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Wang H, He S, Wang J, Qian X, Zhang B, Yang Z, Chen B, Li G, Gong Q, for the Da Qing Diabetes Prevention Outcome Study Group. Assessing and predicting type 2 diabetes risk with triglyceride glucose-body mass index in the Chinese nondiabetic population-Data from long-term follow-up of Da Qing IGT and Diabetes Study. J Diabetes 2024; 16:e70001. [PMID: 39364793 PMCID: PMC11450669 DOI: 10.1111/1753-0407.70001] [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: 02/03/2024] [Revised: 07/05/2024] [Accepted: 07/29/2024] [Indexed: 10/05/2024] Open
Abstract
AIMS We intended to characterize the superiority of triglyceride glucose-body mass index (TyG-BMI) in predicting type 2 diabetes mellitus (T2DM) compared with triglyceride glucose (TyG) and homeostatic model assessment for insulin resistance (HOMA-IR). METHODS A total of 699 nondiabetic participants in the Da Qing IGT and Diabetes Study were involved in the present analysis and classified according to the median of baseline TyG-BMI, namely the G1 (low TyG-BMI) and G2 (high TyG-BMI) groups. Information on developing diabetes was assessed from 1986 to 2020. RESULTS During the 34-year follow-up, after adjustment for confounders, the G2 group had a higher risk of developing type 2 diabetes than the G1 group (hazard ratio [HR]: 1.92, 95% confidence interval [CI]: 1.51-2.45, p < 0.0001). Restricted cubic spline analyses showed that increased TyG-BMI was linearly related to higher risks of type 2 diabetes (p for non-linearity>0.05). Time-dependent receiver operator characteristics curves suggested that TyG-BMI exhibited higher predictive ability than TyG (6-year: area under the curve [AUC]TyG-BMI vs. AUCTyG, 0.78 vs. 0.70, p = 0.03; 34-year: AUCTyG-BMI vs. AUCTyG, 0.79 vs. 0.73, p = 0.04) and HOMA-IR (6-year: AUCTyG-BMI vs. AUCHOMA-IR, 0.78 vs. 0.70, p = 0.07; 34-year: AUCTyG-BMI vs. AUCHOMA-IR, 0.79 vs. 0.71, p = 0.04) in both short and long terms, and the thresholds of TyG-BMI to predict type 2 diabetes were relatively stable (195.24-208.41) over the 34-year follow-up. CONCLUSIONS In this post hoc study, higher TyG-BMI was associated with an increased risk of type 2 diabetes and demonstrated better predictability than TyG and HOMA-IR, favoring the application of TyG-BMI as a potential tool for evaluating the risk of type 2 diabetes in clinical practice.
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Affiliation(s)
- Haixu Wang
- Center of Endocrinology, National Center of Cardiology &Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Siyao He
- Center of Endocrinology, National Center of Cardiology &Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Jinping Wang
- Department of CardiologyDa Qing Oilfield General HospitalDa QingChina
| | - Xin Qian
- Center of Endocrinology, National Center of Cardiology &Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Bo Zhang
- Department of EndocrinologyChina‐Japan Friendship HospitalBeijingChina
| | - Zhiwei Yang
- Department of CardiologyDa Qing Oilfield General HospitalDa QingChina
| | - Bo Chen
- Division of Non‐Communicable Disease Control and Community HealthChinese Center for Disease Control and PreventionBeijingChina
| | - Guangwei Li
- Center of Endocrinology, National Center of Cardiology &Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
- Department of EndocrinologyChina‐Japan Friendship HospitalBeijingChina
| | - Qiuhong Gong
- Center of Endocrinology, National Center of Cardiology &Fuwai HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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Williams ED, Rubio ME. Associations between diabetes mellitus and sensorineural hearing loss from humans and animal studies. Hear Res 2024; 450:109072. [PMID: 38936171 DOI: 10.1016/j.heares.2024.109072] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/14/2024] [Accepted: 06/19/2024] [Indexed: 06/29/2024]
Abstract
There is controversy regarding the association and etiopathogenesis of diabetes mellitus (DM) and sensorineural hearing loss (SNHL). Some studies support that SNHL develops because of angiopathy and/or neuropathy caused by DM, but many of the findings have been inconsistent. This review aims to highlight a select number of studies that effectively describe the relationship between DM and SNHL, thus bringing more attention and awareness to this area of research. This review also describes animal models to understand better the mechanisms of DM contributing to SNHL in the inner ear. The goal of this narrative review is for researchers and healthcare professionals to further their understanding and investigation of the etiopathogenesis of both DM and SNHL, therefore leading to the development of effective treatments for diabetic patients displaying symptoms of SNHL.
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Affiliation(s)
- Essence DeVine Williams
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - María Eulalia Rubio
- Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
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Holendová B, Benáková Š, Křivonosková M, Plecitá-Hlavatá L. Redox Status as a Key Driver of Healthy Pancreatic Beta-Cells. Physiol Res 2024; 73:S139-S152. [PMID: 38647167 PMCID: PMC11412338 DOI: 10.33549/physiolres.935259] [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: 09/04/2024] Open
Abstract
Redox status plays a multifaceted role in the intricate physiology and pathology of pancreatic beta-cells, the pivotal regulators of glucose homeostasis through insulin secretion. They are highly responsive to changes in metabolic cues where reactive oxygen species are part of it, all arising from nutritional intake. These molecules not only serve as crucial signaling intermediates for insulin secretion but also participate in the nuanced heterogeneity observed within the beta-cell population. A central aspect of beta-cell redox biology revolves around the localized production of hydrogen peroxide and the activity of NADPH oxidases which are tightly regulated and serve diverse physiological functions. Pancreatic beta-cells possess a remarkable array of antioxidant defense mechanisms although considered relatively modest compared to other cell types, are efficient in preserving redox balance within the cellular milieu. This intrinsic antioxidant machinery operates in concert with redox-sensitive signaling pathways, forming an elaborate redox relay system essential for beta-cell function and adaptation to changing metabolic demands. Perturbations in redox homeostasis can lead to oxidative stress exacerbating insulin secretion defect being a hallmark of type 2 diabetes. Understanding the interplay between redox signaling, oxidative stress, and beta-cell dysfunction is paramount for developing effective therapeutic strategies aimed at preserving beta-cell health and function in individuals with type 2 diabetes. Thus, unraveling the intricate complexities of beta-cell redox biology presents exciting avenues for advancing our understanding and treatment of metabolic disorders.
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Affiliation(s)
- B Holendová
- Laboratory of Pancreatic Islet Research, Czech Academy of Sciences, Prague 4, Czech Republic.
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Liu S, Zhang R, Zhang L, Yang A, Guo Y, Jiang L, Wang H, Xu S, Zhou H. Oxidative stress suppresses PHB2-mediated mitophagy in β-cells via the Nrf2/PHB2 pathway. J Diabetes Investig 2024; 15:559-571. [PMID: 38260951 PMCID: PMC11060161 DOI: 10.1111/jdi.14147] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 12/20/2023] [Accepted: 12/27/2023] [Indexed: 01/24/2024] Open
Abstract
AIMS/INTRODUCTION Mitochondrial damage caused by oxidative stress is a main driver of pancreatic β-cell dysfunction in the pathogenesis of type 2 diabetes mellitus. Prohibitin2 (PHB2) is a vital inner mitochondrial membrane protein that participates in mitophagy to remove the damaged mitochondria. This study aimed to investigate the role and mechanisms of PHB2-mediated mitophagy in oxidative stress-induced pancreatic β-cell dysfunction. MATERIALS AND METHODS PHB2 and mitophagy-related protein expression were analyzed by real-time polymerase chain reaction and western blotting in RINm5F cells treated with H2O2 and islets of diabetic rats. Mitophagy was observed by mitochondrial and lysosome colocalization. RINm5F cells were transfected by phb2 siRNA or overexpression plasmid to explore the role of PHB2 in mitophagy of RINm5F cells. The mechanism of Nrf2 regulating PHB2 was explored by Nrf2 inhibitor and agonist. RESULTS The expression of PHB2, mitophagy related protein PINK1, and Parkin were decreased in RINm5F cells incubated with H2O2 and in islets of diabetic rats. Overexpression of PHB2 protected β-cells from oxidative stress by promoting mitophagy and inhibiting cell apoptosis, whereas transfection with PHB2 siRNA suppressed mitophagy. Furthermore, PHB2-mediated mitophagy induced by oxidative stress was through the Nrf2/PHB2 pathway in β-cells. Antioxidant NAC alleviated oxidative stress injury by promoting PHB2-mediated mitophagy. CONCLUSION Our study suggested that PHB2-mediated mitophagy can protect β-cells from apoptosis via the Nrf2/PHB2 pathway under oxidative stress. Antioxidants may protect β-cell from oxidative stress by prompting PHB2-mediated mitophagy. PHB2-mediated mitophagy as a potential mechanism takes part in the oxidative stress induced β-cell injury.
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Affiliation(s)
- Shan Liu
- Department of EndocrinologyThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
- Hebei Key Laboratory of Brain Science and Psychiatric‐Psychologic DiseaseShijiazhuangHebeiChina
- Department of EndocrinologyThe Second Hospital of ShijiazhuangShijiazhuangHebeiChina
- Central LaboratoryThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
| | - Rui Zhang
- Hebei Key Laboratory of Brain Science and Psychiatric‐Psychologic DiseaseShijiazhuangHebeiChina
- Central LaboratoryThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
- Hebei International Joint Research Center for Brain ScienceShijiazhuangHebeiChina
| | - Lan Zhang
- Department of RadiologyThe Fourth Affiliated Hospital Zhejiang University School of MedicineYiwuZhejiangChina
| | - Aige Yang
- Department of EndocrinologyThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
| | - Yuqing Guo
- Department of EndocrinologyThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
| | - Lei Jiang
- Hebei Key Laboratory of Brain Science and Psychiatric‐Psychologic DiseaseShijiazhuangHebeiChina
- Central LaboratoryThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
- Hebei International Joint Research Center for Brain ScienceShijiazhuangHebeiChina
| | - Huijuan Wang
- Department of EndocrinologyThe Second Hospital of ShijiazhuangShijiazhuangHebeiChina
| | - Shunjiang Xu
- Hebei Key Laboratory of Brain Science and Psychiatric‐Psychologic DiseaseShijiazhuangHebeiChina
- Central LaboratoryThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
- Hebei International Joint Research Center for Brain ScienceShijiazhuangHebeiChina
| | - Huimin Zhou
- Department of EndocrinologyThe First Hospital of Hebei Medical UniversityShijiazhuangHebeiChina
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Shcholok T, Eftekharpour E. Insights into the Multifaceted Roles of Thioredoxin-1 System: Exploring Knockout Murine Models. BIOLOGY 2024; 13:180. [PMID: 38534450 DOI: 10.3390/biology13030180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 03/05/2024] [Accepted: 03/07/2024] [Indexed: 03/28/2024]
Abstract
Redox balance is increasingly identified as a major player in cellular signaling. A fundamentally simple reaction of oxidation and reduction of cysteine residues in cellular proteins is the central concept in this complex regulatory mode of protein function. Oxidation of key cysteine residues occurs at the physiological levels of reactive oxygen species (ROS), but they are reduced by a supply of thiol antioxidant molecules including glutathione, glutaredoxin, and thioredoxin. While these molecules show complex compensatory roles in experimental conditions, transgenic animal models provide a comprehensive picture to pinpoint the role of each antioxidant. In this review, we have specifically focused on the available literature on thioredoxin-1 system transgenic models that include thioredoxin and thioredoxin reductase proteins. As the identification of thioredoxin protein targets is technically challenging, the true contribution of this system in maintaining cellular balance remains unidentified, including the role of this system in the brain.
