperative blood loss, and concomitant splenectomy were significant risk factors. The nomogram demonstrated significant predictive utility for post-pancreatectomy DM. The C-indexes of the nomogram were 0.739 and 0.719 in the training and validation cohorts, respectively. ROC curves demonstrated the predictive accuracy of the nomogram, and the calibration curves revealed that prediction results were in general agreement with the actual results. The considerable clinical applicability of the nomogram was certified by DCA. The optimal cut-off point for risk prediction value was 2.88, and the cumulative risk curves of each cohort showed significant differences between the high- and low-risk groups. Conclusions The nomogram could predict and identify the NODM risk population, and provide guidance to physicians in monitoring and controlling blood glucose levels in PBLML patients after DP.
Collapse
Affiliation(s)
- Zhihong Chen
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Medical College of Shantou University, Shantou, China
| | - Ning Shi
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Cheng Xing
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- National Translational Medicine of China, Beijing, China
- Department of General Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yiping Zou
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
- Medical College of Shantou University, Shantou, China
| | - Yuanpeng Zhang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Zhenrong Chen
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Fan Wu
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Haosheng Jin
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Rufu Chen
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
| | - Menghua Dai
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- National Translational Medicine of China, Beijing, China
| |
Collapse
|
36
|
Xu N, Liu S, Zhang Y, Chen Y, Zuo Y, Tan X, Liao B, Li P, Feng J. Oxidative stress signaling in the pathogenesis of diabetic cardiomyopathy and the potential therapeutic role of antioxidant naringenin. Redox Rep 2023; 28:2246720. [PMID: 37747066 PMCID: PMC10538464 DOI: 10.1080/13510002.2023.2246720] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/26/2023] Open
Abstract
Diabetes mellitus (DM) is one of the most prevalent metabolic disorders that poses a global threat to human health. It can lead to complications in multiple organs and tissues, owing to its wide-ranging impact on the human body. Diabetic cardiomyopathy (DCM) is a specific cardiac manifestation of DM, which is characterized by heart failure in the absence of coronary heart disease, hypertension and valvular heart disease. Given that oxidative stress is a key factor in the pathogenesis of DCM, intervening to mitigate oxidative stress may serve as a therapeutic strategy for managing DCM. Naringenin is a natural product with anti-oxidative stress properties that can suppress oxidative damage by regulating various oxidative stress signaling pathways. In this review, we address the relationship between oxidative stress and its primary signaling pathways implicated in DCM, and explores the therapeutic potential of naringenin in DCM.
Collapse
Affiliation(s)
- Nan Xu
- Department of Cardiology, The First People's Hospital of Neijiang, Neijiang, People’s Republic of China
| | - Siqi Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Yongqiang Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Yujing Chen
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Yumei Zuo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Xiaoqiu Tan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Bin Liao
- Department of Cardiovascular Surgery, The Affiliated Hospital of Southwest Medical University, Metabolic Vascular Diseases Key Laboratory of Sichuan Province, Luzhou, People’s Republic of China
| | - Pengyun Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, People’s Republic of China
| |
Collapse
|
37
|
Rojas-Espinosa O, Arce-Mendoza AY, Islas-Trujillo S, Muñiz-Buenrostro A, Arce-Paredes P, Popoca-Galván O, Moreno-Altamirano B, Rivero Silva M. Necrosis, netosis, and apoptosis in pulmonary tuberculosis and type-2 diabetes mellitus. Clues from the patient's serum. Tuberculosis (Edinb) 2023; 143:102426. [PMID: 38180029 DOI: 10.1016/j.tube.2023.102426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/17/2023] [Accepted: 10/22/2023] [Indexed: 01/06/2024]
Abstract
Pulmonary tuberculosis (PTB) and type 2 diabetes mellitus (T2DM) are two inflammatory diseases whose pathology involves neutrophils (NEU) as key participants. Countless inflammatory elements produced at the lesion sites leak into the blood and are distributed systemically. The study aimed to investigate the effect of the serum of patients with PTB, T2DM, and PTB + T2DM on the cellular and nuclear morphology of healthy NEU. Monolayers of NEU were prepared and incubated with sera from PTB (n꓿ 10), T2DM (n꓿10), PTB + T2DM (n꓿ 10) patients, or sera from healthy people (n = 10). Monolayers were stained for histones, elastase, and myeloperoxidase for NETosis, annexin V for apoptosis, and Iris fuchsia for necrosis. Hoechst stain (DNA) was used to identify the nuclear alterations. Necrosis was the predominant alteration. Sera from PTB + T2DM were the most potent change inducers. Normal sera did not induce cell alterations. The blood of TBP and T2DM patients carries a myriad of abnormal elements that induce necrosis of NEU in normal people, thus reflecting what might occur in the neutrophils of the patients themselves. These findings reinforce the participation of NEU in the pathology of these diseases. Necrosis is expected to be the most frequent neutrophil-induced alteration in tuberculosis and diabetes mellitus.
