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Ramerth A, Chapple B, Winter J, Moore W. The Other Side of the Perfect Cup: Coffee-Derived Non-Polyphenols and Their Roles in Mitigating Factors Affecting the Pathogenesis of Type 2 Diabetes. Int J Mol Sci 2024; 25:8966. [PMID: 39201652 PMCID: PMC11354961 DOI: 10.3390/ijms25168966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/01/2024] [Accepted: 08/03/2024] [Indexed: 09/02/2024] Open
Abstract
The global prevalence of type 2 diabetes (T2D) is 10.5% among adults in the age range of 20-79 years. The primary marker of T2D is persistent fasting hyperglycemia, resulting from insulin resistance and β-cell dysfunction. Multiple factors can promote the development of T2D, including obesity, inflammation, and oxidative stress. In contrast, dietary choices have been shown to prevent the onset of T2D. Oatmeal, lean proteins, fruits, and non-starchy vegetables have all been reported to decrease the likelihood of T2D onset. One of the most widely consumed beverages in the world, coffee, has also demonstrated an impressive ability to reduce T2D risk. Coffee contains a diverse array of bioactive molecules. The antidiabetic effects of coffee-derived polyphenols have been thoroughly described and recently reviewed; however, several non-polyphenolic molecules are less prominent but still elicit potent physiological actions. This review summarizes the effects of select coffee-derived non-polyphenols on various aspects of T2D pathogenesis.
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Affiliation(s)
| | | | | | - William Moore
- School of Health Sciences, Department of Biology and Chemistry, Liberty University, Lynchburg, VA 24515, USA; (A.R.); (B.C.); (J.W.)
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2
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Robertson RP. Antioxidants for Early Treatment of Type 2 Diabetes in Rodents and Humans: Lost in Translation? Diabetes 2024; 73:653-658. [PMID: 38387049 PMCID: PMC11043055 DOI: 10.2337/db23-0901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 02/13/2024] [Indexed: 02/24/2024]
Abstract
Reactive oxygen species (ROS) are formed by virtually all tissues. In normal concentrations they facilitate many physiologic activities, but in excess they cause oxidative stress and tissue damage. Local antioxidant enzyme synthesis in cells is regulated by the cytoplasmic KEAP-1/Nrf2 complex, which is stimulated by ROS, to release Nrf2 for entry into the nucleus, where it upregulates antioxidant gene expression. Major antioxidant enzymes include glutathione peroxidase (GPx), catalase (CAT), superoxide dismutases (SOD), hemoxygenases (HO), and peroxiredoxins (Prdx). Notably, the pancreatic islet β-cell does not express GPx or CAT, which puts it at greater risk for ROS damage caused by postprandial hyperglycemia. Experimentally, overexpression of GPx in β-cell lines and isolated islets, as well as in vivo studies using genetic models of type 2 diabetes (T2D), has demonstrated enhanced protection against hyperglycemia and oxidative stress. Oral treatment of diabetic rodents with ebselen, a GPx mimetic that is approved for human clinical use, reproduced these findings. Prdx detoxify hydrogen peroxide and reduce lipid peroxides. This suggests that pharmacologic development of more potent, β-cell-specific antioxidants could be valuable as a treatment for oxidative stress due to postprandial hyperglycemia in early T2D in humans. ARTICLE HIGHLIGHTS
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Affiliation(s)
- R. Paul Robertson
- Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA
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3
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Dludla PV, Mabhida SE, Ziqubu K, Nkambule BB, Mazibuko-Mbeje SE, Hanser S, Basson AK, Pheiffer C, Kengne AP. Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress. World J Diabetes 2023; 14:130-146. [PMID: 37035220 PMCID: PMC10075035 DOI: 10.4239/wjd.v14.i3.130] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/26/2022] [Accepted: 02/28/2023] [Indexed: 03/15/2023] Open
Abstract
Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes (T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with T2D. Similarly, important markers of oxidative stress, such as increased reactive oxygen species and depleted intracellular antioxidants, are consistent with pancreatic β-cell damage in conditions of T2D. Such effects illustrate a pathological relationship between an abnormal inflammatory response and generation of oxidative stress during the progression of T2D. The current review explores preclinical and clinical research on the patho-logical implications of inflammation and oxidative stress during the development of β-cell dysfunction in T2D. Moreover, important molecular mechanisms and relevant biomarkers involved in this process are discussed to divulge a pathological link between inflammation and oxidative stress during β-cell failure in T2D. Underpinning the clinical relevance of the review, a systematic analysis of evidence from randomized controlled trials is covered, on the potential therapeutic effects of some commonly used antidiabetic agents in modulating inflammatory makers to improve β-cell function.
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Affiliation(s)
- Phiwayinkosi V Dludla
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Sihle E Mabhida
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Khanyisani Ziqubu
- Department of Biochemistry, North-West University, Mmabatho 2745, South Africa
| | - Bongani B Nkambule
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
| | | | - Sidney Hanser
- Department of Physiology and Environmental Health, University of Limpopo, Sovenga 0727, South Africa
| | - Albert Kotze Basson
- Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa 3880, South Africa
| | - Carmen Pheiffer
- Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town 7505, South Africa
| | - Andre Pascal Kengne
- Department of Medicine, University of Cape Town, Cape Town 7500, South Africa
- Non-Communicable Diseases Research Unit, South African Medical Research Council, Tygerberg 7505, South Africa
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4
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Chemistry of Hydrogen Peroxide Formation and Elimination in Mammalian Cells, and Its Role in Various Pathologies. STRESSES 2022. [DOI: 10.3390/stresses2030019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hydrogen peroxide (H2O2) is a compound involved in some mammalian reactions and processes. It modulates and signals the redox metabolism of cells by acting as a messenger together with hydrogen sulfide (H2S) and the nitric oxide radical (•NO), activating specific oxidations that determine the metabolic response. The reaction triggered determines cell survival or apoptosis, depending on which downstream metabolic pathways are activated. There are several ways to produce H2O2 in cells, and cellular systems tightly control its concentration. At the cellular level, the accumulation of hydrogen peroxide can trigger inflammation and even apoptosis, and when its concentration in the blood reaches toxic levels, it can lead to bioenergetic failure. This review summarizes existing research from a chemical perspective on the role of H2O2 in various enzymatic pathways and how this biochemistry leads to physiological or pathological responses.
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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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Moon JS, Riopel M, Seo JB, Herrero-Aguayo V, Isaac R, Lee YS. HIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity. Diabetes 2022; 71:1508-1524. [PMID: 35472707 PMCID: PMC9233300 DOI: 10.2337/db21-0736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 04/08/2022] [Indexed: 11/13/2022]
Abstract
In obesity, increased mitochondrial metabolism with the accumulation of oxidative stress leads to mitochondrial damage and β-cell dysfunction. In particular, β-cells express antioxidant enzymes at relatively low levels and are highly vulnerable to oxidative stress. Early in the development of obesity, β-cells exhibit increased glucose-stimulated insulin secretion in order to compensate for insulin resistance. This increase in β-cell function under the condition of enhanced metabolic stress suggests that β-cells possess a defense mechanism against increased oxidative damage, which may become insufficient or decline at the onset of type 2 diabetes. Here, we show that metabolic stress induces β-cell hypoxia inducible factor 2α (HIF-2α), which stimulates antioxidant gene expression (e.g., Sod2 and Cat) and protects against mitochondrial reactive oxygen species (ROS) and subsequent mitochondrial damage. Knockdown of HIF-2α in Min6 cells exaggerated chronic high glucose-induced mitochondrial damage and β-cell dysfunction by increasing mitochondrial ROS levels. Moreover, inducible β-cell HIF-2α knockout mice developed more severe β-cell dysfunction and glucose intolerance on a high-fat diet, along with increased ROS levels and decreased islet mitochondrial mass. Our results provide a previously unknown mechanism through which β-cells defend against increased metabolic stress to promote β-cell compensation in obesity.
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Affiliation(s)
- Jae-Su Moon
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Matthew Riopel
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Jong Bae Seo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Vicente Herrero-Aguayo
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Maimonides Institute of Biomedical Research of Cordoba, Cordoba, Spain
| | - Roi Isaac
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
| | - Yun Sok Lee
- Division of Endocrinology and Metabolism, Department of Medicine, University of California San Diego, La Jolla, CA
- Corresponding author: Yun Sok Lee,
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7
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Geraniol ameliorated serum lipid profile and improved antioxidant defense system in pancreas, liver and heart tissues of alloxan-induced diabetic rats. Biologia (Bratisl) 2021. [DOI: 10.1007/s11756-021-00925-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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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: 35] [Impact Index Per Article: 7.0] [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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9
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Peroxisomal Hydrogen Peroxide Metabolism and Signaling in Health and Disease. Int J Mol Sci 2019; 20:ijms20153673. [PMID: 31357514 PMCID: PMC6695606 DOI: 10.3390/ijms20153673] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 07/24/2019] [Accepted: 07/25/2019] [Indexed: 12/29/2022] Open
Abstract
Hydrogen peroxide (H2O2), a non-radical reactive oxygen species generated during many (patho)physiological conditions, is currently universally recognized as an important mediator of redox-regulated processes. Depending on its spatiotemporal accumulation profile, this molecule may act as a signaling messenger or cause oxidative damage. The focus of this review is to comprehensively evaluate the evidence that peroxisomes, organelles best known for their role in cellular lipid metabolism, also serve as hubs in the H2O2 signaling network. We first briefly introduce the basic concepts of how H2O2 can drive cellular signaling events. Next, we outline the peroxisomal enzyme systems involved in H2O2 metabolism in mammals and reflect on how this oxidant can permeate across the organellar membrane. In addition, we provide an up-to-date overview of molecular targets and biological processes that can be affected by changes in peroxisomal H2O2 metabolism. Where possible, emphasis is placed on the molecular mechanisms and factors involved. From the data presented, it is clear that there are still numerous gaps in our knowledge. Therefore, gaining more insight into how peroxisomes are integrated in the cellular H2O2 signaling network is of key importance to unravel the precise role of peroxisomal H2O2 production and scavenging in normal and pathological conditions.