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Affiliation(s)
- Tetiana Shcholok
- Department of Physiology and Pathophysiology, University of Manitoba, 631-BMSB, 745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada
| | - Eftekhar Eftekharpour
- Department of Physiology and Pathophysiology, University of Manitoba, 631-BMSB, 745 Bannatyne Ave, Winnipeg, MB R3E 0J9, Canada
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Karunakaran U, Elumalai S, Chung SM, Maedler K, Won KC, Moon JS. Mitochondrial aldehyde dehydrogenase-2 coordinates the hydrogen sulfide - AMPK axis to attenuate high glucose-induced pancreatic β-cell dysfunction by glutathione antioxidant system. Redox Biol 2024; 69:102994. [PMID: 38128451 PMCID: PMC10776427 DOI: 10.1016/j.redox.2023.102994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/05/2023] [Accepted: 12/09/2023] [Indexed: 12/23/2023] Open
Abstract
Progression of β-cell loss in diabetes mellitus is significantly influenced by persistent hyperglycemia. At the cellular level, a number of signaling cascades affect the expression of apoptotic genes, ultimately resulting in β-cell failure; these cascades have not been elucidated. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) plays a central role in the detoxification of reactive aldehydes generated from endogenous and exogenous sources and protects against mitochondrial deterioration in cells. Here we report that under diabetogenic conditions, ALDH2 is strongly inactivated in β-cells through CDK5-dependent glutathione antioxidant imbalance by glucose-6-phosphate dehydrogenase (G6PD) degradation. Intriguingly, CDK5 inhibition strengthens mitochondrial antioxidant defense through ALDH2 activation. Mitochondrial ALDH2 activation selectively preserves β-cells against high-glucose-induced dysfunction by activating AMPK and Hydrogen Sulfide (H2S) signaling. This is associated with the stabilization and enhancement of the activity of G6PD by SIRT2, a cytoplasmic NAD+-dependent deacetylase, and is thereby linked to an elevation in the GSH/GSSG ratio, which leads to the inhibition of mitochondrial dysfunction under high-glucose conditions. Furthermore, treatment with NaHS, an H2S donor, selectively preserves β-cell function by promoting ALDH2 activity, leading to the inhibition of lipid peroxidation by high-glucose concentrations. Collectively, our results provide the first direct evidence that ALDH2 activation enhances H2S-AMPK-G6PD signaling, leading to improved β-cell function and survival under high-glucose conditions via the glutathione redox balance.
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Affiliation(s)
- Udayakumar Karunakaran
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea.
| | - Suma Elumalai
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea
| | - Seung Min Chung
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea; Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Kathrin Maedler
- Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany
| | - Kyu Chang Won
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea; Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea.
| | - Jun Sung Moon
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu, Republic of Korea; Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea.
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Sithara S, Crowley T, Walder K, Aston-Mourney K. Identification of reversible and druggable pathways to improve beta-cell function and survival in Type 2 diabetes. Islets 2023; 15:2165368. [PMID: 36709757 PMCID: PMC9888462 DOI: 10.1080/19382014.2023.2165368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
Targeting β-cell failure could prevent, delay or even partially reverse Type 2 diabetes. However, development of such drugs is limited as the molecular pathogenesis is complex and incompletely understood. Further, while β-cell failure can be modeled experimentally, only some of the molecular changes will be pathogenic. Therefore, we used a novel approach to identify molecular pathways that are not only changed in a diabetes-like state but also are reversible and can be targeted by drugs. INS1E cells were cultured in high glucose (HG, 20 mM) for 72 h or HG for an initial 24 h followed by drug addition (exendin-4, metformin and sodium salicylate) for the remaining 48 h. RNAseq (Illumina TruSeq), gene set enrichment analysis (GSEA) and pathway analysis (using Broad Institute, Reactome, KEGG and Biocarta platforms) were used to identify changes in molecular pathways. HG decreased function and increased apoptosis in INS1E cells with drugs partially reversing these effects. HG resulted in upregulation of 109 pathways while drug treatment downregulated 44 pathways with 21 pathways in common. Interestingly, while hyperglycemia extensively upregulated metabolic pathways, they were not altered with drug treatment, rather pathways involved in the cell cycle featured more heavily. GSEA for hyperglycemia identified many known pathways validating the applicability of our cell model to human disease. However, only a fraction of these pathways were downregulated with drug treatment, highlighting the importance of considering druggable pathways. Overall, this provides a powerful approach and resource for identifying appropriate targets for the development of β-cell drugs.
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Affiliation(s)
- Smithamol Sithara
- School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin University, Geelong, Australia
| | - Tamsyn Crowley
- School of Medicine, Bioinformatics Core Research Facility, Deakin University, Geelong, Australia
| | - Ken Walder
- School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin University, Geelong, Australia
| | - Kathryn Aston-Mourney
- School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin University, Geelong, Australia
- CONTACT Kathryn Aston-Mourney Building Nb, 75 Pidgons Rd, Geelong, VIC3216, Australia
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Qin B. Can Antidiabetic Medications Affect Telomere Length in Patients with Type 2 Diabetes? A Mini-Review. Diabetes Metab Syndr Obes 2023; 16:3739-3750. [PMID: 38028989 PMCID: PMC10676684 DOI: 10.2147/dmso.s428560] [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: 07/02/2023] [Accepted: 10/07/2023] [Indexed: 12/01/2023] Open
Abstract
The fight against aging is an eternal pursuit of humankind. The aging rate of patients with type 2 diabetes mellitus (T2DM) is higher than that of healthy individuals. Reducing the aging rate of patients with T2DM and extending their life expectancy are challenges that endocrinologists are eager to overcome. Many studies have shown that antidiabetic medications have potent anti-aging potential. Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere shortening is a hallmark of aging. This review summarizes clinical trials that have explored the association between antidiabetic medications and telomere length (TL) in patients with T2DM and explore the mystery of delaying aging in patients with T2DM from the perspective of telomeres. Various antidiabetic medications may have different effects on TL in patients with T2DM. Metformin and sitagliptin may protect telomeres in patients with T2DM, while exogenous insulin may promote telomere shortening in patients with T2DM. The effect of acarbose and glyburide on TL in patients with T2DM is still uncertain due to the absence of evidence from longitudinal studies.
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Affiliation(s)
- Baoding Qin
- Department of Endocrinology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China
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Rizvi F, Ahmed R, Bashir MA, Ullah S, Zafar H, Atia-Tul-Wahab, Siddiqui H, Choudhary MI. Synthesis, density functional theory and kinetic studies of aminopyridine based α-glucosidase inhibitors. Future Med Chem 2023; 15:1757-1772. [PMID: 37842772 DOI: 10.4155/fmc-2023-0123] [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] [Indexed: 10/17/2023] Open
Abstract
Aims: The current study aimed to develop new thiourea derivatives as potential α-glucosidase inhibitors for the management of hyperglycemia in patients of Type 2 diabetes, with a focus on identifying safer and more effective antidiabetic agents. Materials & methods: New thiourea derivatives (1-16) were synthesized through single-step chemical transformation and evaluated for in vitro α-glucosidase inhibition. Kinetic studies identified the mode of inhibition, free energy and type of interactions were analyzed through density functional theory and molecular docking. Results & conclusion: Compound 5 was identified as the most potent, noncompetitive and noncytotoxic inhibitor of α-glucosidase enzyme with a half-maximal inhibitory concentration of 24.62 ± 0.94 μM. Computational studies reinforce experimental results, demonstrating significant enzyme interactions via hydrophobic and π-π stacking forces.
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Affiliation(s)
- Fazila Rizvi
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Raheel Ahmed
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Muhammad Arslan Bashir
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Saeed Ullah
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Humaira Zafar
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Atia-Tul-Wahab
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Hina Siddiqui
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Muhammad Iqbal Choudhary
- H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
- Department of Biochemistry, King Abdul Aziz University, Jeddah, 21452, Saudi Arabia
- Department of Chemistry, Faculty of Science and Technology, University of Airlangga, Komplek Campus C, Surabaya, 60115, Indonesia
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Toyokuni S, Kong Y, Zheng H, Maeda Y, Katabuchi M, Motooka Y. Three-Dimensional Regulation of Ferroptosis at the Intersection of Iron, Sulfur, and Oxygen Executing Scrap and Build Toward Evolution. Antioxid Redox Signal 2023; 39:807-815. [PMID: 36401504 DOI: 10.1089/ars.2022.0142] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Significance: Iron is an essential element for every life on earth as a primary media for electron flow. Sulfur compounds as sulfhydryls counteract catalytic activity of iron whereas sulfur overdose is also toxic. In aerobic organisms, oxygen is the major media for electron transfer with higher intracellular mobility, which cooperates with the iron system. Based on the importance of iron, there is no active pathway to excrete iron outside the body in higher species. Whereas bacterial infection causes a scramble for iron in situ, cancer can be the outcome of the side effects of long use of iron and oxygen. Recent Advances: Ferroptosis is a recently coined cell death, defined as catalytic Fe(II)-dependent regulated necrosis accompanied by lipid peroxidation. Researchers recently recognized that ferroptosis is involved in a variety of physiological and pathological contexts, including embryonic erythropoiesis, aging, neurodegeneration and cancer cell death. Alternatively, carcinogenesis is a process to obtain iron addiction with ferroptosis-resistance, based on rodent animal studies. Critical Issues: Here we propose that ferroptosis is three-dimensionally regulated by iron, sulfur and oxygen, which correspond to oxidants, antioxidants and membrane fluidity with susceptibility to lipid peroxidation, respectively. Future Directions: Whereas life attempts to prevent ferroptosis, ferroptotic cells eventually emit iron-loaded ferritin as extracellular vesicles to maintain monopoly of iron. Antioxid. Redox Signal. 39, 807-815.
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Affiliation(s)
- Shinya Toyokuni
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Center for Low-Temperature Plasma Sciences, Nagoya University, Nagoya, Japan
| | - Yingyi Kong
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hao Zheng
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuki Maeda
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Misako Katabuchi
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yashiro Motooka
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Krawczyk M, Burzynska-Pedziwiatr I, Wozniak LA, Bukowiecka-Matusiak M. Impact of Polyphenols on Inflammatory and Oxidative Stress Factors in Diabetes Mellitus: Nutritional Antioxidants and Their Application in Improving Antidiabetic Therapy. Biomolecules 2023; 13:1402. [PMID: 37759802 PMCID: PMC10526737 DOI: 10.3390/biom13091402] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Revised: 09/10/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and oxidative stress. Oxidative stress plays a crucial role in the development and progression of diabetes and its complications. Nutritional antioxidants derived from dietary sources have gained significant attention due to their potential to improve antidiabetic therapy. This review will delve into the world of polyphenols, investigating their origins in plants, metabolism in the human body, and relevance to the antioxidant mechanism in the context of improving antidiabetic therapy by attenuating oxidative stress, improving insulin sensitivity, and preserving β-cell function. The potential mechanisms of, clinical evidence for, and future perspectives on nutritional antioxidants as adjuvant therapy in diabetes management are discussed.
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Kuang M, Yang R, Huang X, Wang C, Sheng G, Xie G, Zou Y. Assessing temporal differences in the predictive power of baseline TyG-related parameters for future diabetes: an analysis using time-dependent receiver operating characteristics. J Transl Med 2023; 21:299. [PMID: 37138277 PMCID: PMC10158224 DOI: 10.1186/s12967-023-04159-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/25/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND It is known that measuring the triglyceride glucose (TyG) index and TyG-related parameters [triglyceride glucose-body mass index (TyG-BMI), triglyceride glucose-waist circumference (TyG-WC), and triglyceride glucose-waist to height ratio (TyG-WHtR)] can predict diabetes; this study aimed to compare the predictive value of the baseline TyG index and TyG-related parameters for the onset of diabetes at different future periods. METHODS We conducted a longitudinal cohort study involving 15,464 Japanese people who had undergone health physical examinations. The subject's TyG index and TyG-related parameters were measured at the first physical examination, and diabetes was defined according to the American Diabetes Association criteria. Multivariate Cox regression models and time-dependent receiver operating characteristic (ROC) curves were constructed to examine and compare the risk assessment/predictive value of the TyG index and TyG-related parameters for the onset of diabetes in different future periods. RESULTS The mean follow-up period of the current study cohort was 6.13 years, with a maximum of 13 years, and the incidence density of diabetes was 39.88/10,000 person-years. In multivariate Cox regression models with standardized hazard ratios (HRs), we found that both the TyG index and TyG-related parameters were significantly and positively associated with diabetes risk and that the TyG-related parameters were stronger in assessing diabetes risk than the TyG index, with TyG-WC being the best parameter (HR per SD increase: 1.70, 95% CI 1.46, 1.97). In addition, TyG-WC also showed the highest predictive accuracy in time-dependent ROC analysis for diabetes occurring in the short-term (2-6 years), while TyG-WHtR had the highest predictive accuracy and the most stable predictive threshold for predicting the onset of diabetes in the medium- to long-term (6-12 years). CONCLUSIONS These results suggest that the TyG index combined with BMI, WC, and WHtR can further improve its ability to assess/predict the risk of diabetes in different future periods, where TyG-WC was not only the best parameter for assessing diabetes risk but also the best risk marker for predicting future diabetes in the short-term, while TyG-WHtR may be more suitable for predicting future diabetes in the medium- to long-term.