Collapse
Affiliation(s)
- Oscar Rojas-Espinosa
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11340, Ciudad de México, Mexico.
| | - Alma Yolanda Arce-Mendoza
- Departamento de Inmunología, Facultad de Medicina, Universidad Autónoma de Nuevo León, 64460, Monterrey, Mexico.
| | - Sergio Islas-Trujillo
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11340, Ciudad de México, Mexico.
| | - Antonio Muñiz-Buenrostro
- Departamento de Inmunología, Facultad de Medicina, Universidad Autónoma de Nuevo León, 64460, Monterrey, Mexico.
| | - Patricia Arce-Paredes
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11340, Ciudad de México, Mexico.
| | - Omar Popoca-Galván
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11340, Ciudad de México, Mexico.
| | - Bertha Moreno-Altamirano
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11340, Ciudad de México, Mexico.
| | - Miguel Rivero Silva
- Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, 11340, Ciudad de México, Mexico.
| |
Collapse
|
38
|
Xue D, Narisu N, Taylor DL, Zhang M, Grenko C, Taylor HJ, Yan T, Tang X, Sinha N, Zhu J, Vandana JJ, Nok Chong AC, Lee A, Mansell EC, Swift AJ, Erdos MR, Zhong A, Bonnycastle LL, Zhou T, Chen S, Collins FS. Functional interrogation of twenty type 2 diabetes-associated genes using isogenic human embryonic stem cell-derived β-like cells. Cell Metab 2023; 35:1897-1914.e11. [PMID: 37858332 PMCID: PMC10841752 DOI: 10.1016/j.cmet.2023.09.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/26/2023] [Accepted: 09/28/2023] [Indexed: 10/21/2023]
Abstract
Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional roles of many loci remain unexplored. Here, we engineered isogenic knockout human embryonic stem cell lines for 20 genes associated with T2D risk. We examined the impacts of each knockout on β cell differentiation, functions, and survival. We generated gene expression and chromatin accessibility profiles on β cells derived from each knockout line. Analyses of T2D-association signals overlapping HNF4A-dependent ATAC peaks identified a likely causal variant at the FAIM2 T2D-association signal. Additionally, the integrative association analyses identified four genes (CP, RNASE1, PCSK1N, and GSTA2) associated with insulin production, and two genes (TAGLN3 and DHRS2) associated with β cell sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental line and identified a single likely functional variant at each of 23 T2D-association signals.
Collapse
Affiliation(s)
- Dongxiang Xue
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Narisu Narisu
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - D Leland Taylor
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Meili Zhang
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Caleb Grenko
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Henry J Taylor
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA; Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, CB1 8RN Cambridge, UK
| | - Tingfen Yan
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Xuming Tang
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Neelam Sinha
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jiajun Zhu
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - J Jeya Vandana
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Medicine, The Rockefeller University, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Angie Chi Nok Chong
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Angela Lee
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Erin C Mansell
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Amy J Swift
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Michael R Erdos
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Aaron Zhong
- Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Lori L Bonnycastle
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Ting Zhou
- Stem Cell Research Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
| | - Francis S Collins
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| |
Collapse
|
39
|
Bahar M, Demirci N, Bahar L, Şahin L. The effect of swimming and running exercises on oxidant-antioxidant and lipid profiles in streptozotocin-induced diabetic rats. Hippokratia 2023; 27:148-154. [PMID: 39372322 PMCID: PMC11451506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Background Lifestyle changes in Diabetes Mellitus (DM) positively affect blood glucose and all risk factors. This study aims to determine the effect of swimming and running exercises on oxidant-antioxidant and lipid profiles in streptozotocin (STZ)-induced type 1 diabetic and non-diabetic rats. Methods We included forty-eight adult male Wistar albino rats in this study, and we randomly classified them into six groups (eight per group). The groups were organized as Control Sedentary, Control Exercise-swimming, Control Exercise-running (CE-r), Diabetes Sedentary (DS), Diabetes Exercise-swimming (DE-s), and Diabetes Exercise running (DE-r). Half of these rats were subjected to experimental diabetes via STZ. We evaluated total oxidant capacity (TOC), total antioxidant capacity (TAC), superoxide dismutase (SOD), and as lipid parameters: high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides. The rats were sacrificed at the end of the four weeks. Results We found a significant difference between DE-s and DE-r groups in terms of TOC (p =0.043) and SOD (p =0.030). The highest TAC was found in the CE-r group, and the highest TOC was found in the DS group. Exercise significantly reduced LDL levels. There was no significant difference between the DE-s and DE-r groups (p =0.084) for lipid profiles (HDL). Conclusion Based on the lower TOC (oxidant) and higher SOD (antioxidant) levels in the diabetic running group, these results suggest that running may be more beneficial than swimming for diabetics. HIPPOKRATIA 2023, 27 (4):148-154.