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10
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Abuid NJ, Gattás-Asfura KM, Schofield EA, Stabler CL. Layer-by-Layer Cerium Oxide Nanoparticle Coating for Antioxidant Protection of Encapsulated Beta Cells. Adv Healthc Mater 2019; 8:e1801493. [PMID: 30633854 PMCID: PMC6625950 DOI: 10.1002/adhm.201801493] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 12/21/2018] [Indexed: 01/15/2023]
Abstract
In type 1 diabetes, the replacement of the destroyed beta cells could restore physiological glucose regulation and eliminate the need for exogenous insulin. Immunoisolation of these foreign cellular transplants via biomaterial encapsulation is widely used to prevent graft rejection. While highly effective in blocking direct cell-to-cell contact, nonspecific inflammatory reactions to the implant lead to the overproduction of reactive oxygen species, which contribute to foreign body reaction and encapsulated cell loss. For antioxidant protection, cerium oxide nanoparticles (CONPs) are a self-renewable, ubiquitous, free radical scavenger currently explored in several biomedical applications. Herein, 2-12 alternating layers of CONP/alginate are assembled onto alginate microbeads containing beta cells using a layer-by-layer (LbL) technique. The resulting nanocomposite coatings demonstrate robust antioxidant activity. The degree of cytoprotection correlates with layer number, indicating tunable antioxidant protection. Coating of alginate beads with 12 layers of CONP/alginate provides complete protection to the entrapped beta cells from exposure to 100 × 10-6 m H2 O2 , with no significant changes in cellular metabolic activity, oxidant capacity, or insulin secretion dynamics, when compared to untreated controls. The flexibility of this LbL method, as well as its nanoscale profile, provides a versatile approach for imparting antioxidant protection to numerous biomedical implants, including beta cell transplantation.
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Affiliation(s)
- Nicholas J Abuid
- Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA
| | - Kerim M Gattás-Asfura
- Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA
| | - Emily A Schofield
- Department of Biomedical Engineering, University of Florida, 1275 Center Drive, Gainesville, FL, 32610, USA
| | - Cherie L Stabler
- Department of Biomedical Engineering, UF Diabetes Institute, University of Florida, Gainesville, FL, 32610, USA
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11
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Raghav A, Ahmad J, Naseem I. Chronic unpredictable environmental stress impair biochemical and physiological homeostasis: Role in diabetes mellitus. Diabetes Metab Syndr 2019; 13:1021-1030. [PMID: 31336438 DOI: 10.1016/j.dsx.2019.01.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 01/17/2019] [Indexed: 10/27/2022]
Abstract
AIMS Chronic unpredictable environmental stress (CUES) may induce predisposition to diabetes mellitus. This study investigates the role of CUES on impaired homeostasis. MATERIAL AND METHODS Stressed group mice (n = 20) were exposed to CUES for 16 weeks. Weekly body weight, feed consumption, feed efficiency ratio, fasting blood glucose were monitored. Plasma HbA1c, plasma cortisol, plasma epinephrine and plasma insulin, serum lipids, antioxidants and carbohydrate metabolizing enzymes activity were assessed along with DNA damage and histopathological examination of liver, kidney, pancreas, spleen and skeletal muscles. RESULTS AND CONCLUSION s: Fasting blood glucose levels & HbA1c in the stressed were significantly higher compared to control (p < 0.001). Serum lipids were found insignificantly higher in stressed mice compared to control. Body weights of the stressed mice and feed efficiency ratio were found significant (p < 0.001). Plasma corticosterone, plasma epinephrine, HOMA-IR was found to be significantly higher in the stressed group (p < 0.001). Plasma insulin level was found to be significantly lower in the stressed group (p < 0.001). Significant changes were observed in antioxidants level, carbohydrate metabolizing enzymes activity, peripheral tissues and DNA integrity. CUES initiates pathogenesis of diabetes.
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Affiliation(s)
- Alok Raghav
- Rajiv Gandhi Centre for Diabetes and Endocrinology, J.N Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh, 202002, India
| | - Jamal Ahmad
- Rajiv Gandhi Centre for Diabetes and Endocrinology, J.N Medical College, Faculty of Medicine, Aligarh Muslim University, Aligarh, 202002, India.
| | - Imrana Naseem
- Department of Biochemistry, Aligarh Muslim University, Aligarh, 202002, India
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12
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Stancill JS, Broniowska KA, Oleson BJ, Naatz A, Corbett JA. Pancreatic β-cells detoxify H 2O 2 through the peroxiredoxin/thioredoxin antioxidant system. J Biol Chem 2019; 294:4843-4853. [PMID: 30659092 DOI: 10.1074/jbc.ra118.006219] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 01/15/2019] [Indexed: 01/07/2023] Open
Abstract
Oxidative stress is thought to promote pancreatic β-cell dysfunction and contribute to both type 1 and type 2 diabetes. Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, are mediators of oxidative stress that arise largely from electron leakage during oxidative phosphorylation. Reports that β-cells express low levels of antioxidant enzymes, including catalase and GSH peroxidases, have supported a model in which β-cells are ill-equipped to detoxify ROS. This hypothesis seems at odds with the essential role of β-cells in the control of metabolic homeostasis and organismal survival through exquisite coupling of oxidative phosphorylation, a prominent ROS-producing pathway, to insulin secretion. Using glucose oxidase to deliver H2O2 continuously over time and Amplex Red to measure extracellular H2O2 concentration, we found here that β-cells can remove micromolar levels of this oxidant. This detoxification pathway utilizes the peroxiredoxin/thioredoxin antioxidant system, as selective chemical inhibition or siRNA-mediated depletion of thioredoxin reductase sensitized β-cells to continuously generated H2O2 In contrast, when delivered as a bolus, H2O2 induced the DNA damage response, depleted cellular energy stores, and decreased β-cell viability independently of thioredoxin reductase inhibition. These findings show that β-cells have the capacity to detoxify micromolar levels of H2O2 through a thioredoxin reductase-dependent mechanism and are not as sensitive to oxidative damage as previously thought.
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Affiliation(s)
- Jennifer S Stancill
- From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Katarzyna A Broniowska
- From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Bryndon J Oleson
- From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - Aaron Naatz
- From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
| | - John A Corbett
- From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226
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13
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Catalase and nonalcoholic fatty liver disease. Pflugers Arch 2018; 470:1721-1737. [PMID: 30120555 DOI: 10.1007/s00424-018-2195-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/01/2018] [Accepted: 08/06/2018] [Indexed: 02/06/2023]
Abstract
Obesity and insulin resistance are considered the main causes of nonalcoholic fatty liver disease (NAFLD), and oxidative stress accelerates the progression of NAFLD. Free fatty acids, which are elevated in the liver by obesity or insulin resistance, lead to incomplete oxidation in the mitochondria, peroxisomes, and microsomes, leading to the production of reactive oxygen species (ROS). Among the ROS generated, H2O2 is mainly produced in peroxisomes and decomposed by catalase. However, when the H2O2 concentration increases because of decreased expression or activity of catalase, it migrates to cytosol and other organelles, causing cell injury and participating in the Fenton reaction, resulting in serious oxidative stress. To date, numerous studies have been shown to inhibit the pathogenesis of NAFLD, but treatment for this disease mainly depends on weight loss and exercise. Various molecules such as vitamin E, metformin, liraglutide, and resveratrol have been proposed as therapeutic agents, but further verification of the dose setting, clinical application, and side effects is needed. Reducing oxidative stress may be a fundamental method for improving not only the progression of NAFLD but also obesity and insulin resistance. However, the relationship between NAFLD progression and antioxidants, particularly catalase, which is most commonly expressed in the liver, remains unclear. Therefore, this review summarizes the role of catalase, focusing on its potential therapeutic effects in NAFLD progression.
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14
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Barra JM, Tse HM. Redox-Dependent Inflammation in Islet Transplantation Rejection. Front Endocrinol (Lausanne) 2018; 9:175. [PMID: 29740396 PMCID: PMC5924790 DOI: 10.3389/fendo.2018.00175] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 04/03/2018] [Indexed: 12/19/2022] Open
Abstract
Type 1 diabetes is an autoimmune disease that results in the progressive destruction of insulin-producing pancreatic β-cells inside the islets of Langerhans. The loss of this vital population leaves patients with a lifelong dependency on exogenous insulin and puts them at risk for life-threatening complications. One method being investigated to help restore insulin independence in these patients is islet cell transplantation. However, challenges associated with transplant rejection and islet viability have prevented long-term β-cell function. Redox signaling and the production of reactive oxygen species (ROS) by recipient immune cells and transplanted islets themselves are key players in graft rejection. Therefore, dissipation of ROS generation is a viable intervention that can protect transplanted islets from immune-mediated destruction. Here, we will discuss the newly appreciated role of redox signaling and ROS synthesis during graft rejection as well as new strategies being tested for their efficacy in redox modulation during islet cell transplantation.
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15
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Amelioration of streptozotocin‑induced pancreatic β cell damage by morin: Involvement of the AMPK‑FOXO3‑catalase signaling pathway. Int J Mol Med 2017; 41:1409-1418. [PMID: 29286118 PMCID: PMC5819920 DOI: 10.3892/ijmm.2017.3357] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 12/13/2017] [Indexed: 01/24/2023] Open
Abstract
Pancreatic β cells are sensitive to oxidative stress, which is one of the predominant causes of cell damage and the emergence of diabetes. The identification of effective therapeutic strategies to protect pancreatic cells from oxidative stress has increased interest in the screening of antioxidants from natural products. The present study aimed to investigate the protective effects of morin against streptozotocin (STZ)‑induced cell damage in a rat insulinoma cell line (RINm5F pancreatic β cells) and to identify the underlying mechanisms. The results indicated that morin inhibited the increase in intracellular reactive oxygen species, attenuated the activity of poly (ADP‑ribose) polymerase, restored intracellular nicotinamide adenine dinucleotide levels and reduced the apoptotic cell death of STZ‑treated pancreatic β cells. Treatment with morin significantly upregulated catalase in pancreatic β cells, and ameliorated the STZ‑induced loss of catalase at the genetic, protein and enzymatic level. In further experiments, morin induced the phosphorylation of 5' adenosine monophosphate‑activated protein kinase (AMPK), which subsequently promoted the translocation of forkhead box O3 (FOXO3) to the nucleus. Specific small interfering RNAs (siRNAs) against AMPK and FOXO3 suppressed morin‑induced catalase expression. Furthermore, catalase‑specific siRNA abolished the protective effects of morin against STZ‑stimulated cell death. Taken together, these results indicated that morin protected RINm5F cells from STZ‑induced cell damage by triggering the phosphorylation of AMPK, thus resulting in subsequent activation of FOXO3 and induction of catalase.