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Affiliation(s)
- Maobin Kuang
- Medical College of Nanchang University, Nanchang, 330006, Jiangxi, China
- Department of Cardiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China
| | - Ruijuan Yang
- Medical College of Nanchang University, Nanchang, 330006, Jiangxi, China
- Department of Endocrinology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China
| | - Xin Huang
- Medical College of Nanchang University, Nanchang, 330006, Jiangxi, China
- Department of Cardiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China
| | - Chao Wang
- Medical College of Nanchang University, Nanchang, 330006, Jiangxi, China
- Department of Cardiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China
| | - Guotai Sheng
- Department of Cardiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China
| | - Guobo Xie
- Department of Cardiology, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China.
| | - Yang Zou
- Jiangxi Cardiovascular Research Institute, Jiangxi Provincial People's Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China.
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13
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Yamashima T, Seike T, Oikawa S, Kobayashi H, Kido H, Yanagi M, Yamamiya D, Li S, Boontem P, Mizukoshi E. Hsp70.1 carbonylation induces lysosomal cell death for lifestyle-related diseases. Front Mol Biosci 2023; 9:1063632. [PMID: 36819480 PMCID: PMC9936620 DOI: 10.3389/fmolb.2022.1063632] [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: 10/07/2022] [Accepted: 12/28/2022] [Indexed: 02/05/2023] Open
Abstract
Alzheimer's disease, type 2 diabetes, and non-alcoholic steatohepatitis (NASH) constitute increasingly prevalent disorders. Individuals with type 2 diabetes are well-known to be susceptible to Alzheimer's disease. Although the pathogenesis of each disorder is multifactorial and the causal relation remains poorly understood, reactive oxygen species (ROS)-induced lipid and protein oxidation conceivably plays a common role. Lipid peroxidation product was recently reported to be a key factor also for non-alcoholic steatohepatitis, because of inducing hepatocyte degeneration/death. Here, we focus on implication of the representative lipid-peroxidation product 'hydroxynonenal' for the cell degeneration/death of brain, pancreas, and liver. Since Hsp70.1 has dual roles as a chaperone and lysosomal membrane stabilizer, hydroxynonenal-mediated oxidative injury (carbonylation) of Hsp70.1 was highlighted. After intake of high-fat diets, oxidation of free fatty acids in mitochondria generates ROS which enhance oxidation of ω-6 polyunsaturated fatty acids (PUFA) involved within biomembranes and generate hydroxynonenal. In addition, hydroxynonenal is generated during cooking deep-fried foods with vegetable oils especially containing linoleic acids. These intrinsic and exogenous hydroxynonenal synergically causes an increase in its serum and organ levels to induce Hsp70.1 oxidation. As it is amphiphilic; being water-soluble but displays strong lipophilic characteristics, hydroxynonenal can diffuse within the cells and react with targets like senile and/or atheromatous plaques outside the cells. Hydroxynonenal can deepen and expand lysosomal injuries by facilitating 'calpain-mediated cleavage of the carbonylated Hsp70.1'. Despite the unique anatomical, physiological, and biochemical characteristics of each organ for its specific disease, there should be a common cascade of the cell degeneration/death which is caused by hydroxynonenal. This review aims to implicate hydroxynonenal-mediated Hsp70.1 carbonylation for lysosomal membrane permeabilization/rupture and the resultant cathepsin leakage for inducing cell degeneration/death. Given the tremendous number of worldwide people suffering various lifestyle-related diseases, it is valuable to consider how ω-6 PUFA-rich vegetable oils is implicated for the organ disorder.
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Affiliation(s)
- Tetsumori Yamashima
- Department of Psychiatry and Behavioral Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan,Department of Cell Metabolism and Nutrition, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan,*Correspondence: Tetsumori Yamashima,
| | - Takuya Seike
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Shinji Oikawa
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hatasu Kobayashi
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hidenori Kido
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Masahiro Yanagi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Daisuke Yamamiya
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Shihui Li
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Piyakarn Boontem
- Department of Cell Metabolism and Nutrition, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
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14
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Lee SH, Tsutsui M, Matsunaga A, Oe T. Lipid hydroperoxide-derived insulin resistance and its inhibition by pyridoxamine in skeletal muscle cells. Toxicol Res 2023; 39:147-156. [PMID: 36726824 PMCID: PMC9839902 DOI: 10.1007/s43188-022-00155-z] [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: 07/14/2022] [Revised: 10/28/2022] [Accepted: 11/15/2022] [Indexed: 11/30/2022] Open
Abstract
Oxidative stress is strongly associated with the onset and/or progression of diabetes. Under conditions of oxidative stress, lipid hydroperoxides are decomposed to reactive aldehydes that have been reported to induce insulin resistance by modifying proteins involved in insulin signaling. Pyridoxamine (PM) can inhibit the formation of advanced glycation/lipoxidation end products by scavenging reactive carbonyl species. Thus, PM has emerged as a promising drug candidate for various chronic conditions, including diabetic complications. In this study, L6 skeletal muscle cells were treated with 4-oxo-2(E)-nonenal (ONE), one of the most abundant and reactive lipid-derived aldehydes. Cellular insulin resistance was assessed by measuring insulin-stimulated glucose uptake using 2-deoxyglucose. ONE induced a time- and dose-dependent decrease in glucose uptake. Liquid chromatography/electrospray ionization-mass spectrometry analysis of the reaction between ONE and insulin receptor substrate 1 (IRS1) lysate identified multiple modifications that could disturb the interaction between IRS1 and activated IR, leading to insulin resistance. Pretreatment of the cells with PM restored the ONE-induced decrease in glucose uptake. Concomitantly, the formation of PM-ONE adducts in cell culture medium was increased in a PM-dose dependent manner. PM can therefore prevent lipid hydroperoxide-derived insulin resistance by quenching ONE. Supplementary Information The online version contains supplementary material available at 10.1007/s43188-022-00155-z.
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Affiliation(s)
- Seon Hwa Lee
- Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578 Japan
| | - Mizuki Tsutsui
- Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578 Japan
| | - Atsushi Matsunaga
- Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578 Japan
| | - Tomoyuki Oe
- Department of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578 Japan
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15
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Stancill JS, Corbett JA. Hydrogen peroxide detoxification through the peroxiredoxin/thioredoxin antioxidant system: A look at the pancreatic β-cell oxidant defense. VITAMINS AND HORMONES 2022; 121:45-66. [PMID: 36707143 PMCID: PMC10058777 DOI: 10.1016/bs.vh.2022.11.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Reactive oxygen species (ROS), such as hydrogen peroxide, are formed when molecular oxygen obtains additional electrons, increasing its reactivity. While low concentrations of hydrogen peroxide are necessary for regulation of normal cellular signaling events, high concentrations can be toxic. To maintain this balance between beneficial and deleterious concentrations of hydrogen peroxide, cells utilize antioxidants. Our recent work supports a primary role for peroxiredoxin, thioredoxin, and thioredoxin reductase as the oxidant defense pathway used by insulin-producing pancreatic β-cells. These three players work in an antioxidant cycle based on disulfide exchange, with oxidized targets ultimately being reduced using electrons provided by NADPH. Peroxiredoxins also participate in hydrogen peroxide-based signaling through disulfide exchange with redox-regulated target proteins. This chapter will describe the catalytic mechanisms of thioredoxin, thioredoxin reductase, and peroxiredoxin and provide an in-depth look at the roles these enzymes play in antioxidant defense pathways of insulin-secreting β-cells. Finally, we will evaluate the physiological relevance of peroxiredoxin-mediated hydrogen peroxide signaling as a regulator of β-cell function.
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Affiliation(s)
- Jennifer S Stancill
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States.
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16
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Verma AK, Singh P, Al-Saeed FA, Ahmed AE, Kumar S, Kumar A, Dev K, Dohare R. Unravelling the role of telomere shortening with ageing and their potential association with diabetes, cancer, and related lifestyle factors. Tissue Cell 2022; 79:101925. [DOI: 10.1016/j.tice.2022.101925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/18/2022] [Accepted: 09/10/2022] [Indexed: 11/26/2022]
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17
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Mukai E, Fujimoto S, Inagaki N. Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells. Biomolecules 2022; 12:biom12091228. [PMID: 36139067 PMCID: PMC9496160 DOI: 10.3390/biom12091228] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 11/18/2022] Open
Abstract
The dysfunction of pancreatic β-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in β-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is essential for insulin secretion. High glucose metabolism for insulin secretion generates reactive oxygen species (ROS) in mitochondria. In addition, the expression of antioxidant enzymes is very low in β-cells. Therefore, β-cells are easily exposed to oxidative stress. In islet studies using a nonobese T2DM animal model that exhibits selective impairment of glucose-induced insulin secretion (GSIS), quenching ROS generated by glucose stimulation and accumulated under glucose toxicity can improve impaired GSIS. Acute ROS generation and toxicity cause glucose metabolism disorders through different molecular mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is a master regulator of antioxidant defense and a potential therapeutic target in oxidative stress-related diseases, suggesting the possible involvement of Nrf2 in β-cell dysfunction caused by ROS. In this review, we describe the mechanisms of insulin secretory defects induced by oxidative stress in diabetic β-cells.
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Affiliation(s)
- Eri Mukai
- Medical Physiology and Metabolism Laboratory, Department of Biomedical Sciences, College of Life Sciences, Ritsumeikan University, Kusatsu 5258577, Japan
- Correspondence:
| | - Shimpei Fujimoto
- Department of Endocrinology, Metabolism, and Nephrology, Kochi Medical School, Kochi University, Kochi 7838505, Japan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 6068507, Japan
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18
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Abstract
Diabetes is a chronic metabolic disease affecting an increasing number of people. Although diabetes has negative health outcomes for diagnosed individuals, a population at particular risk are pregnant women, as diabetes impacts not only a pregnant woman's health but that of her child. In this review, we cover the current knowledge and unanswered questions on diabetes affecting an expectant mother, focusing on maternal and fetal outcomes.
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Affiliation(s)
- Cecilia González Corona
- Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, One Baylor Plaza, Houston, TX 77030, USA
| | - Ronald J. Parchem
- Center for Cell and Gene Therapy, Stem Cells and Regenerative Medicine Center, One Baylor Plaza, Houston, TX 77030, USA,Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
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19
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The effect of balanities aeqyptiaca defatted protein meal and protein concentrate supplemented diet on biochemical and molecular stability of diabetic wister albino rat. Biomed Pharmacother 2022; 153:113510. [DOI: 10.1016/j.biopha.2022.113510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/27/2022] [Accepted: 07/30/2022] [Indexed: 11/17/2022] Open
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20
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Stancill JS, Hansen PA, Mathison AJ, Schmidt EE, Corbett JA. Deletion of Thioredoxin Reductase Disrupts Redox Homeostasis and Impairs β-Cell Function. FUNCTION (OXFORD, ENGLAND) 2022; 3:zqac034. [PMID: 35873655 PMCID: PMC9301323 DOI: 10.1093/function/zqac034] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 06/17/2022] [Accepted: 06/27/2022] [Indexed: 01/07/2023]
Abstract
Reactive oxygen species (ROS) have been implicated as mediators of pancreatic β-cell damage. While β-cells are thought to be vulnerable to oxidative damage, we have shown, using inhibitors and acute depletion, that thioredoxin reductase, thioredoxin, and peroxiredoxins are the primary mediators of antioxidant defense in β-cells. However, the role of this antioxidant cycle in maintaining redox homeostasis and β-cell survival in vivo remains unclear. Here, we generated mice with a β-cell specific knockout of thioredoxin reductase 1 (Txnrd1fl/fl; Ins1Cre/+ , βKO). Despite blunted glucose-stimulated insulin secretion, knockout mice maintain normal whole-body glucose homeostasis. Unlike pancreatic islets with acute Txnrd1 inhibition, βKO islets do not demonstrate increased sensitivity to ROS. RNA-sequencing analysis revealed that Txnrd1-deficient β-cells have increased expression of nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated genes, and altered expression of genes involved in heme and glutathione metabolism, suggesting an adaptive response. Txnrd1-deficient β-cells also have decreased expression of factors controlling β-cell function and identity which may explain the mild functional impairment. Together, these results suggest that Txnrd1-knockout β-cells compensate for loss of this essential antioxidant pathway by increasing expression of Nrf2-regulated antioxidant genes, allowing for protection from excess ROS at the expense of normal β-cell function and identity.