Collapse
Affiliation(s)
- M Bahar
- Institute of Education Sciences, Faculty of Sports Sciences, Mersin University, Mersin, Türkiye
| | - N Demirci
- Department of Coaching, Faculty of Sports Sciences, Mersin University, Mersin, Türkiye
| | - L Bahar
- Department of Stem Cell and Regenerative Medicine,Health Sciences Institute, Mersin University, Mersin, Türkiye
| | - L Şahin
- Department of Physiology, Faculty of Medicine, Mersin University, Mersin, Türkiye
| |
Collapse
|
40
|
Sarkar S, Elliott EC, Henry HR, Ludovico ID, Melchior JT, Frazer-Abel A, Webb-Robertson BJ, Davidson WS, Holers VM, Rewers MJ, Metz TO, Nakayasu ES. Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response. Clin Proteomics 2023; 20:38. [PMID: 37735622 PMCID: PMC10512508 DOI: 10.1186/s12014-023-09429-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 08/25/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development. METHODS This systematic review was registered with Open Science Framework ( https://doi.org/10.17605/OSF.IO/N8TSA ). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria. RESULTS A total of 13 studies met our inclusion criteria, resulting in the identification of 266 unique proteins, with 31 (11.6%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found 2 subsets: 17 proteins (C3, C1R, C8G, C4B, IBP2, IBP3, ITIH1, ITIH2, BTD, APOE, TETN, C1S, C6A3, SAA4, ALS, SEPP1 and PI16) and 3 proteins (C3, CLUS and C4A) have consistent regulation in at least 2 independent studies at post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development. CONCLUSIONS Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays.
Collapse
Affiliation(s)
- Soumyadeep Sarkar
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Emily C Elliott
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Hayden R Henry
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Ivo Díaz Ludovico
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - John T Melchior
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ashley Frazer-Abel
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | | | - W Sean Davidson
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - V Michael Holers
- Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Marian J Rewers
- Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Thomas O Metz
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Ernesto S Nakayasu
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
| |
Collapse
|
41
|
Xie Q, Zhang X, Zhou Q, Xu Y, Sun L, Wen Q, Wang W, Chen Q. Antioxidant and anti-inflammatory properties of ginsenoside Rg1 for hyperglycemia in type 2 diabetes mellitus: systematic reviews and meta-analyses of animal studies. Front Pharmacol 2023; 14:1179705. [PMID: 37745069 PMCID: PMC10514510 DOI: 10.3389/fphar.2023.1179705] [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: 03/04/2023] [Accepted: 08/02/2023] [Indexed: 09/26/2023] Open
Abstract
Background: According to existing laboratory data, ginsenoside Rg1 may help cure diabetes and its complications by reducing oxidative stress (OS) and managing inflammation. However, this conclusion lacks reliability and is unclear. As a result, the purpose of this systematic review and meta-analysis was to evaluate the antioxidant and anti-inflammatory effects of ginsenoside Rg1 in the treatment of diabetes and its complications. Methods: We searched for relevant studies published through December 2022, including electronic bibliographic databases such as PubMed, EMBASE, Web of Science, CNKI, and Wanfang. The SYstematic Review Center for Laboratory Animal Experimentation Risk of Bias (SYRCLE RoB) tool was used to conduct a meta-analysis to assess the methodological quality of animal research. The meta-analysis was conducted using RevMan5.4 software, following the Cochrane Handbook for Systematic Reviews of Interventions. This study is registered in the International Systems Review Prospective Registry (PROSPERO) as CRD42023386830. Results: Eighteen eligible studies involving 401 animals were included. Ginsenoside Rg1 was significantly correlated with blood glucose (BG), insulin levels, body weight, superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels. In addition, according to subgroup analysis, the hypoglycemic, anti-inflammatory, and antioxidant effects of ginsenoside Rg1 in type 2 diabetic animals were not affected by experimental species, modeling, experimental drug dosage, or course of treatment. Conclusion: This meta-analysis presents a summary of the hypoglycemic effects of ginsenoside Rg1, which are achieved through anti-inflammatory and antioxidant mechanisms. These findings provide evidence-based support for the medical efficacy of ginsenoside Rg1. Specifically, ginsenoside Rg1 reduced MDA levels and restored SOD activity to exert its antioxidant activity. It had a positive effect on the reduction of IL-6 and TNF-α levels. However, the inclusion of studies with low methodological quality and the presence of publication bias may undermine the validity of the results. Further investigation with a more rigorous experimental design and comprehensive studies is necessary to fully understand the specific glycemic mechanisms of ginsenosides. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier https://CRD42023386830.