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Bonini MG, Sargis RM. Environmental Toxicant Exposures and Type 2 Diabetes Mellitus: Two Interrelated Public Health Problems on the Rise. CURRENT OPINION IN TOXICOLOGY 2017; 7:52-59. [PMID: 29392186 DOI: 10.1016/j.cotox.2017.09.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Rates of type 2 diabetes mellitus (T2DM) are rising rapidly across the globe and the impact of this devastating disease threatens to plague the 21st century. While some contributing factors are well-recognized (e.g. sedentary lifestyles and caloric excess), others diabetes-promoting risk factors are less established or poorly appreciated. The latter category includes environmental exposures to diabetogenic contaminants. Herein we review some of the latest concepts and mechanisms by which environmental exposures may contribute to rising rates of T2DM with a particular focus on mechanisms involving mitochondrial dysfunction and imbalances in reactive oxygen species (ROS). Furthermore, while the pathogenesis of diabetes includes impairments in insulin sensitivity as well as insulin secretion, we will specifically delve into the links between environmental exposures to toxicants such as arsenic and disruptions in insulin release from pancreatic β-cells. Since β-cell death or dysfunction lies at the heart of both T2DM as well as type 1 diabetes mellitus (T1DM), environmental endocrine disrupting chemicals (EDCs) that disrupt the production or regulated release of the glucose-lowering hormone insulin are likely contributors to diabetes risk. Importantly, understanding the contribution of toxicants to diabetes risk as well as improved understanding of their mechanisms of action offer unique opportunities to modulate diabetes risk via targeted therapeutics or public policy interventions to reduce and remediate exposures.
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Affiliation(s)
- Marcelo G Bonini
- Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
| | - Robert M Sargis
- Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA
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17
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Kim MK, Shin HM, Jung H, Lee E, Kim TK, Kim TN, Kwon MJ, Lee SH, Rhee BD, Park JH. Comparison of pancreatic beta cells and alpha cells under hyperglycemia: Inverse coupling in pAkt-FoxO1. Diabetes Res Clin Pract 2017; 131:1-11. [PMID: 28666105 DOI: 10.1016/j.diabres.2017.05.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Revised: 05/04/2017] [Accepted: 05/16/2017] [Indexed: 01/09/2023]
Abstract
Type 2 diabetes manifests beta cell deficiencies and alpha cell expansion which is consistent with relative insulin deficiency and glucagon oversecretion. The effects of hyperglycemia on alpha cells are not as understood in comparison to beta cells. Hyperglycemia increases oxidative stress, which induces Akt activation or FoxO activation, depending on cell type. Several studies independently reported that FoxO1 translocations in alpha cells and beta cells were opposite. We compared the responses of pancreatic alpha cells and beta cells against hyperglycemia. Alpha TC-1 cells and Beta TC-6 cells were incubated with control (5mM Glucose) or high glucose (33mM Glucose) with or without PI3K inhibitor or FoxO1 inhibitor. We assessed PI3K, pAkt and phosphorylated FoxO1 (pFoxO1) in both cell lines. Immunostaining of BrdU and FoxO1 was detected by green fluorescence microscopy and confocal microscopy. Hyperglycemia and H2O2 decreased PI3K and pAKT in beta cells, but increased them in alpha cells. FoxO1 localizations and pFoxO1 expressions between alpha cells and beta cells were opposite. Proliferation of beta cells was decreased, but alpha cell proliferation was increased under hyperglycemia. Antioxidant enzymes including superoxide dismutase (SOD) and catalase were increased in beta cells and they were reversed with FoxO1 inhibitor treatment. Increased proliferation in alpha cells under hyperglycemia was attenuated with PI3K inhibitor. In conclusion, hyperglycemia increased alpha cell proliferation and glucagon contents which are opposite to beta cells. These differences may be related to contrasting PI3K/pAkt changes in both cells and subsequent FoxO1 modulation.
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Affiliation(s)
- Mi-Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea; Paik Institute for Clinical Research, Molecular Therapy Lab, Inje University, Busan, South Korea.
| | - Hyun Mi Shin
- Paik Institute for Clinical Research, Molecular Therapy Lab, Inje University, Busan, South Korea
| | - HyeSook Jung
- Paik Institute for Clinical Research, Molecular Therapy Lab, Inje University, Busan, South Korea
| | - EunJu Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Tae Kyoon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Tae Nyun Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Min Jeong Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Soon Hee Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Byoung Doo Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea
| | - Jeong Hyun Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, Busan, South Korea; Paik Institute for Clinical Research, Molecular Therapy Lab, Inje University, Busan, South Korea
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18
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Chisci E, De Giorgi M, Zanfrini E, Testasecca A, Brambilla E, Cinti A, Farina L, Kutryb-Zajac B, Bugarin C, Villa C, Grassilli E, Combi R, Gaipa G, Cerrito MG, Rivolta I, Smolenski RT, Lavitrano M, Giovannoni R. Simultaneous overexpression of human E5NT and ENTPD1 protects porcine endothelial cells against H 2O 2-induced oxidative stress and cytotoxicity in vitro. Free Radic Biol Med 2017; 108:320-333. [PMID: 28389406 DOI: 10.1016/j.freeradbiomed.2017.03.038] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 02/28/2017] [Accepted: 03/29/2017] [Indexed: 12/12/2022]
Abstract
Ischemia-reperfusion injury (IRI) and oxidative stress still limit the survival of cells and organs in xenotransplantation models. Ectonucleotidases play an important role in inflammation and IRI in transplantation settings. We tested the potential protective effects derived by the co-expression of the two main vascular ectonucleotidases, ecto-5'-nucleotidase (E5NT) and ecto nucleoside triphosphate diphosphohydrolase 1 (ENTPD1), in an in vitro model of H2O2-induced oxidative stress and cytotoxicity. We produced a dicistronic plasmid (named pCX-DI-2A) for the co-expression of human E5NT and ENTPD1 by using the F2A technology. pCX-DI-2A-transfected porcine endothelial cells simultaneously overexpressed hE5NT and hENTPD1, which were correctly processed and localized on the plasma membrane. Furthermore, such co-expression system led to the synergistic enzymatic activity of hE5NT and hENTPD1 as shown by the efficient catabolism of pro-inflammatory and pro-thrombotic extracellular adenine nucleotides along with the enhanced production of the anti-inflammatory molecule adenosine. Interestingly, we found that the hE5NT/hENTPD1 co-expression system conferred protection to cells against H2O2-induced oxidative stress and cytotoxicity. pCX-DI-2A-transfected cells showed reduced activation of caspase 3/7 and cytotoxicity than mock-, hE5NT- and hENTPD1-transfected cells. Furthermore, pCX-DI-2A-transfected cells showed decreased H2O2-induced production of ROS as compared to the other control cell lines. The cytoprotective phenotype observed in pCX-DI-2A-transfected cells was associated with higher detoxifying activity of catalase as well as increased activation of the survival signaling molecules Akt, extracellular signal-regulated kinases 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK). Our data add new insights to the protective effects of the combination of hE5NT and hENTPD1 against oxidative stress and constitute a proof of concept for testing this new genetic combination in pig-to-non-human primates xenotransplantation models.
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Affiliation(s)
- Elisa Chisci
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Marco De Giorgi
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy; Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
| | - Elisa Zanfrini
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Angela Testasecca
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Elena Brambilla
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Alessandro Cinti
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Laura Farina
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Barbara Kutryb-Zajac
- Department of Biochemistry, Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
| | - Cristina Bugarin
- M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, 20900 Monza, Italy
| | - Chiara Villa
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Emanuela Grassilli
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Romina Combi
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Giuseppe Gaipa
- M. Tettamanti Research Center, Pediatric Clinic, University of Milano Bicocca, 20900 Monza, Italy
| | - Maria Grazia Cerrito
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Ilaria Rivolta
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | | | - Marialuisa Lavitrano
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy
| | - Roberto Giovannoni
- School of Medicine and Surgery, University of Milano-Bicocca, via Cadore 48, 20900 Monza, Italy.
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19
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Ahmed Alfar E, Kirova D, Konantz J, Birke S, Mansfeld J, Ninov N. Distinct Levels of Reactive Oxygen Species Coordinate Metabolic Activity with Beta-cell Mass Plasticity. Sci Rep 2017; 7:3994. [PMID: 28652605 PMCID: PMC5484671 DOI: 10.1038/s41598-017-03873-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 05/08/2017] [Indexed: 11/13/2022] Open
Abstract
The pancreatic beta-cells control glucose homeostasis by secreting insulin in response to nutrient intake. The number of beta-cells is under tight metabolic control, as this number increases with higher nutrient intake. However, the signaling pathways matching nutrition with beta-cell mass plasticity remain poorly defined. By applying pharmacological and genetic manipulations, we show that reactive oxygen species (ROS) regulate dose-dependently beta-cell proliferation in vivo and in vitro. In particular, reducing ROS levels in beta-cells blocks their proliferation in response to nutrients. Using a non-invasive genetic sensor of intracellular hydrogen peroxide (H2O2), we reveal that glucose can directly increase the levels of H2O2. Furthermore, a moderate increase in H2O2 levels can stimulate beta-cell proliferation. Interestingly, while high H2O2 levels are inhibitory to beta-cell proliferation, they expand beta-cell mass in vivo by inducing rapid beta-cell neogenesis. Our study thus reveals a ROS-level-dependent mechanism linking nutrients with beta-cell mass plasticity. Hence, given the requirement of ROS for beta-cell mass expansion, antioxidant therapies should be applied with caution in diabetes.
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Affiliation(s)
- Ezzaldin Ahmed Alfar
- DFG Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany.,Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus of Technische Universität Dresden, Dresden, Germany.,German Center for Diabetes Research (DZD e.V.), Neuherberg, Neuherberg, Germany.,Department of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany
| | - Dilyana Kirova
- Cell Cycle, Biotechnology Center, Technische Universität Dresden, 01307, Dresden, Germany
| | - Judith Konantz
- DFG Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Sarah Birke
- DFG Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany
| | - Jörg Mansfeld
- Cell Cycle, Biotechnology Center, Technische Universität Dresden, 01307, Dresden, Germany.
| | - Nikolay Ninov
- DFG Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany. .,Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus of Technische Universität Dresden, Dresden, Germany. .,German Center for Diabetes Research (DZD e.V.), Neuherberg, Neuherberg, Germany.