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Affiliation(s)
| | - Polly A Hansen
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, 53226, USA
| | - Angela J Mathison
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA,Division of Research, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Edward E Schmidt
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MN 59717, USA,Redox Biology Laboratory, University of Veterinary Medicine, Budapest 1078, Hungary
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21
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Akcay G, Danısman B, Basaranlar G, Guzel P, Derin N, Derin AT. The effect of increase in blood glucose level on hearing loss. Braz J Otorhinolaryngol 2022; 88 Suppl 3:S95-S102. [PMID: 35729043 DOI: 10.1016/j.bjorl.2022.06.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 04/04/2022] [Accepted: 06/05/2022] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Previous studies have shown that hearing function is also vulnerable to the effects of diabetes mellitus which can be shown by brainstem auditory evoked potential and distortion product otoacoustic emission recordings. This study aimed to investigate the changes of brainstem auditory evoked potential and distortion product otoacoustic emission in hyperglycemia and whether there is a relationship between reactive oxygen substances production and hearing deterioration in the rat model. METHODS 25 streptozotocin induced diabetic rats were divided into three groups: control, high blood glucose, and diabetes mellitus. Brainstem auditory evoked potential and distortion product otoacoustic emission were recorded, and thiobarbituric acid reactive substances levels were measured in the brainstem tissue. RESULTS At 8 kHz, the latencies of I, II, III, IV, and V brainstem auditory evoked potential waves in high blood glucose and diabetes mellitus groups were elongated, at 16 kHz, only these wave latencies of the diabetes mellitus group were prolonged compared with the control group. A significant decrease was also found in distortion product otoacoustic emission amplitudes at 4, 6, 8, and 10 kHz in the high blood glucose and diabetes mellitus groups compared to the control group. There was a significant increase in thiobarbituric acid reactive substances values due to the increase in blood glucose levels in the high blood glucose and diabetes mellitus groups compared to the control group. CONCLUSION These results suggested that high blood glucose levels may cause hearing impairment not only in the diabetic state but also in the period of hyperglycemia before the onset of manifest diabetes mellitus and reactive oxygen substances may play an important role in the pathophysiology of diabetes mellitus. We suggest that regulating high glucose levels even before the onset of manifest diabetes mellitus may prevent hazardous effects on hearing function. LEVEL OF EVIDENCE Level 3.
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Affiliation(s)
- Guven Akcay
- Hitit University, Faculty of Medicine, Department of Biophysics, Çorum, Turkey
| | - Betul Danısman
- Atatürk University, Faculty of Medicine, Department of Biophysics, Erzurum, Turkey
| | - Goksun Basaranlar
- İzmir Demokrasi University, Vocational School of Health Services, İzmir, Turkey
| | - Pınar Guzel
- Kozan State Hospital, Department of Otolaryngology Head and Neck Surgery, Adana, Turkey
| | - Narin Derin
- Akdeniz University, Faculty of Medicine, Department of Biophysics, Antalya, Turkey.
| | - Alper Tunga Derin
- Akdeniz University, Faculty of Medicine, Department of Otolaryngology Head and Neck Surgery, Antalya, Turkey
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22
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Ferroptosis as a Novel Determinant of β-Cell Death in Diabetic Conditions. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3873420. [PMID: 35320979 PMCID: PMC8938062 DOI: 10.1155/2022/3873420] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/08/2022] [Accepted: 02/22/2022] [Indexed: 12/21/2022]
Abstract
The main pathological hallmark of diabetes is the loss of functional β-cells. Among several types of β-cell death in diabetes, the involvement of ferroptosis remains elusive. Therefore, we investigated the potential of diabetes-mimicking factors: high glucose (HG), proinflammatory cytokines, hydrogen peroxide (H2O2), or diabetogenic agent streptozotocin (STZ) to induce ferroptosis of β-cells in vitro. Furthermore, we tested the contribution of ferroptosis to injury of pancreatic islets in an STZ-induced in vivo diabetic model. All in vitro treatments increased loss of Rin-5F cells along with the accumulation of reactive oxygen species, lipid peroxides and iron, inactivation of NF-E2-related factor 2 (Nrf2), and decrease in glutathione peroxidase 4 expression and mitochondrial membrane potential (MMP). Ferrostatin 1 (Fer-1), ferroptosis inhibitor, diminished the above-stated effects and rescued cells from death in case of HG, STZ, and H2O2 treatments, while failed to increase MMP and to attenuate cell death after the cytokines' treatment. Moreover, Fer-1 protected pancreatic islets from STZ-induced injury in diabetic in vivo model, since it decreased infiltration of macrophages and accumulation of lipid peroxides and increased the population of insulin-positive cells. Such results revealed differences between diabetogenic stimuli in determining the destiny of β-cells, emerging HG, H2O2, and STZ, but not cytokines, as contributing factors to ferroptosis and shed new light on an antidiabetic strategy based on Nrf2 activation. Thus, targeting ferroptosis in diabetes might be a promising new approach for preservation of the β-cell population. Our results obtained from in vivo study strongly justify this approach.
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23
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Kim MJ, Jeon JH. Recent Advances in Understanding Nrf2 Agonism and Its Potential Clinical Application to Metabolic and Inflammatory Diseases. Int J Mol Sci 2022; 23:ijms23052846. [PMID: 35269986 PMCID: PMC8910922 DOI: 10.3390/ijms23052846] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/26/2022] [Accepted: 03/03/2022] [Indexed: 12/11/2022] Open
Abstract
Oxidative stress is a major component of cell damage and cell fat, and as such, it occupies a central position in the pathogenesis of metabolic disease. Nuclear factor-erythroid-derived 2-related factor 2 (Nrf2), a key transcription factor that coordinates expression of genes encoding antioxidant and detoxifying enzymes, is regulated primarily by Kelch-like ECH-associated protein 1 (Keap1). However, involvement of the Keap1–Nrf2 pathway in tissue and organism homeostasis goes far beyond protection from cellular stress. In this review, we focus on evidence for Nrf2 pathway dysfunction during development of several metabolic/inflammatory disorders, including diabetes and diabetic complications, obesity, inflammatory bowel disease, and autoimmune diseases. We also review the beneficial role of current molecular Nrf2 agonists and summarize their use in ongoing clinical trials. We conclude that Nrf2 is a promising target for regulation of numerous diseases associated with oxidative stress and inflammation. However, more studies are needed to explore the role of Nrf2 in the pathogenesis of metabolic/inflammatory diseases and to review safety implications before therapeutic use in clinical practice.
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Affiliation(s)
- Min-Ji Kim
- Department of Endocrinology in Internal Medicine, Kyungpook National University Hospital, Daegu 41944, Korea;
| | - Jae-Han Jeon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Korea
- Correspondence: ; Tel.: +82-(53)-200-3182; Fax: +82-(53)-200-3155
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24
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Toyokuni S, Kong Y, Zheng H, Maeda Y, Motooka Y, Akatsuka S. Iron as spirit of life to share under monopoly. J Clin Biochem Nutr 2022; 71:78-88. [PMID: 36213789 PMCID: PMC9519419 DOI: 10.3164/jcbn.22-43] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 05/11/2022] [Indexed: 01/18/2023] Open
Abstract
Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multi-system organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.
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Affiliation(s)
- Shinya Toyokuni
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine
| | - Yingyi Kong
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine
| | - Hao Zheng
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine
| | - Yuki Maeda
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine
| | - Yashiro Motooka
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine
| | - Shinya Akatsuka
- Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine
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25
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Lan B, Bai Y, Chang X, Zhang X. Independent and joint effect of relative telomere length and type 2 diabetes on all-cause mortality in American adults. Front Endocrinol (Lausanne) 2022; 13:1035017. [PMID: 36440190 PMCID: PMC9685657 DOI: 10.3389/fendo.2022.1035017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 10/27/2022] [Indexed: 11/11/2022] Open
Abstract
OBJECTIVE The joint effect of leukocyte telomere length (LTL) and type 2 diabetes (T2D) on the risk of all-cause death has been sparsely explored. The study designed to examine the joint effect of T2D and LTL on the probability of death in American adults. METHODS A cohort of 6862 adults with LTL measurements and with or without T2D from the NHANES 1999-2002 with follow-up information until 2015 was studied. Quantitative PCR was used to measure the length of telomeres relative to standard reference DNA (T/S ratio). Individuals were grouped into three tertiles according to the LTL levels, with the first tertile demonstrating the lowest one and used as the reference group. The effects of LTL and T2D status on death were evaluated using Kaplan-Meier curves along with log-rank test. Three Cox proportional hazards models with adjustment for various confounders were used to examine the links between TL and all-cause death possibility using adjusted hazard ratios (HRs). RESULTS Adults in the sample averaged 45.54 years of age, with 49.51% being male. After a median follow-up period of 14.4 years, 1543 (22.5%) individuals died from all cause. The probability of all-cause mortality was higher among individuals with LTL in the highest tertile than individuals in the lowest tertile (aHR = 0.89; 95%CI: 0.77-1.03); however, the difference did not reach the level of statistical significance (P = 0.11). Conversely, the individuals with T2D had a higher probability of death than individuals without (aHR = 1.26; 95%CI: 1.06-1.50; P = 0.0092). When LTL and T2D status were investigated jointly, subjects in the highest TLT tertile and with T2D had the highest probability of mortality compared with their counterparts (aHR = 1.34; 95%CI: 1.07-1.68; P = 0.0101). However, there was no independent effect of low TLT on mortality as demonstrated among individuals with diabetes (aHR = 1.14; 95%CI: 0.95-1.38; P = 0.1662). CONCLUSION The joint effect of TLT and T2D was larger than the sum of the independent effects on the risk of all-cause death. Participants with high TLT and diabetes showed the highest possibility of death compared with other groups.
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Affiliation(s)
- Beidi Lan
- Department of Structural Heart Disease, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuan Bai
- Department of Cardiology, Changhai Hospital of The Navy Military Medical University, Shanghai, China
| | - Xiaoyi Chang
- Department of State-Owned Assets Management, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiaoxia Zhang
- Department of Pharmacy, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Kostopoulou E, Kalaitzopoulou E, Papadea P, Skipitari M, Rojas Gil AP, Spiliotis BE, Georgiou CD. Oxidized lipid-associated protein damage in children and adolescents with type 1 diabetes mellitus: New diagnostic/prognostic clinical markers. Pediatr Diabetes 2021; 22:1135-1142. [PMID: 34633133 DOI: 10.1111/pedi.13271] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/21/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Type 1 diabetes mellitus (DM1), a chronic metabolic disorder of autoimmune origin, has been associated with oxidative stress (OS), which plays a central role in the onset, progression, and long-term complications of DM1. The markers of OS lipid peroxidation products, lipid hydroperoxides (LOOH), and also malondialdehyde (MDA) and thiobarbituric reactive substances (TBARS) that oxidatively modify proteins (Pr) (i.e., PrMDA and PrTBARS, respectively), have been associated with DM2, DM1, diabetic neuropathy, and microalbuminuria. OBJECTIVE/SUBJECTS Here, we investigated LOOH, PrMDA and PrTBARS in 50 children and adolescents with DM1 and 21 controls. RESULTS The novel OS marker PrTBARS was assessed for the first time in children and adolescents with DM1. LOOH and the pair PrMDA/PrTBARS, representing early and late peroxidation stages, respectively, are found to be significantly higher (130%, 50/90%, respectively, at p < 0.001) in patients with DM1 compared to controls. The studied OS parameters did not differ with age, age at diagnosis, sex, duration of DM1, presence of recent ketosis/ketoacidosis, or mode of treatment. CONCLUSIONS We propose that LOOH, PrMDA and the new marker PrTBARS could serve as potential diagnostic clinical markers for identifying OS in children and adolescents with DM1, and may, perhaps, hold promise as a prognostic tool for future complications associated with the disease.
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Affiliation(s)
- Eirini Kostopoulou
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras School of Medicine, Patras, Greece
| | | | | | | | - Andrea Paola Rojas Gil
- Faculty of Health Sciences, Department of Nursing, University of Peloponnese, Tripoli, Greece
| | - Bessie E Spiliotis
- Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of Patras School of Medicine, Patras, Greece
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Naseri M, Sereshki ZK, Ghavami B, Zangii BM, Kamalinejad M, Moghaddam PM, Asghari M, Nejad SAH, Emadi F, Ghaffari F. Preliminary results of effect of barley (<em>Hordeum vulgare L.</em>) extract on liver, pancreas, kidneys and cardiac tissues in streptozotocin induced diabetic rats. Eur J Transl Myol 2021; 32. [PMID: 34818878 PMCID: PMC8992669 DOI: 10.4081/ejtm.2022.10108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 10/14/2021] [Indexed: 12/05/2022] Open
Abstract
Diabetes mellitus (DM) and its complications impose a significant burden on patients and the health care system. In the Traditional Persian Medicine (TPM), barley is recommended for treatment of DM. This study sought to assess the effect of barley seed aqueous extract on hepatic, pancreatic, renal and cardiac tissues in normal (non-diabetic) and Streptozotocin-induced diabetic rats. Twenty-one male Wistar rats were randomly divided into diabetic and non-diabetic groups. Diabetes was induced by single intraperitoneal injection of Streptozotocin. After one week, the diabetic and non-diabetic groups were randomly divided into control and barley seed extract subgroups namely N group (non-diabetic control rats), S group (seed extract treated non-diabetic rats), D group (diabetic control rats) and DS group (seed extract treated diabetic rats). After 6 weeks, all rats were sacrificed for histopathological analysis and specimens were stained routinely for histological studies. The abnormal histological signs significantly decreased in the DS group compared to D group. Also, protective effects of barley seed extract against histopathological changes were seen in S group compared to N group.These findings suggest that barley seed extract exerts a protective effect on different tissues in diabetes.