Collapse
Affiliation(s)
- Qian Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoran Zhang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qian Zhou
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yumei Xu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lisha Sun
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qing Wen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wei Wang
- School of Biomedical Sciences, Mianyang Normal University, Mianyang, China
| | - Qiu Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| |
Collapse
|
42
|
El Azab EF, Alakilli SYM, Saleh AM, Alhassan HH, Alanazi HH, Ghanem HB, Yousif SO, Alrub HA, Anber N, Elfaki EM, Hamza A, Abdulmalek S. Actinidia deliciosa Extract as a Promising Supplemental Agent for Hepatic and Renal Complication-Associated Type 2 Diabetes (In Vivo and In Silico-Based Studies). Int J Mol Sci 2023; 24:13759. [PMID: 37762060 PMCID: PMC10530616 DOI: 10.3390/ijms241813759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/27/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Type 2 diabetes (T2D) is a chronic metabolic condition associated with obesity, oxidative stress-mediated inflammation, apoptosis, and impaired insulin signaling. The utilization of phytochemical therapy generated from plants has emerged as a promising approach for the treatment of diabetes and its complications. Kiwifruit is recognized for its substantial content of antioxidative phenolics. Therefore, this work aimed to examine the effect of Actinidia deliciosa (kiwi fruit) on hepatorenal damage in a high-fat diet (HFD) and streptozotocin (STZ)-induced T2D in rats using in vivo and in silico analyses. An increase in hepatic and renal lipid peroxidation was observed in diabetic rats accompanied by a decrease in antioxidant status. Furthermore, it is important to highlight that there were observable inflammatory and apoptotic responses in the hepatic and renal organs of rats with diabetes, along with a dysregulation of the phosphorylation levels of mammalian target of rapamycin (mTOR), protein kinase B (Akt), and phosphoinositide 3-kinase (PI3K) signaling proteins. However, the administration of kiwi extract to diabetic rats alleviated hepatorenal dysfunction, inflammatory processes, oxidative injury, and apoptotic events with activation of the insulin signaling pathway. Furthermore, molecular docking and dynamic simulation studies revealed quercetin, chlorogenic acid, and melezitose as components of kiwi extract that docked well with potential as effective natural products for activating the silent information regulator 1(SIRT-1) pathway. Furthermore, phenolic acids in kiwi extract, especially syringic acid, P-coumaric acid, caffeic acid, and ferulic acid, have the ability to inhibit the phosphatase and tensin homolog (PTEN) active site. In conclusion, it can be argued that kiwi extract may present a potentially beneficial adjunctive therapy approach for the treatment of diabetic hepatorenal complications.
Collapse
Affiliation(s)
- Eman Fawzy El Azab
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences at Al-Qurayyat, Jouf University, Al-Qurayyat 77454, Saudi Arabia; (H.H.A.); (S.O.Y.); (H.A.A.); (E.M.E.); (A.H.)
| | - Saleha Y. M. Alakilli
- Department of Biological Sciences, Faculty of Sciences, King Abdulaziz University, Jeddah 23761, Saudi Arabia;
| | - Abdulrahman M. Saleh
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt;
| | - Hassan H. Alhassan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72341, Saudi Arabia; (H.H.A.); (H.B.G.)
| | - Hamad H. Alanazi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences at Al-Qurayyat, Jouf University, Al-Qurayyat 77454, Saudi Arabia; (H.H.A.); (S.O.Y.); (H.A.A.); (E.M.E.); (A.H.)
| | - Heba Bassiony Ghanem
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, Sakaka 72341, Saudi Arabia; (H.H.A.); (H.B.G.)
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt
| | - Sara Osman Yousif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences at Al-Qurayyat, Jouf University, Al-Qurayyat 77454, Saudi Arabia; (H.H.A.); (S.O.Y.); (H.A.A.); (E.M.E.); (A.H.)