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20
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Georges P, Muirhead RP, Williams L, Holman S, Tabiin MT, Dean SK, Tuch BE. Comparison of Size, Viability, and Function of Fetal Pig Islet-Like Cell Clusters after Digestion Using Collagenase or Liberase. Cell Transplant 2017. [DOI: 10.3727/000000002783985477] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Liberase is a highly purified blend of collagenases that has been specifically developed to eliminate the numerous problems associated with the conventional use of crude collagenase when isolating islet-like cell clusters (ICCs) from pancreases of different species. The influence of Liberase on yield, size, viability, and function of ICCs has been documented when this enzyme was used to digest adult but not fetal pancreases. In this study, we compared the effects of collagenase and Liberase on fetal pig ICCs. A total of eight fetal pig pancreas digestions were analyzed. Fetuses were obtained from Large White Landrace pigs of gestational age 80 ± 2.1 days. The pancreases were digested with either 3 mg/ml collagenase P or 1.2 mg/ml Liberase HI. The time taken to digest the pancreas was shorter for collagenase when compared with Liberase (22 ± 2 vs. 31 ± 2 min). The size of ICCs was similar for both collagenase (83 ± 0.5 μm) and Liberase (79 ± 0.4 μm) as was the number of ICCs produced per pancreas (7653 ± 1297 vs. 8101 ± 1177). Viability, as assessed using fluorescent markers, was slightly greater for Liberase (79 ± 1% vs. 76 ± 1%, p < 0.05). Responsiveness to β-cell stimulus (20 mM KCl) was similar for both methods of isolation, as was the insulin content of the ICCs, both in vitro and at 1 month after transplantation of 1500 ICCs beneath the renal capsule of immunoincompetent mice. Despite the high content of endotoxins in collagenase, the above results show that this enzyme was equally as efficient as Liberase in isolating functional ICCs from fetal pig pancreas.
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Affiliation(s)
- Pauline Georges
- Diabetes Transplant Unit, Prince of Wales Hospital and The University of New South Wales, Sydney, New South Wales, 2031, Australia
| | - Roslyn P. Muirhead
- Diabetes Transplant Unit, Prince of Wales Hospital and The University of New South Wales, Sydney, New South Wales, 2031, Australia
| | - Lindy Williams
- Diabetes Transplant Unit, Prince of Wales Hospital and The University of New South Wales, Sydney, New South Wales, 2031, Australia
| | - Sara Holman
- Diabetes Transplant Unit, Prince of Wales Hospital and The University of New South Wales, Sydney, New South Wales, 2031, Australia
| | - Muhammad Tani Tabiin
- Diabetes Transplant Unit, Prince of Wales Hospital and The University of New South Wales, Sydney, New South Wales, 2031, Australia
| | - Sophia K. Dean
- Diabetes Transplant Unit, Prince of Wales Hospital and The University of New South Wales, Sydney, New South Wales, 2031, Australia
| | - Bernard E. Tuch
- Diabetes Transplant Unit, Prince of Wales Hospital and The University of New South Wales, Sydney, New South Wales, 2031, Australia
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21
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Rehman K, Akash MSH. Mechanism of Generation of Oxidative Stress and Pathophysiology of Type 2 Diabetes Mellitus: How Are They Interlinked? J Cell Biochem 2017; 118:3577-3585. [PMID: 28460155 DOI: 10.1002/jcb.26097] [Citation(s) in RCA: 321] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 04/26/2017] [Indexed: 12/14/2022]
Abstract
Oxidative stress has been considered as a major hallmark for the pathogenesis and development of type 2 diabetes mellitus (T2DM), but still it is debatable whether it is a mere aggregation of inflammatory-induced responses or clinical entity that underlies with various pathophysiological factors. In this regard, the latest studies have shown the increasing trends for the involvement of reactive oxygen species (ROS) and oxidative stress in the pathogenesis and development of T2DM. ROS are highly reactive species and almost all cellular components are chemically changed due to the influence of ROS that ultimately results in the production of lipid peroxidation. Lipid peroxidation is a major causative factor for the development of oxidative stress that leads to overt T2DM and its associated micro- and macro-vascular complications. In this article, we have briefly described the role of various causative factors, transcriptional and metabolic pathways which are responsible to increase the production of oxidative stress, a most pivotal factor for the pathogenesis and development of T2DM. Therefore, we conclude that measurement of oxidative stress biomarkers may be one of the optional tool for the diagnosis and prediction of T2DM. Moreover, the key findings described in this article also provides a new conceptual framework for forthcoming investigations on the role of oxidative stress in pathogenesis of T2DM and drug discovery. J. Cell. Biochem. 118: 3577-3585, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Kanwal Rehman
- Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan
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22
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Apigenin attenuates streptozotocin-induced pancreatic β cell damage by its protective effects on cellular antioxidant defense. In Vitro Cell Dev Biol Anim 2017; 53:554-563. [PMID: 28181104 DOI: 10.1007/s11626-017-0135-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Accepted: 01/19/2017] [Indexed: 12/30/2022]
Abstract
Pancreatic beta cells are very sensitive to oxidative stress, which is one of the major causes of cell damages in diabetes. Growing interest has focused on the development of effective therapeutics to protect pancreatic cells from oxidative stress and searching for potentially protective antioxidants for treating diabetes. Apigenin, a plant-derived flavonoid, was investigated to determine whether it could protect rat insulinoma cell lines (RINm5F pancreatic beta cells) against streptozotocin (STZ)-induced oxidative damages and the mechanisms implicated. Our results showed that STZ treatment could induce oxidative stress and consequent cytotoxic effects in RINm5F cells. Pretreatment with apigenin effectively decreased the intracellular reactive oxygen species (ROS) production, attenuated cellular DNA damage, diminished lipid peroxidation, relieved protein carbonylation, and restored the cell apoptosis of pancreatic beta cells stressed by STZ. Our further experiments demonstrated that the beneficial effects of apigenin were related to ameliorate the loss of antioxidant enzymes of the STZ-treated cells in the level of gene transcription, protein expression, and enzyme activity. That suggested apigenin was not only a free radical scavenger but also a regulator to antioxidant defenses of pancreatic cells. Taken all together, our findings suggested that apigenin could attenuate the STZ-induced oxidative damages in pancreatic beta cells and might serve as a novel agent for the treatment of diabetes.
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23
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Heit C, Marshall S, Singh S, Yu X, Charkoftaki G, Zhao H, Orlicky DJ, Fritz KS, Thompson DC, Vasiliou V. Catalase deletion promotes prediabetic phenotype in mice. Free Radic Biol Med 2017; 103:48-56. [PMID: 27939935 PMCID: PMC5513671 DOI: 10.1016/j.freeradbiomed.2016.12.011] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 11/02/2016] [Accepted: 12/07/2016] [Indexed: 01/22/2023]
Abstract
Hydrogen peroxide is produced endogenously and can be toxic to living organisms by inducing oxidative stress and cell damage. However, it has also been identified as a signal transduction molecule. By metabolizing hydrogen peroxide, catalase protects cells and tissues against oxidative damage and may also influence signal transduction mechanisms. Studies suggest that acatalasemic individuals (i.e., those with very low catalase activity) have a higher risk for the development of diabetes. We now report catalase knockout (Cat-/-) mice, when fed a normal (6.5% lipid) chow, exhibit an obese phenotype that manifests as an increase in body weight that becomes more pronounced with age. The mice demonstrate altered hepatic and muscle lipid deposition, as well as increases in serum and hepatic triglycerides (TGs), and increased hepatic transcription and protein expression of PPARγ. Liver morphology revealed steatosis with inflammation. Cat-/- mice also exhibited pancreatic morphological changes that correlated with impaired glucose tolerance and increased fasting serum insulin levels, conditions consistent with pre-diabetic status. RNA-seq analyses revealed a differential expression of pathways and genes in Cat-/- mice, many of which are related to metabolic syndrome, diabetes, and obesity, such as Pparg and Cidec. In conclusion, the results of the present study show mice devoid of catalase develop an obese, pre-diabetic phenotype and provide compelling evidence for catalase (or its products) being integral in metabolic regulation.
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Affiliation(s)
- Claire Heit
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO 80045, USA
| | - Stephanie Marshall
- Department of Environmental Health Services, Yale School of Public Health, Yale University, 60 College St, New Haven CT 06520-8034, USA
| | - Surrendra Singh
- Department of Environmental Health Services, Yale School of Public Health, Yale University, 60 College St, New Haven CT 06520-8034, USA
| | - Xiaoqing Yu
- Department of Biostatistics, Yale School of Public Health, Yale University, New Haven CT 06520, USA
| | - Georgia Charkoftaki
- Department of Environmental Health Services, Yale School of Public Health, Yale University, 60 College St, New Haven CT 06520-8034, USA
| | - Hongyu Zhao
- Department of Biostatistics, Yale School of Public Health, Yale University, New Haven CT 06520, USA
| | - David J Orlicky
- Department of Pathology, School of Medicine University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Kristofer S Fritz
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO 80045, USA
| | - David C Thompson
- Department of Clinical Pharmacy, School of Pharmacy, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, CO 80045, USA
| | - Vasilis Vasiliou
- Department of Environmental Health Services, Yale School of Public Health, Yale University, 60 College St, New Haven CT 06520-8034, USA.