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Affiliation(s)
- Mohsen Naseri
- Traditional Medicine Clinical Trial Research Center, Shahed University, Tehran, Iran; Department of Traditional Persian Medicine, School of Medicine, Shahed University, Tehran, Iran; Hikmat, Islamic and Traditional Medicine Department, The Academy of Medical Sciences, Tehran.
| | - Zahra Khalaj Sereshki
- Department of Gynecology, School of Medicine, Yas Hospital, Tehran University of Medical Sciences, Tehran.
| | - Behnaz Ghavami
- Department of Gynecology, School of Medicine, Arash Hospital, Tehran University of Medical Sciences, Tehran.
| | - Bagher Minaii Zangii
- Department of Histology, School of Medicine, Tehran University of Medical Sciences, Tehran.
| | | | - Parvaneh Mohseni Moghaddam
- Department of Physiology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Majid Asghari
- School of Persian Medicine, Qom University of Medical Sciences, Qom.
| | - Seyed Abbas Hashemi Nejad
- Traditional Medicine Clinical Trial Research Center, Shahed University, Tehran, Iran; Department of Traditional Persian Medicine, School of Medicine, Shahed University, Tehran.
| | - Fatemeh Emadi
- Traditional Medicine Clinical Trial Research Center, Shahed University, Tehran, Iran; Department of Traditional Persian Medicine, School of Medicine, Shahed University, Tehran.
| | - Farzaneh Ghaffari
- School of Traditional Medicine, Shahid Beheshti University of Medical Sciences, Tehran.
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Wang X, Carvalho V, Wang Q, Wang J, Li T, Chen Y, Ni C, Liu L, Yuan Y, Qiu S, Sun Z. Screening and Identification of Key Genes for Activation of Islet Stellate Cell. Front Endocrinol (Lausanne) 2021; 12:695467. [PMID: 34566887 PMCID: PMC8458934 DOI: 10.3389/fendo.2021.695467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 08/16/2021] [Indexed: 11/13/2022] Open
Abstract
Background It has been demonstrated that activated islet stellate cells (ISCs) play a critical role in islet fibrogenesis and significantly contribute to the progression of type 2 diabetes mellitus. However, the key molecules responsible for ISCs activation have not yet been determined. This study aimed to identify the potential key genes involved in diabetes-induced activation of ISCs. Method Stellate cells were isolated from three 10-week-old healthy male Wistar rats and three Goto-Kakizaki (GK) rats. Cells from each rat were primary cultured under the same condition. A Genome-wide transcriptional sequence of stellate cells was generated using the Hiseq3000 platform. The identified differentially expressed genes were validated using quantitative real-time PCR and western blotting in GK rats, high fat diet (HFD) rats, and their controls. Results A total of 204 differentially expressed genes (DEGs) between GK. ISCs and Wistar ISCs (W.ISCs) were identified, accounting for 0.58% of all the 35,362 genes detected. After the Gene Ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses, the mRNA levels of these genes were further confirmed by real-time PCR in cultured ISCs. We then selected Fos, Pdpn, Bad as the potential key genes for diabetes-induced activation of ISCs. Finally, we confirmed the protein expression levels of FOS, podoplanin, and Bad by western blotting and immunofluorescence in GK rats, HFD rats, and their controls. The results showed that the expression level of FOS was significantly decreased, while podoplanin and Bad were significantly increased in GK.ISCs and HFD rats compared with controls, which were consistent with the expression of α-smooth muscle actin. Conclusions A total of 204 DEGs were found between the GK.ISCs and W.ISCs. After validating the expression of potential key genes from GK rats and HFD rats, Fos, Pdpn, and Bad might be potential key genes involved in diabetes-induced activation of ISCs.
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Affiliation(s)
- Xiaohang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Vladmir Carvalho
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Qianqian Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Jinbang Wang
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Tingting Li
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yang Chen
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Chengming Ni
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Lili Liu
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Yang Yuan
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Shanhu Qiu
- Department of General Practice, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
| | - Zilin Sun
- Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine, Southeast University, Nanjing, China
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Rogacka D. Insulin resistance in glomerular podocytes: Potential mechanisms of induction. Arch Biochem Biophys 2021; 710:109005. [PMID: 34371008 DOI: 10.1016/j.abb.2021.109005] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/19/2021] [Accepted: 08/05/2021] [Indexed: 01/15/2023]
Abstract
Glomerular podocytes are a target for the actions of insulin. Accumulating evidence indicates that exposure to nutrient overload induces insulin resistance in these cells, manifested by abolition of the stimulatory effect of insulin on glucose uptake. Numerous recent studies have investigated potential mechanisms of the induction of insulin resistance in podocytes. High glucose concentrations stimulated reactive oxygen species production through NADPH oxidase activation, decreased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and reduced deacetylase sirtuin 1 (SIRT1) protein levels and activity. Calcium signaling involving transient receptor potential cation channel C, member 6 (TRPC6) also was demonstrated to play an essential role in the regulation of insulin-dependent signaling and glucose uptake in podocytes. Furthermore, podocytes exposed to diabetic environment, with elevated insulin levels become insulin resistant as a result of degradation of insulin receptor (IR), resulting in attenuation of insulin signaling responsiveness. Also elevated levels of palmitic acid appear to be an important factor and contributor to podocytes insulin resistance. This review summarizes cellular and molecular alterations that contribute to the development of insulin resistance in glomerular podocytes.
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Affiliation(s)
- Dorota Rogacka
- Mossakowski Medical Research Institute, Polish Academy of Sciences, Laboratory of Molecular and Cellular Nephrology, Wita Stwosza 63, 80-308, Gdansk, Poland; University of Gdansk, Faculty of Chemistry, Department of Molecular Biotechnology, Wita Stwosza 63, 80-308, Gdansk, Poland.
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Karunakaran U, Elumalai S, Moon JS, Won KC. CD36 Signal Transduction in Metabolic Diseases: Novel Insights and Therapeutic Targeting. Cells 2021; 10:cells10071833. [PMID: 34360006 PMCID: PMC8305429 DOI: 10.3390/cells10071833] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/14/2021] [Accepted: 07/17/2021] [Indexed: 12/24/2022] Open
Abstract
The cluster of differentiation 36 (CD36) is a scavenger receptor present on various types of cells and has multiple biological functions that may be important in inflammation and in the pathogenesis of metabolic diseases, including diabetes. Here, we consider recent insights into how the CD36 response becomes deregulated under metabolic conditions, as well as the therapeutic benefits of CD36 inhibition, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with metabolic diseases. To facilitate this process further, it is important to pinpoint regulatory mechanisms that are relevant under physiological and pathological conditions. In particular, understanding the mechanisms involved in dictating specific CD36 downstream cellular outcomes will aid in the discovery of potent compounds that target specific CD36 downstream signaling cascades.
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Affiliation(s)
- Udayakumar Karunakaran
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea; (U.K.); (S.E.)
| | - Suma Elumalai
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea; (U.K.); (S.E.)
| | - Jun-Sung Moon
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea; (U.K.); (S.E.)
- Yeungnam University College of Medicine, Daegu 42415, Korea
- Correspondence: (J.-S.M.); (K.-C.W.); Tel.: +82-53-620-3825 (J.-S.M.); +82-53-620-3846 (K.-C.W.)
| | - Kyu-Chang Won
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea; (U.K.); (S.E.)
- Yeungnam University College of Medicine, Daegu 42415, Korea
- Correspondence: (J.-S.M.); (K.-C.W.); Tel.: +82-53-620-3825 (J.-S.M.); +82-53-620-3846 (K.-C.W.)
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Babych M, Nguyen PT, Côté-Cyr M, Kihal N, Quittot N, Golizeh M, Sleno L, Bourgault S. Site-Specific Alkylation of the Islet Amyloid Polypeptide Accelerates Self-Assembly and Potentiates Perturbation of Lipid Membranes. Biochemistry 2021; 60:2285-2299. [PMID: 34264642 DOI: 10.1021/acs.biochem.1c00308] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
The accumulation of insoluble amyloids in the pancreatic islets is a pathological hallmark of type II diabetes and correlates closely with the loss of β-cell mass. The predominant component of these amyloid deposits is the islet amyloid polypeptide (IAPP). The factors contributing to the conversion of IAPP from a monomeric bioactive peptide hormone into insoluble amyloid fibrils remain partially elusive. In this study, we investigated the effect of the oxidative non-enzymatic post-translational modification induced by the reactive metabolite 4-hydroxynonenal (HNE) on IAPP aggregation and cytotoxicity. Incubation of IAPP with exogenous HNE accelerated its self-assembly into β-sheet fibrils and led to the formation of a Michael adduct on the His-18 side chain. To model this covalent modification, the imidazole N(π) position of histidine was alkylated using a close analogue of HNE, the octyl chain. IAPP lipidated at His-18 showed a hastened random coil-to-β-sheet conformational conversion into fibrillar assemblies with a distinct morphology, a low level of binding to thioflavin T, and a high surface hydrophobicity. Introducing an octyl chain on His-18 enhanced the ability of the peptide to perturb synthetic lipid vesicles, to permeabilize the plasma membrane, and to induce the death of pancreatic β-cells. Alkylated IAPP triggered the self-assembly of unmodified IAPP by prompting primary nucleation and increased its capacity to perturb the plasma membrane, indicating that only a small proportion of the modified peptide is necessary to shift the balance toward the formation of proteotoxic species. This study underlines the importance of studying IAPP post-translational modifications induced by oxidative metabolites in the context of pancreatic amyloids.
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Affiliation(s)
- Margaryta Babych
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Phuong Trang Nguyen
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Mélanie Côté-Cyr
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Nadjib Kihal
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Noé Quittot
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
| | - Makan Golizeh
- Department of Mathematical and Physical Sciences, Concordia University of Edmonton, Edmonton, AB T5B 4E4, Canada
| | - Lekha Sleno
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada
| | - Steve Bourgault
- Department of Chemistry, Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montreal H3C 3P8, Canada.,Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, http://proteo.ca/en/
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Ajayi AM, Adedapo ADA, Badaki VB, Oyagbemi AA, Adedapo AA. Chrysophyllum albidum fruit ethanol extract ameliorates hyperglycaemia and elevated blood pressure in streptozotocin-induced diabetic rats through modulation of oxidative stress, NF-κB and PPAR-γ. Biomed Pharmacother 2021; 141:111879. [PMID: 34225016 DOI: 10.1016/j.biopha.2021.111879] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 06/23/2021] [Accepted: 06/28/2021] [Indexed: 01/05/2023] Open
Abstract
Oxidative stress and inflammation arising from hyperglycaemia have been identified as important targets in mitigating hyperglycaemia-induced organ dysfunction in diabetics. Chrysophyllum albidum fruit is commonly consumed as fruit snacks because of its beneficial effects in diabetes management. This study aim to evaluate the protective mechanisms of Chrysophyllum albidum fruit extract (CAFE) in streptozotocin-induced rats involving attenuation of oxidative stress, nuclear factor-kappa B (NF-κB) and peroxisome proliferator-activated receptor-gamma (PPAR-γ). CAFE was investigated for in vitro antioxidant and alpha amylase inhibitory activity. Male Wistar rats were made diabetic by single intraperitoneal injection of streptozotocin (60 mg/kg). The rats were then treated with CAFE (100 and 200 mg/kg) and pioglitazone (10 mg/kg) for two weeks. Fasting blood sugar (FBS), blood pressure parameters, lipid profile, oxidative stress parameters, NF-κB and PPAR-γ were determined. The extract showed antioxidant and alpha amylase inhibitory activities. CAFE significantly reduced STZ-induced hyperglycaemia after 7 and 14 days of treatment. CAFE also reduced STZ-induced elevation of diastolic blood pressure and mean arterial pressure and as well reduced atherogenic index in diabetic rats. It significantly decreased lipid peroxidation but increased the enzymatic and non-enzymatic antioxidant markers in the plasma, liver, kidney and pancreas. The immunohistochemical analysis revealed that CAFE significantly decreased hepatic and renal tissues NF-κB while increasing PPAR-γ gene expressions. The results of this study collectively showed the protective effect of Chrysophyllum albidum fruit extract in streptozotocin-induced diabetic rats via modulation of oxidative stress and NF-κB/ PPAR-γ expressions.