- Department of Clinical Chemistry, Faculty of medical Laboratory Sciences, Sudan University of Science and Technology, Khartoum 13311, Sudan
| | - Heba Abu Alrub
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences at Al-Qurayyat, Jouf University, Al-Qurayyat 77454, Saudi Arabia; (H.H.A.); (S.O.Y.); (H.A.A.); (E.M.E.); (A.H.)
| | - Nahla Anber
- Emergency Hospital, Mansoura University, Mansoura 35516, Egypt;
| | - Elyasa Mustafa Elfaki
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences at Al-Qurayyat, Jouf University, Al-Qurayyat 77454, Saudi Arabia; (H.H.A.); (S.O.Y.); (H.A.A.); (E.M.E.); (A.H.)
| | - Alneil Hamza
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences at Al-Qurayyat, Jouf University, Al-Qurayyat 77454, Saudi Arabia; (H.H.A.); (S.O.Y.); (H.A.A.); (E.M.E.); (A.H.)
| | - Shaymaa Abdulmalek
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt;
| |
Collapse
|
43
|
Taldaev A, Savina AD, Olicheva VV, Ivanov SV, Terekhov RP, Ilyasov IR, Zhevlakova AK, Selivanova IA. Protective Properties of Spheroidal Taxifolin Form in Streptozotocin-Induced Diabetic Rats. Int J Mol Sci 2023; 24:11962. [PMID: 37569337 PMCID: PMC10418707 DOI: 10.3390/ijms241511962] [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: 06/20/2023] [Revised: 07/19/2023] [Accepted: 07/23/2023] [Indexed: 08/13/2023] Open
Abstract
One of the key factors in the pathogenesis of diabetes and its complications is oxidative stress. To inhibit this process, antioxidants may be helpful. Herein, we focused on the protective properties of taxifolin spheroidal form (TS) in the streptozotocin rat model of diabetes mellitus. After 4 weeks of treatment with TS, the fasting blood glucose level of the diabetic animals decreased by 12% compared with the level right after the injection of streptozotocin. While the feed intake in the untreated diabetic rats increased by 5.3% compared with the healthy group, the TS-treated group showed a pronounced 15.3% decrease. Therapeutic administration of TS has a protective effect on the pancreas and the liver against the cytotoxic action of streptozotocin. The plasma antioxidant capacity of all diabetic groups appeared to be approximately 15% lower than in healthy rats with no significant difference between the TS-treated and untreated diabetic animals. Apparently, this can be attributed to taxifolin and plasma proteins binding. These data demonstrate the potential of TS in antidiabetic therapy.
Collapse
Affiliation(s)
- Amir Taldaev
- Laboratory of Nanobiotechnology, Institute of Biomedical Chemistry, Pogodinskaya Str. 10/8, 119121 Moscow, Russia
| | - Anastasiya D. Savina
- Nelubin Institute of Pharmacy, Sechenov First Moscow State Medical University, Trubetskaya Str. 8/2, 119991 Moscow, Russia
| | - Vera V. Olicheva
- Nelubin Institute of Pharmacy, Sechenov First Moscow State Medical University, Trubetskaya Str. 8/2, 119991 Moscow, Russia
| | - Sergey V. Ivanov
- Laboratory of Psychopharmacology, V.V. Zakusov Research Institute of Pharmacology, 125315 Moscow, Russia
| | - Roman P. Terekhov
- Nelubin Institute of Pharmacy, Sechenov First Moscow State Medical University, Trubetskaya Str. 8/2, 119991 Moscow, Russia
| | - Igor R. Ilyasov
- Nelubin Institute of Pharmacy, Sechenov First Moscow State Medical University, Trubetskaya Str. 8/2, 119991 Moscow, Russia
| | - Anastasiya K. Zhevlakova
- Nelubin Institute of Pharmacy, Sechenov First Moscow State Medical University, Trubetskaya Str. 8/2, 119991 Moscow, Russia
| | - Irina A. Selivanova
- Nelubin Institute of Pharmacy, Sechenov First Moscow State Medical University, Trubetskaya Str. 8/2, 119991 Moscow, Russia
| |
Collapse
|
44
|
Matson K, Macleod A, Mehta N, Sempek E, Tang X. Impacts of MicroRNA-483 on Human Diseases. Noncoding RNA 2023; 9:37. [PMID: 37489457 PMCID: PMC10366739 DOI: 10.3390/ncrna9040037] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/13/2023] [Accepted: 06/21/2023] [Indexed: 07/26/2023] Open
Abstract
MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate gene expression by targeting specific messenger RNAs (mRNAs) in distinct cell types. This review provides a com-prehensive overview of the current understanding regarding the involvement of miR-483-5p and miR-483-3p in various physiological and pathological processes. Downregulation of miR-483-5p has been linked to numerous diseases, including type 2 diabetes, fatty liver disease, diabetic nephropathy, and neurological injury. Accumulating evidence indicates that miR-483-5p plays a crucial protective role in preserving cell function and viability by targeting specific transcripts. Notably, elevated levels of miR-483-5p in the bloodstream strongly correlate with metabolic risk factors and serve as promising diagnostic markers. Consequently, miR-483-5p represents an appealing biomarker for predicting the risk of developing diabetes and cardiovascular diseases and holds potential as a therapeutic target for intervention strategies. Conversely, miR-483-3p exhibits significant upregulation in diabetes and cardiovascular diseases and has been shown to induce cellular apoptosis and lipotoxicity across various cell types. However, some discrepancies regarding its precise function have been reported, underscoring the need for further investigation in this area.