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24
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KOBAYASHI M, KURATA T, HAMANA Y, HIRAMITSU M, INOUE T, MURAI A, HORIO F. Coffee Ingestion Suppresses Hyperglycemia in Streptozotocin-Induced Diabetic Mice. J Nutr Sci Vitaminol (Tokyo) 2017; 63:200-207. [DOI: 10.3177/jnsv.63.200] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Misato KOBAYASHI
- Department of Applied Molecular Bioscience, Graduate School of Bioagricultural Sciences, Nagoya University
| | - Takao KURATA
- Department of Applied Molecular Bioscience, Graduate School of Bioagricultural Sciences, Nagoya University
| | - Yoshiki HAMANA
- Department of Applied Molecular Bioscience, Graduate School of Bioagricultural Sciences, Nagoya University
| | | | - Takashi INOUE
- Research & Development Division, Pokka Sapporo Food & Beverage Ltd
| | - Atsushi MURAI
- Department of Applied Molecular Bioscience, Graduate School of Bioagricultural Sciences, Nagoya University
| | - Fumihiko HORIO
- Department of Applied Molecular Bioscience, Graduate School of Bioagricultural Sciences, Nagoya University
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25
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Schott-Ohly P, Lgssiar A, Partke HJ, Hassan M, Friesen N, Gleichmann H. Prevention of Spontaneous and Experimentally Induced Diabetes in Mice with Zinc Sulfate-Enriched Drinking Water is Associated with Activation and Reduction of NF-κB and AP-1 in Islets, Respectively. Exp Biol Med (Maywood) 2016; 229:1177-85. [PMID: 15564445 DOI: 10.1177/153537020422901113] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Recently, we reported that zinc sulfate-enriched (25 mM) drinking water (Zn2+) protected male C57BL/6 mice from diabetes induced by multiple low doses of streptozotocin (MLD-STZ) and that MLD-STZ activates the transcription factors nuclear factor (NF)-κB and activator protein (AP)-1 in islets of these mice. Therefore, we studied the effect of Zn2+ on spontaneous diabetes in female nonobese diabetic (NOD) mice and on the activity of NF-κB and AP-1 in islets of NOD and MLD-STZ–injected male C57BL/6 mice. We hypothesized that Zn2+ may affect NF-κB, which may play a key role in immune-mediated diabetogenesis. Here we continuously administered Zn2+ to NOD mice, to both parents and their F1 offspring, and treated C57BL/6 male mice with MLD-STZ either alone or in addition to Zn2+. We assessed effects of Zn2+ on insulitis and peri-insulitis in 8-week-old NOD mice and analyzed NF-κB and AP-1 activities in islets. Zn2+ significantly prevented diabetes in female F1 offspring and significantly reduced insulitis and peri-insulitis. Zn2+ significantly stimulated NF-κB and AP-1 activation in NOD mice, in contrast, in C57BL/6 mice, Zn2+ significantly reduced their activation by MLD-STZ. These data demonstrate that NF-κB may play a critical role in immune-mediated diabetes. Depending on the mode of β-cell destruction, Zn2+ may prevent apoptosis through activation of NF-κB in NOD mice or prevent inflammatory immune destruction through inhibition of NF-κB in MLD-STZ-treated C57BL/6 mice.
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Affiliation(s)
- Patricia Schott-Ohly
- German Diabetes Center, German Diabetes Research Institute, D-40225 Düsseldorf, Germany
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26
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Kim MJ, Hwang YH, Kim YH, Lee DY. Immunomodulation of cell-penetrating tat-metallothionein for successful outcome of xenotransplanted pancreatic islet. J Drug Target 2016; 25:350-359. [PMID: 27829285 DOI: 10.1080/1061186x.2016.1258704] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Pancreatic islet transplantation is a promising treatment for treatment of type 1 diabetes; however, transplantation outcomes have been disappointing due to early graft loss that is mediated by many immune responses. Immune cells not only directly damaged islet but also produced reactive oxygen species (ROS), which is highly toxic to islet cells. Metallothionein (MT) can provide protection against oxidative stress by scavenging various ranges of ROS including superoxide, hydroxyl radical, hydrogen peroxide and nitric oxide. For scavenging immune response-induced ROS, cell-penetrating Tat peptide-metallothionein (Tat-MT) was delivered into islets. The viability of Tat-MT-treated islets was not damaged during co-culture with macrophages or ROS-generating paraquat. When Tat-MT-treated islets were xenotransplanted, ROS production was significantly attenuated at the islets. Eventually, the survival time of Tat-MT-treated islets was significantly enhanced without any immunosuppressant medicine. Additionally, we confirmed that the survival time of Tat-MT-treated islets in all animals was dramatically improved when accompanied with low dose immunosuppressive agents (tacrolimus and anti-CD154 monoclonal antibody), indicating that Tat-MT delivery could have synergistic effect with immunosuppressants. Collectively, this new combination therapy of Tat-MT delivery with low dose immunosuppressant would be a powerful remedy for successful outcome of islet xenotransplantation.
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Affiliation(s)
- Min Jun Kim
- a Departments of Bioengineering , College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University , Seoul , Republic of Korea
| | - Yong Hwa Hwang
- a Departments of Bioengineering , College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University , Seoul , Republic of Korea
| | - Yong Hee Kim
- a Departments of Bioengineering , College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University , Seoul , Republic of Korea
| | - Dong Yun Lee
- a Departments of Bioengineering , College of Engineering, and BK21 PLUS Future Biopharmaceutical Human Resources Training and Research Team, Hanyang University , Seoul , Republic of Korea.,b Institute of Nano Science and Technology (INST), Hanyang University , Seoul , Republic of Korea
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Abstract
OBJECTIVES Mechanisms of toxicity and cell damage were investigated in novel clonal human pancreatic beta cell line, 1.1B4, after exposure to streptozotocin, alloxan, ninhydrin, and hydrogen peroxide. METHODS Viability, DNA damage, insulin secretion/content, [Ca]i, and glucokinase/hexokinase, mRNA expression were measured by MTT assay, comet assay, radioimmunoassay, fluorometric imaging plate reader, enzyme-coupled photometry, and real-time polymerase chain reaction, respectively. RESULTS Chemicals significantly reduced 1.1B4 cell viability in a time/concentration-dependent manner. Chronic 18-hour exposure decreased cellular insulin, glucokinase, and hexokinase activities. Chemicals decreased transcription of INS, GCK, PCSK1, PCSK2, and GJA1 (involved in secretory function). Insulin release and [Ca]i responses to nutrients and membrane-depolarizing agents were impaired. Streptozotocin and alloxan up-regulated transcription of genes, SOD1 and SOD2 (antioxidant enzymes). Ninhydrin and hydrogen peroxide up-regulated SOD2 transcription, whereas alloxan and hydrogen peroxide increased CAT transcription. Chemicals induced DNA damage, apoptosis, and increased caspase 3/7 activity. Streptozotocin and alloxan decreased transcription of BCL2 while increasing transcription of BAX. Chemicals did not affect transcription of HSPA4 and HSPA5 and nitrite production. CONCLUSIONS 1.1B4 cells represent a useful model of human beta cells. Chemicals impaired 1.1B4 cell secretory function and activated antioxidant defense and apoptotic pathways without activating endoplasmic reticulum stress response/nitrosative stress.
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Di Meo S, Reed TT, Venditti P, Victor VM. Role of ROS and RNS Sources in Physiological and Pathological Conditions. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:1245049. [PMID: 27478531 PMCID: PMC4960346 DOI: 10.1155/2016/1245049] [Citation(s) in RCA: 810] [Impact Index Per Article: 90.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 05/04/2016] [Accepted: 05/23/2016] [Indexed: 12/19/2022]
Abstract
There is significant evidence that, in living systems, free radicals and other reactive oxygen and nitrogen species play a double role, because they can cause oxidative damage and tissue dysfunction and serve as molecular signals activating stress responses that are beneficial to the organism. Mitochondria have been thought to both play a major role in tissue oxidative damage and dysfunction and provide protection against excessive tissue dysfunction through several mechanisms, including stimulation of opening of permeability transition pores. Until recently, the functional significance of ROS sources different from mitochondria has received lesser attention. However, the most recent data, besides confirming the mitochondrial role in tissue oxidative stress and protection, show interplay between mitochondria and other ROS cellular sources, so that activation of one can lead to activation of other sources. Thus, it is currently accepted that in various conditions all cellular sources of ROS provide significant contribution to processes that oxidatively damage tissues and assure their survival, through mechanisms such as autophagy and apoptosis.
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Affiliation(s)
- Sergio Di Meo
- Dipartimento di Biologia, Università di Napoli “Federico II”, 80126 Napoli, Italy
| | - Tanea T. Reed
- Department of Chemistry, Eastern Kentucky University, Richmond, KY 40475, USA
| | - Paola Venditti
- Dipartimento di Biologia, Università di Napoli “Federico II”, 80126 Napoli, Italy
| | - Victor Manuel Victor
- Service of Endocrinology, University Hospital Dr. Peset, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), 46010 Valencia, Spain
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Lei XG, Zhu JH, Cheng WH, Bao Y, Ho YS, Reddi AR, Holmgren A, Arnér ESJ. Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications. Physiol Rev 2016; 96:307-64. [PMID: 26681794 DOI: 10.1152/physrev.00010.2014] [Citation(s) in RCA: 274] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate "paradoxical" outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of "antioxidant" nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that "paradoxical" roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways.
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Affiliation(s)
- Xin Gen Lei
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Jian-Hong Zhu
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Wen-Hsing Cheng
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Yongping Bao
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Ye-Shih Ho
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Amit R Reddi
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Arne Holmgren
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Elias S J Arnér
- Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing,China; Department of Animal Science, Cornell University, Ithaca, New York; Department of Preventive Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, China; Department of Food Science, Nutrition and Health Promotion, Mississippi State University, Mississippi State, Mississippi; Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom; Institute of Environmental Health Sciences, Wayne State University, Detroit, Michigan; Georgia Institute of Technology, School of Chemistry and Biochemistry, Parker Petit Institute for Bioengineering and Biosciences, Atlanta, Georgia; and Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
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DINIĆ S, GRDOVIĆ N, USKOKOVIĆ A, ĐORĐEVIĆ M, MIHAILOVIĆ M, JOVANOVIĆ JA, POZNANOVIĆ G, VIDAKOVIĆ M. CXCL12 protects pancreatic β-cells from oxidative stress by a Nrf2-induced increase in catalase expression and activity. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2016; 92:436-454. [PMID: 27840391 PMCID: PMC5328787 DOI: 10.2183/pjab.92.436] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Due to intrinsically low levels of antioxidant enzyme expression and activity, insulin producing pancreatic β-cells are particularly susceptible to free radical attack. In diabetes mellitus, which is accompanied by high levels of oxidative stress, this feature of β-cells significantly contributes to their damage and dysfunction. In light of the documented pro-survival effect of chemokine C-X-C Ligand 12 (CXCL12) on pancreatic β-cells, we examined its potential role in antioxidant protection. We report that CXCL12 overexpression enhanced the resistance of rat insulinoma (Rin-5F) and primary pancreatic islet cells to hydrogen peroxide (H2O2). CXCL12 lowered the levels of DNA damage and lipid peroxidation and preserved insulin expression. This effect was mediated through an increase in catalase (CAT) activity. By activating downstream p38, Akt and ERK kinases, CXCL12 facilitated Nrf2 nuclear translocation and enhanced its binding to the CAT gene promoter, inducing constitutive CAT expression and activity that was essential for protecting β-cells from H2O2.