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Affiliation(s)
- Abayomi M Ajayi
- Department of Pharmacology & Therapeutics, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria.
| | - Aduragbenro D A Adedapo
- Department of Pharmacology & Therapeutics, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria.
| | - Victoria B Badaki
- Department of Pharmacology & Therapeutics, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria.
| | | | - Adeolu A Adedapo
- Department of Veterinary Pharmacology and Toxicology, University of Ibadan, Ibadan, Oyo State, Nigeria.
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Ferroptosis in Different Pathological Contexts Seen through the Eyes of Mitochondria. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5537330. [PMID: 34211625 PMCID: PMC8205588 DOI: 10.1155/2021/5537330] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/08/2021] [Accepted: 05/25/2021] [Indexed: 12/12/2022]
Abstract
Ferroptosis is a recently described form of regulated cell death characterized by intracellular iron accumulation and severe lipid peroxidation due to an impaired cysteine-glutathione-glutathione peroxidase 4 antioxidant defence axis. One of the hallmarks of ferroptosis is a specific morphological phenotype characterized by extensive ultrastructural changes of mitochondria. Increasing evidence suggests that mitochondria play a significant role in the induction and execution of ferroptosis. The present review summarizes existing knowledge about the mitochondrial impact on ferroptosis in different pathological states, primarily cancer, cardiovascular diseases, and neurodegenerative diseases. Additionally, we highlight pathologies in which the ferroptosis/mitochondria relation remains to be investigated, where the process of ferroptosis has been confirmed (such as liver- and kidney-related pathologies) and those in which ferroptosis has not been studied yet, such as diabetes. We will bring attention to avenues that could be followed in future research, based on the use of mitochondria-targeted approaches as anti- and proferroptotic strategies and directed to the improvement of existing and the development of novel therapeutic strategies.
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Nagai Y, Matsuoka TA, Shimo N, Miyatsuka T, Miyazaki S, Tashiro F, Miyazaki JI, Katakami N, Shimomura I. Glucotoxicity-induced suppression of Cox6a2 expression provokes β-cell dysfunction via augmented ROS production. Biochem Biophys Res Commun 2021; 556:134-141. [PMID: 33839409 DOI: 10.1016/j.bbrc.2021.03.148] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 03/26/2021] [Indexed: 12/14/2022]
Abstract
Oxidative stress is a deteriorating factor for pancreatic β-cells under chronic hyperglycemia in diabetes. However, the molecular mechanism underlying the increase in oxidative stress in β-cells under diabetic conditions remains unclear. We demonstrated previously that the selective alleviation of glucotoxicity ameliorated the downregulation of several β-cell factors, including Cox6a2. Cox6a2 encodes a subunit of the respiratory chain complex IV in mitochondria. In this study, we analyzed the role of Cox6a2 in pancreatic β-cell function and its pathophysiological significance in diabetes mellitus. Cox6a2-knockdown experiments in MIN6-CB4 cells indicated an increased production of reactive oxygen species as detected by CellROX Deep Red reagent using flow cytometry. In systemic Cox6a2-knockout mice, impaired glucose tolerance was observed under a high-fat high-sucrose diet. However, insulin resistance was reduced when compared with control littermates. This indicates a relative insufficiency of β-cell function. To examine the transcriptional regulation of Cox6a2, ATAC-seq with islet DNA was performed and an open-chromatin area within the Cox6a2 enhancer region was detected. Reporter gene analysis using this area revealed that MafA directly regulates Cox6a2 expression. These findings suggest that the decreased expression of Cox6a2 increases the levels of reactive oxygen species and that Mafa is associated with decreased Cox6a2 expression under glucotoxic conditions.
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Affiliation(s)
- Yasuki Nagai
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Taka-Aki Matsuoka
- First Department of Medicine, Wakayama Medical University, Wakayama, Japan.
| | - Naoki Shimo
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
| | - Takeshi Miyatsuka
- Department of Metabolism and Endocrinology, Juntendo University, Graduate School of Medicine, Tokyo, Japan
| | - Satsuki Miyazaki
- Division of Stem Cell Regulation Research, Center for Medical Research and Education, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Fumi Tashiro
- Division of Stem Cell Regulation Research, Center for Medical Research and Education, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Jun-Ichi Miyazaki
- The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan
| | - Naoto Katakami
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan; Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
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Liu JY, Zhang YC, Xie RR, Song LN, Yang WL, Xin Z, Cao X, Yang JK. Nifuroxazide improves insulin secretion and attenuates high glucose-induced inflammation and apoptosis in INS-1 cells. Eur J Pharmacol 2021; 899:174042. [PMID: 33745960 DOI: 10.1016/j.ejphar.2021.174042] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 03/12/2021] [Accepted: 03/12/2021] [Indexed: 12/14/2022]
Abstract
Inflammation and oxidative stress are important factors that cause islet β-cell dysfunction. STAT3 is not only a major factor in cell proliferation and differentiation, but also plays an important role in mediating inflammation. As a potent inhibitor of STAT3, the effect of Nifuroxazide (Nifu) on pancreatic islet cells in a high glucose environment has not been reported. In the present study, we used high concentration glucose-induced INS-1 cells to examine the effects of Nifu on high glucose-induced cell function by glucose-stimulated insulin secretion (GSIS). The effects of Nifu on high glucose-induced oxidative stress were recorded by oxidative factors and antioxidant factors. Simultaneously, the effect of Nifu on the inflammatory response, apoptosis, and STAT3/SOCS3 signal pathway were validated by quantitative real-time PCR (qRT-PCR) and Western blot. Our study indicated that Nifu significantly improved cell vitality and insulin secretion of INS-1 cells induced by high glucose. We found Nifu significantly inhibited pro-oxidative factors (ROS, MDA) and promoted anti-oxidative factors (SOD, GSH-PX, CAT). Meanwhile, qRT-PCR and Western blot results showed that inflammatory and apoptosis factors were remarkably inhibited by Nifu. Further research indicated that Nifu clearly suppressed the activation of the STAT3/SOCS3 signaling pathway. In conclusion, Nifu can significantly improve the insulin secretion function, protect oxidative stress injury, and reduce inflammatory response and apoptosis in high glucose-induced INS-1 cells. Therefore, Nifu has a new positive effect on maintaining the normal function of pancreatic islet cells in a high glucose environment and provides new drug candidates for the treatment and prevention of diabetes.
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Affiliation(s)
- Jing-Yi Liu
- Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Yi-Chen Zhang
- Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Rong-Rong Xie
- Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Li-Ni Song
- Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Wei-Li Yang
- Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Zhong Xin
- Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Xi Cao
- Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
| | - Jin-Kui Yang
- Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
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36
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Dham D, Roy B, Gowda A, Pan G, Sridhar A, Zeng X, Thandavarayan RA, Palaniyandi SS. 4-Hydroxy-2-nonenal, a lipid peroxidation product, as a biomarker in diabetes and its complications: challenges and opportunities. Free Radic Res 2021; 55:547-561. [PMID: 33336611 DOI: 10.1080/10715762.2020.1866756] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Over 30 million Americans are diagnosed with diabetes and this number is only expected to increase. There are various causes that induce complications with diabetes, including oxidative stress. In oxidative stress, lipid peroxidation-derived reactive carbonyl species such as 4-hydroxy-2-nonenal (4-HNE) is shown to cause damage in organs that leads to diabetic complications. We provided evidence to show that 4-HNE or/and 4-HNE-protein adducts are elevated in various organ systems of diabetic patients and animal models. We then discussed the advantages and disadvantages of different methodologies used for the detection of 4-HNE in diabetic tissues. We also discussed how novel approaches such as electrochemistry and nanotechnology can be used for monitoring 4-HNE levels in biological systems in real-time. Thus, this review enlightens the involvement of 4-HNE in the pathogenesis of diabetes and its complications and efficient methods to identify it. Furthermore, the article presents that 4-HNE can be developed as a biomarker for end-organ damage in diabetes such as diabetic cardiac complications.
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Affiliation(s)
- Deiva Dham
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA
| | - Bipradas Roy
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA
| | - Amita Gowda
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA
| | - Guodong Pan
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA
| | - Arun Sridhar
- Department of Chemistry, Oakland University, Rochester, MI, USA
| | - Xiangqun Zeng
- Department of Chemistry, Oakland University, Rochester, MI, USA
| | - Rajarajan A Thandavarayan
- Department of Cardiovascular Sciences, Centre for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX, USA
| | - Suresh Selvaraj Palaniyandi
- Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI, USA.,Department of Physiology, Wayne State University, Detroit, MI, USA
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Stancill JS, Corbett JA. The Role of Thioredoxin/Peroxiredoxin in the β-Cell Defense Against Oxidative Damage. Front Endocrinol (Lausanne) 2021; 12:718235. [PMID: 34557160 PMCID: PMC8453158 DOI: 10.3389/fendo.2021.718235] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/19/2021] [Indexed: 02/02/2023] Open
Abstract
Oxidative stress is hypothesized to play a role in pancreatic β-cell damage, potentially contributing to β-cell dysfunction and death in both type 1 and type 2 diabetes. Oxidative stress arises when naturally occurring reactive oxygen species (ROS) are produced at levels that overwhelm the antioxidant capacity of the cell. ROS, including superoxide and hydrogen peroxide, are primarily produced by electron leak during mitochondrial oxidative metabolism. Additionally, peroxynitrite, an oxidant generated by the reaction of superoxide and nitric oxide, may also cause β-cell damage during autoimmune destruction of these cells. β-cells are thought to be susceptible to oxidative damage based on reports that they express low levels of antioxidant enzymes compared to other tissues. Furthermore, markers of oxidative damage are observed in islets from diabetic rodent models and human patients. However, recent studies have demonstrated high expression of various isoforms of peroxiredoxins, thioredoxin, and thioredoxin reductase in β-cells and have provided experimental evidence supporting a role for these enzymes in promoting β-cell function and survival in response to a variety of oxidative stressors. This mini-review will focus on the mechanism by which thioredoxins and peroxiredoxins detoxify ROS and on the protective roles of these enzymes in β-cells. Additionally, we speculate about the role of this antioxidant system in promoting insulin secretion.
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38
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Erdemli Z, Altinoz E, Erdemli ME, Gul M, Bag HG, Gul S. Ameliorative effects of crocin on tartrazine dye-induced pancreatic adverse effects: a biochemical and histological study. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2021; 28:2209-2218. [PMID: 32870427 DOI: 10.1007/s11356-020-10578-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 08/20/2020] [Indexed: 06/11/2023]
Abstract
The present study aimed to analyze the impact of tartrazine (T) and crocin (Cr) applications on the pancreas tissues of the Wistar rats. A total of 40 Wistar rats were randomly divided into 4 groups with 10 rats in each group, including the Control, T, Cr, and T + Cr groups. After 3 weeks of application, the pancreatic tissues of the rats were removed under anesthesia and rat blood samples were obtained. Tissues were analyzed with biochemical and histopathological methods. It was determined that T administration increased malondialdehyde (MDA), total oxidant status (TOS), oxidative stress index (OSI), glucose, triglyceride, LDL, VLDL, and total cholesterol levels. However, it decreased reduced glutathione (GSH), total antioxidant status (TAS), superoxide dismutase (SOD), catalase (CAT), and HDL levels when compared with the other groups. It was observed that Cr administration significantly increased GSH, SOD, CAT, TAS, and HDL levels when compared with the control group. In the T group, histopathological changes were observed in pancreatic tissue, leading to damages in exocrine pancreas and islets of Langerhans and increased caspase-3 immunoreactivity (p ≤ 0.001). Co-administration of Cr and T brought the biochemical and histopathological findings closer to the control group levels. The administration of T induced damage in the pancreas with the administered dose and frequency. Cr can increase the antioxidant capacity in pancreas tissue. Co-administration of T and Cr contributed to the reduction of the toxic effects induced by T. It could be suggested that Cr administration ameliorated T toxicity.