Collapse
Affiliation(s)
| | | | | | | | - Xiaoqing Tang
- Department of Biological Sciences, Michigan Technological University, Houghton, MI 49931, USA; (K.M.); (A.M.); (N.M.); (E.S.)
| |
Collapse
|
45
|
Xue D, Narisu N, Taylor DL, Zhang M, Grenko C, Taylor HJ, Yan T, Tang X, Sinha N, Zhu J, Vandana JJ, Chong ACN, Lee A, Mansell EC, Swift AJ, Erdos MR, Zhou T, Bonnycastle LL, Zhong A, Chen S, Collins FS. Functional interrogation of twenty type 2 diabetes-associated genes using isogenic hESC-derived β-like cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.07.539774. [PMID: 37214922 PMCID: PMC10197532 DOI: 10.1101/2023.05.07.539774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Genetic studies have identified numerous loci associated with type 2 diabetes (T2D), but the functional role of many loci has remained unexplored. In this study, we engineered isogenic knockout human embryonic stem cell (hESC) lines for 20 genes associated with T2D risk. We systematically examined β-cell differentiation, insulin production and secretion, and survival. We performed RNA-seq and ATAC-seq on hESC-β cells from each knockout line. Analyses of T2D GWAS signals overlapping with HNF4A-dependent ATAC peaks identified a specific SNP as a likely causal variant. In addition, we performed integrative association analyses and identified four genes ( CP, RNASE1, PCSK1N and GSTA2 ) associated with insulin production, and two genes ( TAGLN3 and DHRS2 ) associated with sensitivity to lipotoxicity. Finally, we leveraged deep ATAC-seq read coverage to assess allele-specific imbalance at variants heterozygous in the parental hESC line, to identify a single likely functional variant at each of 23 T2D GWAS signals.
Collapse
|
46
|
Zhang S, Zhao J, Wu M, Zhou Y, Wu X, Du A, Tao Y, Huang S, Cai S, Zhou M, Wei T, Zhang Y, Xie L, Wu Y, Xiao J. Over-activation of TRPM2 ion channel accelerates blood-spinal cord barrier destruction in diabetes combined with spinal cord injury rat. Int J Biol Sci 2023; 19:2475-2494. [PMID: 37215981 PMCID: PMC10197895 DOI: 10.7150/ijbs.80672] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Accepted: 04/24/2023] [Indexed: 05/24/2023] Open
Abstract
Spinal cord injury (SCI) is a devastating neurological disorder that often results in loss of motor and sensory function. Diabetes facilitates the blood-spinal cord barrier (BSCB) destruction and aggravates SCI recovery. However, the molecular mechanism underlying it is still unclear. Our study has focused on transient receptor potential melastatin 2 (TRPM2) channel and investigated its regulatory role on integrity and function of BSCB in diabetes combined with SCI rat. We have confirmed that diabetes is obviously not conductive to SCI recovery through accelerates BSCB destruction. Endothelial cells (ECs) are the important component of BSCB. It was observed that diabetes significantly worsens mitochondrial dysfunction and triggers excessive apoptosis of ECs in spinal cord from SCI rat. Moreover, diabetes impeded neovascularization in spinal cord from SCI rat with decreases of VEGF and ANG1. TRPM2 acts as a cellular sensor of ROS. Our mechanistic studies showed that diabetes significantly induces elevated ROS level to activate TRPM2 ion channel of ECs. Then, TRPM2 channel mediated the Ca2+ influx and subsequently activated p-CaMKII/eNOS pathway, and which in turn triggered the ROS production. Consequently, over-activation of TRPM2 ion channel results in excessive apoptosis and weaker angiogenesis during SCI recovery. Inhibition of TRPM2 with 2-Aminoethyl diphenylborinate (2-APB) or TRPM2 siRNA will ameliorate the apoptosis of ECs and promote angiogenesis, subsequently enhance BSCB integrity and improve the locomotor function recovery of diabetes combined with SCI rat. In conclusion, TRPM2 channel may be a key target for the treatment of diabetes combined with SCI rat.