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Affiliation(s)
- Svetlana DINIĆ
- Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia
| | - Nevena GRDOVIĆ
- Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia
| | - Aleksandra USKOKOVIĆ
- Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia
| | - Miloš ĐORĐEVIĆ
- Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia
| | - Mirjana MIHAILOVIĆ
- Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia
| | - Jelena Arambašić JOVANOVIĆ
- Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia
| | - Goran POZNANOVIĆ
- Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia
| | - Melita VIDAKOVIĆ
- Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Belgrade, Serbia
- Correspondence should be addressed: M. Vidaković, Department of Molecular Biology, Institute for Biological Research, University of Belgrade, Bulevar despota Stefana 142, 11060 Belgrade, Serbia (e-mail: )
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Chen S, Han J, Liu Y. Dual Opposing Roles of Metallothionein Overexpression in C57BL/6J Mouse Pancreatic β-Cells. PLoS One 2015; 10:e0137583. [PMID: 26335571 PMCID: PMC4559390 DOI: 10.1371/journal.pone.0137583] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2015] [Accepted: 08/18/2015] [Indexed: 11/20/2022] Open
Abstract
Background Growing evidence indicates that oxidative stress (OS), a persistent state of excess amounts of reactive oxygen species (ROS) along with reactive nitrogen species (RNS), plays an important role in insulin resistance, diabetic complications, and dysfunction of pancreatic β-cells. Pancreatic β-cells contain exceptionally low levels of antioxidant enzymes, rendering them susceptible to ROS-induced damage. Induction of antioxidants has been proposed to be a way for protecting β-cells against oxidative stress. Compared to other antioxidants that act against particular β-cell damages, metallothionein (MT) is the most effective in protecting β-cells from several oxidative stressors including nitric oxide, peroxynitrite, hydrogen peroxide, superoxide and streptozotocin (STZ). We hypothesized that MT overexpression in pancreatic β-cells would preserve β-cell function in C57BL/6J mice, an animal model susceptible to high fat diet-induced obesity and type 2 diabetes. Research Design and Methods The pancreatic β-cell specific MT overexpression was transferred to C57BL/6J background by backcrossing. We studied transgenic MT (MT-tg) mice and wild-type (WT) littermates at 8 weeks and 18 weeks of age. Several tests were performed to evaluate the function of islets, including STZ in vivo treatment, intraperitoneal glucose tolerance tests (IPGTT) and plasma insulin levels during IPGTT, pancreatic and islet insulin content measurement, insulin secretion, and islet morphology assessment. Gene expression in islets was performed by quantitative real-time PCR and PCR array analysis. Protein levels in pancreatic sections were evaluated by using immunohistochemistry. Results The transgenic MT protein was highly expressed in pancreatic islets. MT-tg overexpression significantly protected mice from acute STZ-induced ROS at 8 weeks of age; unexpectedly, however, MT-tg impaired glucose stimulated insulin secretion (GSIS) and promoted the development of diabetes. Pancreatic β-cell function was significantly impaired, and islet morphology was also abnormal in MT-tg mice, and more severe damage was detected in males. The unique gene expression pattern and abnormal protein levels were observed in MT-tg islets. Conclusions MT overexpression protected β-cells from acute STZ-induced ROS damages at young age, whereas it impaired GSIS and promoted the development of diabetes in adult C57BL/6J mice, and more severe damage was found in males.
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Affiliation(s)
- Suqin Chen
- The Research Institute for Children, Children’s Hospital at New Orleans, New Orleans, Louisiana, United States of America
- Department of Medical Genetics, Zhongshan Medical College, Sun Yat-sen University, Guangzhou, Guangdong Province, People’s Republic of China
- * E-mail:
| | - Junying Han
- The Research Institute for Children, Children’s Hospital at New Orleans, New Orleans, Louisiana, United States of America
| | - Yeqi Liu
- The Research Institute for Children, Children’s Hospital at New Orleans, New Orleans, Louisiana, United States of America
- Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
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Uruno A, Yagishita Y, Yamamoto M. The Keap1–Nrf2 system and diabetes mellitus. Arch Biochem Biophys 2015; 566:76-84. [DOI: 10.1016/j.abb.2014.12.012] [Citation(s) in RCA: 130] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 12/07/2014] [Accepted: 12/09/2014] [Indexed: 12/30/2022]
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Hypoxic resistance of hypodermically transplanted pancreatic islets by using cell-absorbable antioxidant Tat-metallothionein. J Control Release 2013; 172:1092-101. [DOI: 10.1016/j.jconrel.2013.09.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2013] [Revised: 09/13/2013] [Accepted: 09/26/2013] [Indexed: 11/22/2022]
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Karunakaran U, Park KG. A systematic review of oxidative stress and safety of antioxidants in diabetes: focus on islets and their defense. Diabetes Metab J 2013; 37:106-12. [PMID: 23641350 PMCID: PMC3638220 DOI: 10.4093/dmj.2013.37.2.106] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
A growing body of evidence suggests that hyperglycemia-induced oxidative stress plays an important role in diabetic complications, especially β-cell dysfunction and failure. Under physiological conditions, reactive oxygen species serve as second messengers that facilitate signal transduction and gene expression in pancreatic β-cells. However, under pathological conditions, an imbalance in redox homeostasis leads to aberrant tissue damage and β-cell death due to a lack of antioxidant defense systems. Taking into account the vulnerability of islets to oxidative damage, induction of endogenous antioxidant enzymes or exogenous antioxidant administration has been proposed as a way to protect β-cells against diabetic insults. Here, we consider recent insights into how the redox response becomes deregulated under diabetic conditions, as well as the therapeutic benefits of antioxidants, which may provide clues for developing strategies aimed at the treatment or prevention of diabetes associated with β-cell failure.
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Affiliation(s)
- Udayakumar Karunakaran
- Departments of Internal Medicine, Biochemistry and Cell Biology, Research Institute of Aging and Metabolism and World Class University Program, Kyungpook National University School of Medicine, Daegu, Korea
| | - Keun-Gyu Park
- Departments of Internal Medicine, Biochemistry and Cell Biology, Research Institute of Aging and Metabolism and World Class University Program, Kyungpook National University School of Medicine, Daegu, Korea
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SONG JIALE, ZHAO XIN, WANG QIANG, ZHANG TING. Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells. Mol Med Rep 2013; 7:1607-12. [DOI: 10.3892/mmr.2013.1396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2012] [Accepted: 03/19/2013] [Indexed: 11/06/2022] Open
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Xie H, Liu F, Liu L, Dan J, Luo Y, Yi Y, Chen X, Li J. Protective role of AQP3 in UVA-induced NHSFs apoptosis via Bcl2 up-regulation. Arch Dermatol Res 2013; 305:397-406. [PMID: 23463292 DOI: 10.1007/s00403-013-1324-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 01/30/2013] [Accepted: 02/01/2013] [Indexed: 01/19/2023]
Abstract
Aquaporin-3 (AQP3), a water/glycerol-transporting protein that facilitates water, urea, and glycerol transport, can inhibit arsenite-induced apoptosis by up-regulating Bcl-2. However, whether it has a protective role in ultraviolet A (UVA)-induced apoptosis in normal human skin fibroblasts is not known. In this study, we demonstrate that mild UVA treatment fails to induce oxidative cell stress and apoptosis in normal human skin fibroblasts (NHSFs) overexpressing AQP3. After severe UVA irradiation, there was an increase in oxidative cell stress and apoptosis when AQP3 levels decreased. We also found that silencing AQP3 sensitized NHSFs to low-dose UVA. Overexpressing AQP3 was protective against high-dose UVA-induced oxidative stress and apoptosis. Besides, we observed that Bcl-2 may be involved in UVA-induced apoptosis. Our findings suggested that the water/glycerol-transporting protein AQP3 plays a role in resistance to UVA-induced apoptosis.
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Affiliation(s)
- Hongfu Xie
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha 410008, China
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Huang SH, Lin GJ, Chien MW, Chu CH, Yu JC, Chen TW, Hueng DY, Liu YL, Sytwu HK. Adverse Effect on Syngeneic Islet Transplantation by Transgenic Coexpression of Decoy Receptor 3 and Heme Oxygenase-1 in the Islet of NOD Mice. Transplant Proc 2013; 45:580-4. [DOI: 10.1016/j.transproceed.2012.02.032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 02/14/2012] [Indexed: 01/12/2023]
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Song JLE, Zhao X, Wang Q. Protective effects of Quercus salicina on alloxan-induced oxidative stress in HIT-T15 pancreatic β cells. Exp Ther Med 2013; 5:947-951. [PMID: 23408741 PMCID: PMC3570244 DOI: 10.3892/etm.2013.885] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/02/2013] [Indexed: 01/11/2023] Open
Abstract
The present study was designed to investigate the protective effect of hot water extracts from Quercus salicina leaves (QSWE) on alloxan-induced oxidative stress in HIT-T15 Syrian hamster pancreatic insulinoma cells. The HIT-T15 cells were treated with alloxan (1 mM) for 1 h and then co-incubated with the QSWE for 24 h. Alloxan significantly decreased the viability of the HIT-T15 cells (P<0.05). QSWE did not exhibit significantly cytotoxic effects and increased the viability of the HIT-T15 cells in a concentration-dependent manner. To further investigate the protective effects of QSWE on alloxan-induced oxidative stress in HIT-T15 cells, the cellular levels of reactive oxygen species (ROS), lipid peroxidation and endogenous antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-px), were analyzed. QSWE decreased the intracellular levels of ROS and lipid peroxidation and increased the activity of antioxidant enzymes. These results suggest that QSWE exerted cytoprotective activity against alloxan-induced oxidative stress in HIT-T15 cells through the inhibition of lipid peroxidation, reduction of ROS levels and stimulation of antioxidant enzyme activity. In addition, QSWE also increased the insulin secretion activity of the alloxan-treated HIT-T15 cells.