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Affiliation(s)
- Zeynep Erdemli
- Department of Medical Biochemistry, Medical Faculty, Inonu University, 44280, Malatya, Turkey.
| | - Eyup Altinoz
- Department of Medical Biochemistry, Medical Faculty, Karabuk University, Karabuk, Turkey
| | - Mehmet Erman Erdemli
- Department of Medical Biochemistry, Medical Faculty, Inonu University, 44280, Malatya, Turkey
| | - Mehmet Gul
- Department of Histology and Embryology, Medical Faculty, Inonu University, Malatya, Turkey
| | - Harika Gozukara Bag
- Department of Biostatistics, Medical Faculty, Inonu University, Malatya, Turkey
| | - Semir Gul
- Department of Histology and Embryology, Medical Faculty, Inonu University, Malatya, Turkey
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Alnaas AA, Watson-Siriboe A, Tran S, Negussie M, Henderson JA, Osterberg JR, Chon NL, Harrott BM, Oviedo J, Lyakhova T, Michel C, Reisdorph N, Reisdorph R, Shearn CT, Lin H, Knight JD. Multivalent lipid targeting by the calcium-independent C2A domain of synaptotagmin-like protein 4/granuphilin. J Biol Chem 2020; 296:100159. [PMID: 33277360 PMCID: PMC7857503 DOI: 10.1074/jbc.ra120.014618] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 11/03/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022] Open
Abstract
Synaptotagmin-like protein 4 (Slp-4), also known as granuphilin, is a Rab effector responsible for docking secretory vesicles to the plasma membrane before exocytosis. Slp-4 binds vesicular Rab proteins via an N-terminal Slp homology domain, interacts with plasma membrane SNARE complex proteins via a central linker region, and contains tandem C-terminal C2 domains (C2A and C2B) with affinity for phosphatidylinositol-(4,5)-bisphosphate (PIP2). The Slp-4 C2A domain binds with low nanomolar apparent affinity to PIP2 in lipid vesicles that also contain background anionic lipids such as phosphatidylserine but much weaker when either the background anionic lipids or PIP2 is removed. Through computational and experimental approaches, we show that this high-affinity membrane binding arises from concerted interaction at multiple sites on the C2A domain. In addition to a conserved PIP2-selective lysine cluster, a larger cationic surface surrounding the cluster contributes substantially to the affinity for physiologically relevant lipid compositions. Although the K398A mutation in the lysine cluster blocks PIP2 binding, this mutated protein domain retains the ability to bind physiological membranes in both a liposome-binding assay and MIN6 cells. Molecular dynamics simulations indicate several conformationally flexible loops that contribute to the nonspecific cationic surface. We also identify and characterize a covalently modified variant that arises through reactivity of the PIP2-binding lysine cluster with endogenous bacterial compounds and binds weakly to membranes. Overall, multivalent lipid binding by the Slp-4 C2A domain provides selective recognition and high-affinity docking of large dense core secretory vesicles to the plasma membrane.
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Affiliation(s)
- Aml A Alnaas
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | | | - Sherleen Tran
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | - Mikias Negussie
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | - Jack A Henderson
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | - J Ryan Osterberg
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | - Nara L Chon
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | - Beckston M Harrott
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | - Julianna Oviedo
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | - Tatyana Lyakhova
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA
| | - Cole Michel
- Department of Pharmaceutical Sciences, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Nichole Reisdorph
- Department of Pharmaceutical Sciences, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Richard Reisdorph
- Department of Pharmaceutical Sciences, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Colin T Shearn
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Hai Lin
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA.
| | - Jefferson D Knight
- Department of Chemistry, University of Colorado Denver, Denver, Colorado, USA.
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40
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Elumalai S, Karunakaran U, Moon JS, Won KC. High glucose-induced PRDX3 acetylation contributes to glucotoxicity in pancreatic β-cells: Prevention by Teneligliptin. Free Radic Biol Med 2020; 160:618-629. [PMID: 32763411 DOI: 10.1016/j.freeradbiomed.2020.07.030] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/25/2022]
Abstract
Chronic hyperglycemia has deleterious effects on pancreatic β-cell function and survival in type 2 diabetes (T2D) due to the low expression level of endogenous antioxidants in the β-cells. Peroxiredoxin-3 (PRDX3) is a mitochondria specific H202 scavenger and protects the cell from mitochondrial damage. However, nothing is known about how glucotoxicity influences PRDX3 function in the pancreatic beta cells. Exposure of rat insulinoma INS-1 cells and human beta cells (1.1B4) to high glucose conditions (30mM) stimulated acetylation of PRDX3 which facilitates its hyper-oxidation causing mitochondrial dysfunction by SIRT1 degradation. SIRT1 deficiency induces beta cell apoptosis via NOX-JNK-p66Shc signalosome activation. Herein we investigated the direct effect of Teneligliptin, a newer DPP-4 inhibitor on beta-cell function and survival in response to high glucose conditions. Teneligliptin treatment enhances SIRT1 protein levels and activity by USP22, an ubiquitin specific peptidase. Activated SIRT1 prevents high glucose-induced PRDX3 acetylation by SIRT3 resulted in inhibition of PRDX3 hyper-oxidation thereby strengthening the mitochondrial antioxidant defense. Notably, we identify PRDX3 as a novel SIRT3 target and show their physical interaction. Intriguingly, inhibition of SIRT1 activity by EX-527 or SIRT1 siRNA knockdown exacerbated the SIRT3 mediated PRDX3 deacetylation which leads to peroxiredoxin-3 hyper-oxidation and beta-cell apoptosis by the activation of NOX-JNK-p66Shc signalosome. Collectively, our results unveil a novel and first direct effect of high glucose on PRDX3 acetylation on beta-cell dysfunction by impaired antioxidant defense and SIRT1 mediated SIRT3-PRDX3 activation by Teneligliptin suppresses high glucose-mediated mitochondrial dysfunction.
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Affiliation(s)
- Suma Elumalai
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Udayakumar Karunakaran
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea
| | - Kyu Chang Won
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea.
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41
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Baeeri M, Rahimifard M, Daghighi SM, Khan F, Salami SA, Moini-Nodeh S, Haghi-Aminjan H, Bayrami Z, Rezaee F, Abdollahi M. Cannabinoids as anti-ROS in aged pancreatic islet cells. Life Sci 2020; 256:117969. [PMID: 32553926 DOI: 10.1016/j.lfs.2020.117969] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/10/2020] [Accepted: 06/11/2020] [Indexed: 02/06/2023]
Abstract
AIMS Cannabinoids are the chemical compounds with a high affinity for cannabinoid receptors affecting the central nervous system through the release of neurotransmitters. However, the current knowledge related to the role of such compounds in the regulation of cellular aging is limited. This study aimed to investigate the effect of cannabidiol and tetrahydrocannabinol on the function of aged pancreatic islets. MAIN METHODS The expression of p53, p38, p21, p16, and Glut2 genes and β-galactosidase activity were measured as hallmarks of cell aging applying real-time PCR, ELISA, and immunocytochemistry techniques. Pdx1 protein expression, insulin release, and oxidative stress markers were compared between young and aged rat pancreatic islet cells. KEY FINDINGS Upon the treatment of aged pancreatic islets cells with cannabidiol and tetrahydrocannabinol, the expression of p53, p38, p21 and the activity of β-galactosidase were reduced. Cannabidiol and tetrahydrocannabinol increase insulin release, Pdx1, Glut2, and thiol molecules expression, while the oxidative stress parameters were decreased. The enhanced expression of Pdx1 and insulin release in aged pancreatic islet cells reflects the extension of cell healthy aging due to the significant reduction of ROS. SIGNIFICANCE This study provides evidence for the involvement of cannabidiol and tetrahydrocannabinol in the oxidation process of cellular aging.
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Affiliation(s)
- Maryam Baeeri
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mahban Rahimifard
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Seyed Mojtaba Daghighi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Fazlullah Khan
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | | | - Shermineh Moini-Nodeh
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Hamed Haghi-Aminjan
- Pharmaceutical Sciences Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Zahra Bayrami
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Farhad Rezaee
- Department of Cell Biology, University of Groningen, Groningen, the Netherlands; Department of Gastroenterology-Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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42
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Cheng F, Luk AO, Tam CHT, Fan B, Wu H, Yang A, Lau ESH, Ng ACW, Lim CKP, Lee HM, Chow E, Kong AP, Keech AC, Joglekar MV, So WY, Jenkins AJ, Chan JCN, Hardikar AA, Ma RCW. Shortened Relative Leukocyte Telomere Length Is Associated With Prevalent and Incident Cardiovascular Complications in Type 2 Diabetes: Analysis From the Hong Kong Diabetes Register. Diabetes Care 2020; 43:2257-2265. [PMID: 32661111 DOI: 10.2337/dc20-0028] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 06/12/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Several studies support potential links between relative leukocyte telomere length (rLTL), a biomarker of biological aging, and type 2 diabetes. This study investigates relationships between rLTL and incident cardiovascular disease (CVD) in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Consecutive Chinese patients with type 2 diabetes (N = 5,349) from the Hong Kong Diabetes Register for whom DNA obtained at baseline was stored and follow-up data were available were studied. rLTL was measured by using quantitative PCR. CVD was diagnosed on the basis of ICD-9 code. RESULTS Mean follow-up was 13.4 years (SD 5.5 years). rLTL was correlated inversely with age, diabetes duration, blood pressure, HbA1c, and urine albumin-to-creatinine ratio (ACR), and positively with estimated glomerular filtration rate (eGFR) (all P < 0.001). Subjects with CVD at baseline had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than did subjects without CVD (4.6 ± 1.2 ΔΔCt) (P < 0.001). Of the 4,541 CVD-free subjects at baseline, the 1,140 who developed CVD during follow-up had a shorter rLTL (4.3 ± 1.2 ΔΔCt) than those who remained CVD-free after adjusting for age, sex, smoking, and albuminuria status (4.7 ± 1.2 ΔΔCt) (P < 0.001). In Cox regression models, shorter rLTL was associated with higher risk of incident CVD (for each unit decrease, hazard ratio 1.252 [95% CI 1.195-1.311], P < 0.001), which remained significant after adjusting for age, sex, BMI, systolic blood pressure, LDL cholesterol, HbA1c, eGFR, and ACR (hazard ratio 1.141 [95% CI 1.084-1.200], P < 0.001). CONCLUSIONS rLTL is significantly shorter in patients with type 2 diabetes and CVD, is associated with cardiometabolic risk factors, and is independently associated with incident CVD. Telomere length may be a useful biomarker for CVD risk in patients with type 2 diabetes.
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Affiliation(s)
- Feifei Cheng
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Andrea O Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Claudia H T Tam
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Baoqi Fan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Hongjiang Wu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Aimin Yang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Eric S H Lau
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Asia Diabetes Foundation, Shatin, Hong Kong SAR, China
| | - Alex C W Ng
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Cadmon K P Lim
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Heung Man Lee
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Elaine Chow
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Alice P Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Anthony C Keech
- NHMRC Clinical Trial Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Mugdha V Joglekar
- NHMRC Clinical Trial Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Wing Yee So
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China
| | - Alicia J Jenkins
- NHMRC Clinical Trial Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Juliana C N Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,The Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Prince of Wales Hospital, Hong Kong SAR, China
| | - Anandwardhan A Hardikar
- NHMRC Clinical Trial Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Ronald C W Ma
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China .,Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong SAR, China.,NHMRC Clinical Trial Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.,The Chinese University of Hong Kong-Shanghai Jiao Tong University Joint Research Centre in Diabetes Genomics and Precision Medicine, Prince of Wales Hospital, Hong Kong SAR, China
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Wu J, Sun X, Jiang Z, Jiang J, Xu L, Tian A, Sun X, Meng H, Li Y, Huang W, Jia Y, Wu H. Protective role of NRF2 in macrovascular complications of diabetes. J Cell Mol Med 2020; 24:8903-8917. [PMID: 32628815 PMCID: PMC7417734 DOI: 10.1111/jcmm.15583] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/05/2020] [Accepted: 05/07/2020] [Indexed: 02/07/2023] Open
Abstract
Macrovascular complications develop in over a half of the diabetic individuals, resulting in high morbidity and mortality. This poses a severe threat to public health and a heavy burden to social economy. It is therefore important to develop effective approaches to prevent or slow down the pathogenesis and progression of macrovascular complications of diabetes (MCD). Oxidative stress is a major contributor to MCD. Nuclear factor (erythroid‐derived 2)‐like 2 (NRF2) governs cellular antioxidant defence system by activating the transcription of various antioxidant genes, combating diabetes‐induced oxidative stress. Accumulating experimental evidence has demonstrated that NRF2 activation protects against MCD. Structural inhibition of Kelch‐like ECH‐associated protein 1 (KEAP1) is a canonical way to activate NRF2. More recently, novel approaches, such as activation of the Nfe2l2 gene transcription, decreasing KEAP1 protein level by microRNA‐induced degradation of Keap1 mRNA, prevention of proteasomal degradation of NRF2 protein and modulation of other upstream regulators of NRF2, have emerged in prevention of MCD. This review provides a brief introduction of the pathophysiology of MCD and the role of oxidative stress in the pathogenesis of MCD. By reviewing previous work on the activation of NRF2 in MCD, we summarize strategies to activate NRF2, providing clues for future intervention of MCD. Controversies over NRF2 activation and future perspectives are also provided in this review.