Collapse
Affiliation(s)
- Susu Zhang
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Jiaxin Zhao
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Man Wu
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yongxiu Zhou
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Xuejuan Wu
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Anyu Du
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yibing Tao
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Shanshan Huang
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Shufang Cai
- The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Wenzhou University, Wenzhou, 325035, China
| | - Mei Zhou
- The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Wenzhou University, Wenzhou, 325035, China
| | - Tao Wei
- The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Wenzhou University, Wenzhou, 325035, China
| | - Yanren Zhang
- The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Wenzhou University, Wenzhou, 325035, China
| | - Ling Xie
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| | - Yanqing Wu
- The Institute of Life Sciences, Engineering Laboratory of Zhejiang Province for Pharmaceutical Development of Growth Factors, Wenzhou University, Wenzhou, 325035, China
| | - Jian Xiao
- Department of Wound Healing, The First Affiliated Hospital and School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325000, China
| |
Collapse
|
47
|
Masenga SK, Kabwe LS, Chakulya M, Kirabo A. Mechanisms of Oxidative Stress in Metabolic Syndrome. Int J Mol Sci 2023; 24:7898. [PMID: 37175603 PMCID: PMC10178199 DOI: 10.3390/ijms24097898] [Citation(s) in RCA: 214] [Impact Index Per Article: 107.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 04/24/2023] [Accepted: 04/25/2023] [Indexed: 05/15/2023] Open
Abstract
Metabolic syndrome is a cluster of conditions associated with the risk of diabetes mellitus type 2 and cardiovascular diseases (CVDs). Metabolic syndrome is closely related to obesity. Increased adiposity promotes inflammation and oxidative stress, which are precursors of various complications involving metabolic syndrome components, namely insulin resistance, hypertension, and hyperlipidemia. An increasing number of studies confirm the importance of oxidative stress and chronic inflammation in the etiology of metabolic syndrome. However, few studies have reviewed the mechanisms underlying the role of oxidative stress in contributing to metabolic syndrome. In this review, we highlight mechanisms by which reactive oxygen species (ROS) increase mitochondrial dysfunction, protein damage, lipid peroxidation, and impair antioxidant function in metabolic syndrome. Biomarkers of oxidative stress can be used in disease diagnosis and evaluation of severity.
Collapse
Affiliation(s)
- Sepiso K. Masenga
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Livingstone P.O. Box 60009, Zambia
- Department of Medicine, Room 536 Robinson Research Building, Vanderbilt University Medical Centre, Nashville, TN 37232-6602, USA
| | - Lombe S. Kabwe
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Livingstone P.O. Box 60009, Zambia
| | - Martin Chakulya
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Livingstone P.O. Box 60009, Zambia
| | - Annet Kirabo
- Department of Medicine, Room 536 Robinson Research Building, Vanderbilt University Medical Centre, Nashville, TN 37232-6602, USA
| |
Collapse
|
48
|
Lichti CF, Wan X. Using mass spectrometry to identify neoantigens in autoimmune diseases: The type 1 diabetes example. Semin Immunol 2023; 66:101730. [PMID: 36827760 PMCID: PMC10324092 DOI: 10.1016/j.smim.2023.101730] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/24/2023]
Abstract
In autoimmune diseases, recognition of self-antigens presented by major histocompatibility complex (MHC) molecules elicits unexpected attack of tissue by autoantibodies and/or autoreactive T cells. Post-translational modification (PTM) may alter the MHC-binding motif or TCR contact residues in a peptide antigen, transforming the tolerance to self to autoreactivity. Mass spectrometry-based immunopeptidomics provides a valuable mechanism for identifying MHC ligands that contain PTMs and can thus provide valuable insights into pathogenesis and therapeutics of autoimmune diseases. A plethora of PTMs have been implicated in this process, and this review highlights their formation and identification.