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Affiliation(s)
- Jia-LE Song
- Department of Food Science and Nutrition, Pusan National University, Busan 609-735, Republic of Korea
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Role of peroxisomes in ROS/RNS-metabolism: Implications for human disease. Biochim Biophys Acta Mol Basis Dis 2012; 1822:1363-73. [DOI: 10.1016/j.bbadis.2011.12.001] [Citation(s) in RCA: 383] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Revised: 11/25/2011] [Accepted: 12/02/2011] [Indexed: 12/27/2022]
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Ramesh B, Saralakumari D. Antihyperglycemic, hypolipidemic and antioxidant activities of ethanolic extract of Commiphora mukul gum resin in fructose-fed male Wistar rats. J Physiol Biochem 2012; 68:573-82. [PMID: 22581434 DOI: 10.1007/s13105-012-0175-x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Accepted: 04/27/2012] [Indexed: 01/11/2023]
Abstract
High fructose feeding (66 % of fructose) induces type-2 diabetes in rats, which is associated with the insulin resistance, hyperinsulinemia, hypertriglyceridemia and oxidative stress. The present study was undertaken to evaluate the effect of ethanol extract of Commiphora mukul gum resin (CMEE) on blood glucose, plasma insulin, lipid profiles, reduced glutathione, lipid peroxidation, protein oxidation and enzymatic antioxidants like superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, glutathione-S-transferase in fructose-induced type-2 diabetic rats. A significant gain in body weight, hyperglycemia, hyperinsulinemia, increased lipid profiles, lipid peroxidation, protein oxidation and decreased reduced glutathione, activities of enzymatic antioxidants and insulin sensitivity (increased homeostasis assessment assay) were observed in high-fructose-induced diabetic rats. The administration of CMEE (200 mg/kg/day) daily for 60 days in high-fructose-induced diabetic rats reversed the above parameters significantly. CMEE has the ability to improve insulin sensitivity and delay the development of insulin resistance, aggravate antioxidant status in diabetic rats and may be used as an adjuvant therapy for patients with insulin resistance.
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Affiliation(s)
- B Ramesh
- Department of Biochemistry, Sri Venkateswara University, Tirupati 517502, Andhra Pradesh, India
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Zhang X, Degenstein L, Cao Y, Stein J, Osei K, Wang J. β-Cells with relative low HIMP1 overexpression levels in a transgenic mouse line enhance basal insulin production and hypoxia/hypoglycemia tolerance. PLoS One 2012; 7:e34126. [PMID: 22470529 PMCID: PMC3309936 DOI: 10.1371/journal.pone.0034126] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2011] [Accepted: 02/22/2012] [Indexed: 11/19/2022] Open
Abstract
Rodent pancreatic β-cells that naturally lack hypoglycemia/hypoxia inducible mitochondrial protein 1 (HIMP1) are susceptible to hypoglycemia and hypoxia influences. A linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 is suggested in a recent study using transformed β-cells lines. To further illuminate this linkage, we applied mouse insulin 1 gene promoter (MIP) to control HIMP1-a isoform cDNA and have generated three lines (L1 to L3) of heterozygous HIMP1 transgenic (Tg) mice by breeding of three founders with C57BL/6J mice. In HIMP1-Tg mice/islets, we performed quantitative polymerase chain reaction (PCR), immunoblot, histology, and physiology studies to investigate HIMP1 overexpression and its link to β-cell function/survival and body glucose homeostasis. We found that the HIMP1 level increased steadily in β-cells of L1 to L3 heterozygous HIMP1-Tg mice. HIMP1 overexpression at relatively lower levels in L1 heterozygotes results in a negligible decline in blood glucose concentrations and an insignificant elevation in blood insulin levels, while HIMP1 overexpression at higher levels are toxic, causing hyperglycemia in L2/3 heterozygotes. Follow-up studies in 5-30-week-old L1 heterozygous mice/islets found that HIMP1 overexpression at relatively lower levels in β-cells has enhanced basal insulin biosynthesis, basal insulin secretion, and tolerances to low oxygen/glucose influences. The findings enforced the linkage between the hypoglycemia/hypoxia susceptibility and the lack of HIMP1 in β-cells, and show a potential value of HIMP1 overexpression at relatively lower levels in modulating β-cell function and survival.
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Affiliation(s)
- Xiaoping Zhang
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Linda Degenstein
- Transgenic Core, The University of Chicago, Chicago, Illinois, United States of America
| | - Yun Cao
- Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America
| | - Jeffrey Stein
- Department of Medicine, The University of Chicago, Chicago, Illinois, United States of America
| | - Kwame Osei
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Jie Wang
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America
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Chou FC, Huang SH, Sytwu HK. Genetically engineered islets and alternative sources of insulin-producing cells for treating autoimmune diabetes: quo vadis? Int J Endocrinol 2012; 2012:296485. [PMID: 22690214 PMCID: PMC3368364 DOI: 10.1155/2012/296485] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2011] [Accepted: 03/29/2012] [Indexed: 01/29/2023] Open
Abstract
Islet transplantation is a promising therapy for patients with type 1 diabetes that can provide moment-to-moment metabolic control of glucose and allow them to achieve insulin independence. However, two major problems need to be overcome: (1) detrimental immune responses, including inflammation induced by the islet isolation/transplantation procedure, recurrence autoimmunity, and allorejection, can cause graft loss and (2) inadequate numbers of organ donors. Several gene therapy approaches and pharmaceutical treatments have been demonstrated to prolong the survival of pancreatic islet grafts in animal models; however, the clinical applications need to be investigated further. In addition, for an alternative source of pancreatic β-cell replacement therapy, the ex vivo generation of insulin-secreting cells from diverse origins of stem/progenitor cells has become an attractive option in regenerative medicine. This paper focuses on the genetic manipulation of islets during transplantation therapy and summarizes current strategies to obtain functional insulin-secreting cells from stem/progenitor cells.
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Affiliation(s)
- Feng-Cheng Chou
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Neihu, Taipei 114, Taiwan
| | - Shing-Hwa Huang
- Department of General Surgery, Tri-Service General Hospital, Taipei 114, Taiwan
| | - Huey-Kang Sytwu
- Department and Graduate Institute of Microbiology and Immunology, National Defense Medical Center, Neihu, Taipei 114, Taiwan
- *Huey-Kang Sytwu:
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Koren-Gluzer M, Aviram M, Meilin E, Hayek T. The antioxidant HDL-associated paraoxonase-1 (PON1) attenuates diabetes development and stimulates β-cell insulin release. Atherosclerosis 2011; 219:510-8. [PMID: 21862013 DOI: 10.1016/j.atherosclerosis.2011.07.119] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Revised: 07/24/2011] [Accepted: 07/25/2011] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To analyze the direct effects of paraoxonase-1 (PON1) on diabetes development and on β-cell insulin release. METHODS AND RESULTS Injection of rePON1 to mice, prior to STZ-induced diabetes, resulted in reduced incidence of diabetes, as well as, in higher serum insulin levels. Incubation of β-cells with PON1 also dose-dependently increased insulin secretion and its cellular content. PON1 increased cell survival under high glucose levels, but not under high STZ concentrations. The addition of the PON1 carrier in the circulation - HDL, to βTC3 cell line, had an additive effect on PON1-induced insulin secretion. PON1 administration to mice or incubation with β-cells was associated with a substantial decreased oxidative stress. Just like PON1, the dietary anti-oxidants, pomegranate juice, punicalagin (major polyphenol in pomegranate) or vitamin E, also increased insulin release from βTC3, but unlike PON1, failed to increase insulin cellular content, suggesting a possible role for PON1 in insulin biosynthesis, separately from PON1 antioxidative effect. Both, PON1 catalytic activity and PON1 association to HDL, were not required for PON1 stimulation of insulin release from β-cells. However, the PON1 free sulfhydryl group was shown to be essential for insulin release by PON1, as blocking the PON1 SH group, abolished PON1 stimulatory effect on insulin secretion. CONCLUSION PON1 is a potent anti-diabetic enzyme that exerts this protection against diabetes through its antioxidative, as well as via its insulin stimulation properties on β-cells.
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Affiliation(s)
- Marie Koren-Gluzer
- The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa 31096, Israel
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Oxidative stress and redox modulation potential in type 1 diabetes. Clin Dev Immunol 2011; 2011:593863. [PMID: 21647409 PMCID: PMC3102468 DOI: 10.1155/2011/593863] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 03/09/2011] [Indexed: 12/21/2022]
Abstract
Redox reactions are imperative to preserving cellular metabolism yet must be strictly regulated. Imbalances between reactive oxygen species (ROS) and antioxidants can initiate oxidative stress, which without proper resolve, can manifest into disease. In type 1 diabetes (T1D), T-cell-mediated autoimmune destruction of pancreatic β-cells is secondary to the primary invasion of macrophages and dendritic cells (DCs) into the islets. Macrophages/DCs, however, are activated by intercellular ROS from resident pancreatic phagocytes and intracellular ROS formed after receptor-ligand interactions via redox-dependent transcription factors such as NF-κB. Activated macrophages/DCs ferry β-cell antigens specifically to pancreatic lymph nodes, where they trigger reactive T cells through synapse formation and secretion of proinflammatory cytokines and more ROS. ROS generation, therefore, is pivotal in formulating both innate and adaptive immune responses accountable for islet cell autoimmunity. The importance of ROS/oxidative stress as well as potential for redox modulation in the context of T1D will be discussed.