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Affiliation(s)
- Junduo Wu
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, China
| | - Xiaodan Sun
- Intensive Care Unit, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ziping Jiang
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China
| | - Jun Jiang
- Department of Neurosurgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Linlin Xu
- Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ao Tian
- Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xuechun Sun
- Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Huali Meng
- Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ying Li
- Department of Dermatology, Affiliated Hospital of Beihua University, Jilin, China
| | - Wenlin Huang
- School of Science and Technology, Georgia Gwinnett College, Lawrenceville, GA, USA
| | - Ye Jia
- Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Hao Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
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44
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Ogunlade B, Adelakun SA, Agie JA. Nutritional supplementation of gallic acid ameliorates Alzheimer-type hippocampal neurodegeneration and cognitive impairment induced by aluminum chloride exposure in adult Wistar rats. Drug Chem Toxicol 2020; 45:651-662. [PMID: 32329360 DOI: 10.1080/01480545.2020.1754849] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Prolonged exposure to aluminum through occupational hazards or food/water intake has been linked to the occurrence of Alzheimer's disease (AD). This study aimed at investigating the neuroprotective effects of Gallic Acid (GA) against aluminum-chloride induced AD in adult Wistar rats. Twenty eight (28) adult Wistar rats were divided into four groups (n = 7). Group A received normal saline as placebo; Group B received 200 mg/kg bw of AlCl3 only; Group C received 100 mg/kg bw of GA only and group D received 100 mg/kg bw of GA and 200 mg/kg bw of AlCl3. At the end of the 60 days experiment, blood samples were collected to obtain serum for analysis and the brain was harvested. Neurobehavioural tests (Morris Water maze, Y-Maze), neurotransmitter levels, oxidative stress markers, serum electrolytes, antioxidant enzymes and histological assessment were carried out. There was a significant decrease in antioxidant enzymes (CAT, GSH and SOD), serum electrolyte (except K+) and neurotransmitter levels (except norepinephrine) with corresponding increase in stress markers (MDA, H2O2 and NO) among group B compared to control but was restored nearly to normal after GA administration. Neurobehavioral tests showed decreased spatial memory impairment and learning deficit in group B compared to control but was ameliorated with GA administration. Histological observation showed neurofibrillary tangles and amyloid plaques in the external granular layer of group B but protected by GA administration. Nutritional supplementation of GA preserve the morphological and physiological integrity of the hippocampus against environmental neurotoxins (AlCl3) by mopping up free radicals associated with oxidative stress induced AD.
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Affiliation(s)
- B Ogunlade
- Human Anatomy Department, Federal University of Technology, Akure, Akure, Nigeria
| | - S A Adelakun
- Human Anatomy Department, Federal University of Technology, Akure, Akure, Nigeria
| | - J A Agie
- Human Anatomy Department, Federal University of Technology, Akure, Akure, Nigeria
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45
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Stancill JS, Happ JT, Broniowska KA, Hogg N, Corbett JA. Peroxiredoxin 1 plays a primary role in protecting pancreatic β-cells from hydrogen peroxide and peroxynitrite. Am J Physiol Regul Integr Comp Physiol 2020; 318:R1004-R1013. [PMID: 32292063 DOI: 10.1152/ajpregu.00011.2020] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Both reactive nitrogen and oxygen species (RNS and ROS), such as nitric oxide, peroxynitrite, and hydrogen peroxide, have been implicated as mediators of pancreatic β-cell damage during the pathogenesis of autoimmune diabetes. While β-cells are thought to be vulnerable to oxidative damage due to reportedly low levels of antioxidant enzymes, such as catalase and glutathione peroxidase, we have shown that they use thioredoxin reductase to detoxify hydrogen peroxide. Thioredoxin reductase is an enzyme that participates in the peroxiredoxin antioxidant cycle. Peroxiredoxins are expressed in β-cells and, when overexpressed, protect against oxidative stress, but the endogenous roles of peroxiredoxins in the protection of β-cells from oxidative damage are unclear. Here, using either glucose oxidase or menadione to continuously deliver hydrogen peroxide, or the combination of dipropylenetriamine NONOate and menadione to continuously deliver peroxynitrite, we tested the hypothesis that β-cells use peroxiredoxins to detoxify both of these reactive species. Either pharmacological peroxiredoxin inhibition with conoidin A or specific depletion of cytoplasmic peroxiredoxin 1 (Prdx1) using siRNAs sensitizes INS 832/13 cells and rat islets to DNA damage and death induced by hydrogen peroxide or peroxynitrite. Interestingly, depletion of peroxiredoxin 2 (Prdx2) had no effect. Together, these results suggest that β-cells use cytoplasmic Prdx1 as a primary defense mechanism against both ROS and RNS.
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Affiliation(s)
- Jennifer S Stancill
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - John T Happ
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin
| | | | - Neil Hogg
- Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - John A Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin
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46
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Moon JS, Karunakaran U, Suma E, Chung SM, Won KC. The Role of CD36 in Type 2 Diabetes Mellitus: β-Cell Dysfunction and Beyond. Diabetes Metab J 2020; 44:222-233. [PMID: 32347024 PMCID: PMC7188969 DOI: 10.4093/dmj.2020.0053] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 03/25/2020] [Indexed: 12/24/2022] Open
Abstract
Impaired β-cell function is the key pathophysiology of type 2 diabetes mellitus, and chronic exposure of nutrient excess could lead to this tragedy. For preserving β-cell function, it is essential to understand the cause and mechanisms about the progression of β-cells failure. Glucotoxicity, lipotoxicity, and glucolipotoxicity have been suggested to be a major cause of β-cell dysfunction for decades, but not yet fully understood. Fatty acid translocase cluster determinant 36 (CD36), which is part of the free fatty acid (FFA) transporter system, has been identified in several tissues such as muscle, liver, and insulin-producing cells. Several studies have reported that induction of CD36 increases uptake of FFA in several cells, suggesting the functional interplay between glucose and FFA in terms of insulin secretion and oxidative metabolism. However, we do not currently know the regulating mechanism and physiological role of CD36 on glucolipotoxicity in pancreatic β-cells. Also, the downstream and upstream targets of CD36 related signaling have not been defined. In the present review, we will focus on the expression and function of CD36 related signaling in the pancreatic β-cells in response to hyperglycemia and hyperlipidemia (ceramide) along with the clinical studies on the association between CD36 and metabolic disorders.
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Affiliation(s)
- Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | | | - Elumalai Suma
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Seung Min Chung
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Kyu Chang Won
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea.
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Esch N, Jo S, Moore M, Alejandro EU. Nutrient Sensor mTOR and OGT: Orchestrators of Organelle Homeostasis in Pancreatic β-Cells. J Diabetes Res 2020; 2020:8872639. [PMID: 33457426 PMCID: PMC7787834 DOI: 10.1155/2020/8872639] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/06/2020] [Accepted: 11/24/2020] [Indexed: 02/08/2023] Open
Abstract
The purpose of this review is to integrate the role of nutrient-sensing pathways into β-cell organelle dysfunction prompted by nutrient excess during type 2 diabetes (T2D). T2D encompasses chronic hyperglycemia, hyperlipidemia, and inflammation, which each contribute to β-cell failure. These factors can disrupt the function of critical β-cell organelles, namely, the ER, mitochondria, lysosomes, and autophagosomes. Dysfunctional organelles cause defects in insulin synthesis and secretion and activate apoptotic pathways if homeostasis is not restored. In this review, we will focus on mTORC1 and OGT, two major anabolic nutrient sensors with important roles in β-cell physiology. Though acute stimulation of these sensors frequently improves β-cell function and promotes adaptation to cell stress, chronic and sustained activity disturbs organelle homeostasis. mTORC1 and OGT regulate organelle function by influencing the expression and activities of key proteins, enzymes, and transcription factors, as well as by modulating autophagy to influence clearance of defective organelles. In addition, mTORC1 and OGT activity influence islet inflammation during T2D, which can further disrupt organelle and β-cell function. Therapies for T2D that fine-tune the activity of these nutrient sensors have yet to be developed, but the important role of mTORC1 and OGT in organelle homeostasis makes them promising targets to improve β-cell function and survival.
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Affiliation(s)
- Nicholas Esch
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mackenzie Moore
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Surgery, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Emilyn U. Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, University of Minnesota, Minneapolis, Minnesota, USA
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48
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Ebrahimi SM, Bathaie SZ, Faridi N, Taghikhani M, Nakhjavani M, Faghihzadeh S. L-lysine protects C2C12 myotubes and 3T3-L1 adipocytes against high glucose damages and stresses. PLoS One 2019; 14:e0225912. [PMID: 31856203 PMCID: PMC6922410 DOI: 10.1371/journal.pone.0225912] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 11/14/2019] [Indexed: 02/06/2023] Open
Abstract
Hyperglycemia is a hallmark of diabetes, which is associated with protein glycation and misfolding, impaired cell metabolism and altered signaling pathways result in endoplasmic reticulum stress (ERS). We previously showed that L-lysine (Lys) inhibits the nonenzymatic glycation of proteins, and protects diabetic rats and type 2 diabetic patients against diabetic complications. Here, we studied some molecular aspects of the Lys protective role in high glucose (HG)-induced toxicity in C2C12 myotubes and 3T3-L1 adipocytes. C2C12 and 3T3-L1 cell lines were differentiated into myotubes and adipocytes, respectively. Then, they were incubated with normal or high glucose (HG) concentrations in the absence/presence of Lys (1 mM). To investigate the role of HG and/or Lys on cell apoptosis, oxidative status, unfolded protein response (UPR) and autophagy, we used the MTT assay and flow cytometry, spectrophotometry and fluorometry, RT-PCR and Western blotting, respectively. In both cell lines, HG significantly reduced cell viability and induced apoptosis, accompanying with the significant increase in reactive oxygen species (ROS) and nitric oxide (NO). Furthermore, the spliced form of X-box binding protein 1 (XBP1), at both mRNA and protein levels, the phosphorylated eukaryotic translation initiation factor 2α (p-eIf2α), and the Light chain 3 (LC3)II/LC3I ratio was also significantly increased. Lys alone had no significant effects on most of these parameters; but, treatment with HG plus Lys returned them all to, or close to, the normal values. The results indicated the protective role of Lys against glucotoxicity induced by HG in C2C12 myotubes and 3T3-L1 adipocytes.
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Affiliation(s)
- S. Mehdi Ebrahimi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - S. Zahra Bathaie
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
- * E-mail: ,
| | - Nassim Faridi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Taghikhani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Soghrat Faghihzadeh
- Department of Statistics, Zanjan University of Medical Sciences, Zanjan, Iran
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49
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Reiterer M, Schmidt-Kastner R, Milton SL. Methionine sulfoxide reductase (Msr) dysfunction in human brain disease. Free Radic Res 2019; 53:1144-1154. [PMID: 31775527 DOI: 10.1080/10715762.2019.1662899] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Extensive research has shown that oxidative stress is strongly associated with aging, senescence and several diseases, including neurodegenerative and psychiatric disorders. Oxidative stress is caused by the overproduction of reactive oxygen species (ROS) that can be counteracted by both enzymatic and nonenzymatic antioxidants. One of these antioxidant mechanisms is the widely studied methionine sulfoxide reductase system (Msr). Methionine is one of the most easily oxidized amino acids and Msr can reverse this oxidation and restore protein function, with MsrA and MsrB reducing different stereoisomers. This article focuses on experimental and genetic research performed on Msr and its link to brain diseases. Studies on several model systems as well as genome-wide association studies are compiled to highlight the role of MSRA in schizophrenia, Alzheimer's disease, and Parkinson's disease. Genetic variation of MSRA may also contribute to the risk of psychosis, personality traits, and metabolic factors.
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Affiliation(s)
- Melissa Reiterer
- Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, USA
| | | | - Sarah L Milton
- Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL, USA
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50
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Hanchang W, Khamchan A, Wongmanee N, Seedadee C. Hesperidin ameliorates pancreatic β-cell dysfunction and apoptosis in streptozotocin-induced diabetic rat model. Life Sci 2019; 235:116858. [DOI: 10.1016/j.lfs.2019.116858] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/29/2019] [Accepted: 09/07/2019] [Indexed: 12/12/2022]
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