Collapse
Affiliation(s)
- Cheryl F Lichti
- Department of Pathology and Immunology, Division of Immunobiology, The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8118, St. Louis, MO 63110, USA.
| | - Xiaoxiao Wan
- Department of Pathology and Immunology, Division of Immunobiology, The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, 660 S. Euclid Ave, Campus Box 8118, St. Louis, MO 63110, USA.
| |
Collapse
|
49
|
Sarkar S, Elliott EC, Henry HR, Ludovico ID, Melchior JT, Frazer-Abel A, Webb-Robertson BJ, Davidson WS, Holers VM, Rewers MJ, Metz TO, Nakayasu ES. Systematic review of type 1 diabetes biomarkers reveals regulation in circulating proteins related to complement, lipid metabolism, and immune response. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.02.21.23286132. [PMID: 36865103 PMCID: PMC9980237 DOI: 10.1101/2023.02.21.23286132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
Aims Type 1 diabetes (T1D) results from an autoimmune attack of the pancreatic β cells that progresses to dysglycemia and symptomatic hyperglycemia. Current biomarkers to track this evolution are limited, with development of islet autoantibodies marking the onset of autoimmunity and metabolic tests used to detect dysglycemia. Therefore, additional biomarkers are needed to better track disease initiation and progression. Multiple clinical studies have used proteomics to identify biomarker candidates. However, most of the studies were limited to the initial candidate identification, which needs to be further validated and have assays developed for clinical use. Here we curate these studies to help prioritize biomarker candidates for validation studies and to obtain a broader view of processes regulated during disease development. Methods This systematic review was registered with Open Science Framework (DOI 10.17605/OSF.IO/N8TSA). Using PRISMA guidelines, we conducted a systematic search of proteomics studies of T1D in the PubMed to identify putative protein biomarkers of the disease. Studies that performed mass spectrometry-based untargeted/targeted proteomic analysis of human serum/plasma of control, pre-seroconversion, post-seroconversion, and/or T1D-diagnosed subjects were included. For unbiased screening, 3 reviewers screened all the articles independently using the pre-determined criteria. Results A total of 13 studies met our inclusion criteria, resulting in the identification of 251 unique proteins, with 27 (11%) being identified across 3 or more studies. The circulating protein biomarkers were found to be enriched in complement, lipid metabolism, and immune response pathways, all of which are found to be dysregulated in different phases of T1D development. We found a subset of 3 proteins (C3, KNG1 & CFAH), 6 proteins (C3, C4A, APOA4, C4B, A2AP & BTD) and 7 proteins (C3, CLUS, APOA4, C6, A2AP, C1R & CFAI) have consistent regulation between multiple studies in samples from individuals at pre-seroconversion, post-seroconversion and post-diagnosis compared to controls, respectively, making them strong candidates for clinical assay development. Conclusions Biomarkers analyzed in this systematic review highlight alterations in specific biological processes in T1D, including complement, lipid metabolism, and immune response pathways, and may have potential for further use in the clinic as prognostic or diagnostic assays.
Collapse
|
50
|
Li W, Qiao J, Lin K, Sun P, Wang Y, Peng Q, Ye X, Liu W, Sun B. Ethyl-acetate fraction from a cinnamon-cortex extract protects pancreatic β-cells from oxidative stress damage. Front Pharmacol 2023; 14:1111860. [PMID: 36950010 PMCID: PMC10025376 DOI: 10.3389/fphar.2023.1111860] [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: 11/30/2022] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Background: The pathogenesis of diabetes mellitus is mediated mainly by oxidative stress produced by damaged pancreatic β-cells. We identified that an ethyl-acetate fraction (EA) from a cinnamon-cortex extract (CCE) is rich in flavonoid, and showed no toxicity to β cells. Objective: In this study, we evaluated the pharmacologic activities of EA on pancreatic β cells using a model of oxidative stress induced by H2O2 or alloxan. Results: The results showed that EA could significantly reduce reactive oxygen (ROS) accumulation to improve the survival of cells. Western blot showed that EA treatment upregulated expression of nuclear factor erythroid 2 related factor 2, heme oxygenase-1, and gamma glutamylcysteine synthetase. The same model study found that EA also can protect β cells against the apoptosis induced by oxidative stress. Furthermore, EA can enhance insulin secretion in rat and mouse β cell lines treated or not with alloxan or H2O2. The expression of the insulin transcription factor PDX-1 increased in an EA concentration-dependent manner. At last, the major functional compounds of EA analysis showed that three compounds, cinnamyl alcohol, coumarin, and cinnamic acid, had similar effects as EA. Conclusions: In sum, our data suggested that EA fraction from CCE can protect β cells from oxidative stress, and increase insulin secretion to improve the function of β cells. This function might be due to these three compounds found in EA. Our findings provide a theoretical basis and functional molecules for the use of CCE against diabetes mellitus.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Wei Liu
- *Correspondence: Binlian Sun, ; Wei Liu,
| | | |
Collapse
|