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Abstract
Pancreatic islets contain low activities of catalase, selenium-dependent glutathione peroxidase 1 (GPX1), and Cu,Zn-superoxide dismutase 1 (SOD1). Thus, enhancing expression of these enzymes in islets has been unquestionably favored. However, such an attempt has produced variable metabolic outcomes. While β cell-specific overexpression of Sod1 enhanced mouse resistance to streptozotocin-induced diabetes, the same manipulation of catalase aggravated onset of type 1 diabetes in nonobese diabetic mice. Global overexpression of Gpx1 in mice induced type 2 diabetes-like phenotypes. Although knockouts of Gpx1 and Sod1 each alone or together decreased pancreatic β cell mass and plasma insulin concentrations, these knockouts improved body insulin sensitivity to different extents. Pancreatic duodenal homeobox 1, forkhead box A2, and uncoupling protein 2 are three key regulators of β cell mass, insulin synthesis, and glucose-stimulated insulin secretion. Phenotypes resulted from altering GPX1 and/or SOD1 were partly mediated through these factors, along with protein kinase B and c-jun terminal kinase. A shifted reactive oxygen species inhibition of protein tyrosine phosphatases in insulin signaling might be attributed to altered insulin sensitivity. Overall, metabolic roles of antioxidant enzymes in β cells and diabetes depend on body oxidative status and target functions. Revealing regulatory mechanisms for this type of dual role will help prevent potential pro-diabetic risk of antioxidant over-supplementation to humans.
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Affiliation(s)
- Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, New York 14853, USA.
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Xiang FL, Lu X, Strutt B, Hill DJ, Feng Q. NOX2 deficiency protects against streptozotocin-induced beta-cell destruction and development of diabetes in mice. Diabetes 2010; 59:2603-11. [PMID: 20627937 PMCID: PMC3279537 DOI: 10.2337/db09-1562] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
OBJECTIVE The role of NOX2-containing NADPH oxidase in the development of diabetes is not fully understood. We hypothesized that NOX2 deficiency decreases reactive oxygen species (ROS) production and immune response and protects against streptozotocin (STZ)-induced β-cell destruction and development of diabetes in mice. RESEARCH DESIGN AND METHODS Five groups of mice--wild-type (WT), NOX2(-/-), WT treated with apocynin, and WT adoptively transferred with NOX2(-/-) or WT splenocytes--were treated with multiple-low-dose STZ. Blood glucose and insulin levels were monitored, and an intraperitoneal glucose tolerance test was performed. Isolated WT and NOX2(-/-) pancreatic islets were treated with cytokines for 48 h. RESULTS Significantly lower blood glucose levels, higher insulin levels, and better glucose tolerance was observed in NOX2(-/-) mice and in WT mice adoptively transferred with NOX2(-/-) splenocytes compared with the respective control groups after STZ treatment. Compared with WT, β-cell apoptosis, as determined by TUNEL staining, and insulitis were significantly decreased, whereas β-cell mass was significantly increased in NOX2(-/-) mice. In response to cytokine stimulation, ROS production was significantly decreased, and insulin secretion was preserved in NOX2(-/-) compared with WT islets. Furthermore, proinflammatory cytokine release induced by concanavalin A was significantly decreased in NOX2(-/-) compared with WT splenocytes. CONCLUSIONS NOX2 deficiency decreases β-cell destruction and preserves islet function in STZ-induced diabetes by reducing ROS production, immune response, and β-cell apoptosis.
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Affiliation(s)
- Fu-Li Xiang
- From the Departments of Medicine, Physiology, and Pharmacology, University of Western Ontario, Lawson Health Research Institute, London, Ontario, Canada
| | - Xiangru Lu
- From the Departments of Medicine, Physiology, and Pharmacology, University of Western Ontario, Lawson Health Research Institute, London, Ontario, Canada
| | - Brenda Strutt
- From the Departments of Medicine, Physiology, and Pharmacology, University of Western Ontario, Lawson Health Research Institute, London, Ontario, Canada
| | - David J. Hill
- From the Departments of Medicine, Physiology, and Pharmacology, University of Western Ontario, Lawson Health Research Institute, London, Ontario, Canada
| | - Qingping Feng
- From the Departments of Medicine, Physiology, and Pharmacology, University of Western Ontario, Lawson Health Research Institute, London, Ontario, Canada
- Corresponding author: Qingping Feng,
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Mohseni-Salehi-Monfared SS, Habibollahzadeh E, Sadeghi H, Baeeri M, Abdollahi M. Efficacy of Setarud (IMOD™), a novel electromagnetically-treated multi-herbal compound, in mouse immunogenic type-1 diabetes. Arch Med Sci 2010; 6:663-9. [PMID: 22419922 PMCID: PMC3298332 DOI: 10.5114/aoms.2010.17078] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Revised: 03/31/2009] [Accepted: 05/12/2009] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION The aim of this study was to evaluate the effects and mechanisms of Setarud (IMOD™) as a multi-herbal medicinal formula on a mouse model of type 1 diabetes. METERIAL AND METHODS: Autoimmune diabetes was induced by multiple low-dose intraperitoneal injection of 40 mg/kg of streptozotocin (STZ) for five consecutive days. IMOD™ was administered at an effective dose of 20 mg/kg/day for 21 days. After 21 days of treatment, the pancreases of the animals were separated and homogenized. In the pancreas tissue, the level of lipid peroxidation as thiobarbituric acid reactive substances (TBARS), total antioxidant power as ferric reducing ability of pancreas (FRAP), myeloperoxidase (MPO), and the concentrations of interleukin-1 (IL-1β) and tumour necrosis factor-α (TNF-α) were evaluated. Glucose changes were tested in the blood. Microscopic changes in the pancreas were followed by histological examinations. RESULTS No significant difference was found between IMOD™ and diabetic control groups in blood glucose pattern. STZ-exposed mice showed a significant increase in pancreatic TBARS, MPO, IL-1β, and TNF-α levels, along with a significant decrease in FRAP value. Co-administration of IMOD™ significantly improved all the mentioned parameters disrupted by STZ administration except for blood glucose and histological changes. CONCLUSION IMOD™ could ameliorate oxidative and immunological distresses of type-1 immunogenic diabetes but could not normalize blood glucose. Further studies are recommended to clarify the effects of IMOD™ on immunological factors to address whether this new agent could be applied in diabetes prevention or therapy.
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Affiliation(s)
- Seyed Sajad Mohseni-Salehi-Monfared
- Faculty of Pharmacy, and Pharmaceutical Sciences Research Centre, Tehran University of Medical Sciences, Tehran, Iran
- Endocrinology and Metabolism Research Centre, Tehran University of Medical Science, Tehran, Iran
| | - Ebad Habibollahzadeh
- Faculty of Pharmacy, and Pharmaceutical Sciences Research Centre, Tehran University of Medical Sciences, Tehran, Iran
| | - Hooman Sadeghi
- Faculty of Pharmacy, and Pharmaceutical Sciences Research Centre, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Baeeri
- Faculty of Pharmacy, and Pharmaceutical Sciences Research Centre, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Endocrinology and Metabolism Research Centre, Tehran University of Medical Science, Tehran, Iran
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Harmon JS, Bogdani M, Parazzoli SD, Mak SSM, Oseid EA, Berghmans M, Leboeuf RC, Robertson RP. beta-Cell-specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db mice. Endocrinology 2009; 150:4855-62. [PMID: 19819955 PMCID: PMC2775976 DOI: 10.1210/en.2009-0708] [Citation(s) in RCA: 146] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Chronic hyperglycemia causes oxidative stress, which contributes to damage in various tissues and cells, including pancreatic beta-cells. The expression levels of antioxidant enzymes in the islet are low compared with other tissues, rendering the beta-cell more susceptible to damage caused by hyperglycemia. The aim of this study was to investigate whether increasing levels of endogenous glutathione peroxidase-1 (GPx-1), specifically in beta-cells, can protect them against the adverse effects of chronic hyperglycemia and assess mechanisms that may be involved. C57BLKS/J mice overexpressing the antioxidant enzyme GPx-1 only in pancreatic beta-cells were generated. The biological effectiveness of the overexpressed GPx-1 transgene was documented when beta-cells of transgenic mice were protected from streptozotocin. The transgene was then introgressed into the beta-cells of db/db mice. Without use of hypoglycemic agents, hyperglycemia in db/db-GPx(+) mice was initially ameliorated compared with db/db-GPx(-) animals and then substantially reversed by 20 wk of age. beta-Cell volume and insulin granulation and immunostaining were greater in db/db-GPx(+) animals compared with db/db-GPx(-) animals. Importantly, the loss of intranuclear musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) that was observed in nontransgenic db/db mice was prevented by GPx-1 overexpression, making this a likely mechanism for the improved glycemic control. These studies demonstrate that enhancement of intrinsic antioxidant defenses of the beta-cell protects it against deterioration during hyperglycemia.
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Affiliation(s)
- Jamie S Harmon
- Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, Washington 98122, USA
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Kikumoto Y, Sugiyama H, Inoue T, Morinaga H, Takiue K, Kitagawa M, Fukuoka N, Saeki M, Maeshima Y, Wang DH, Ogino K, Masuoka N, Makino H. Sensitization to alloxan-induced diabetes and pancreatic cell apoptosis in acatalasemic mice. Biochim Biophys Acta Mol Basis Dis 2009; 1802:240-6. [PMID: 19883754 DOI: 10.1016/j.bbadis.2009.10.009] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2009] [Revised: 10/25/2009] [Accepted: 10/26/2009] [Indexed: 11/26/2022]
Abstract
Human acatalasemia may be a risk factor for the development of diabetes mellitus. However, the mechanism by which diabetes is induced is still poorly understood. The impact of catalase deficiency on the onset of diabetes has been studied in homozygous acatalasemic mutant mice or control wild-type mice by intraperitoneal injection of diabetogenic alloxan. The incidence of diabetes was higher in acatalasemic mice treated with a high dose (180 mg/kg body weight) of alloxan. A higher dose of alloxan accelerated severe atrophy of pancreatic islets and induced pancreatic beta cell apoptosis in acatalasemic mice in comparison to wild-type mice. Catalase activity remained low in the acatalasemic pancreas without the significant compensatory up-regulation of glutathione peroxidase or superoxide dismutase. Furthermore, daily intraperitoneal injection of angiotensin II type 1 (AT1) receptor antagonist telmisartan (0.1 mg/kg body weight) prevented the development of alloxan-induced hyperglycemia in acatalasemic mice. This study suggests that catalase plays a crucial role in the defense against oxidative-stress-mediated pancreatic beta cell death in an alloxan-induced diabetes mouse model. Treatment with telmisartan may prevent the onset of alloxan-induced diabetes even under acatalasemic conditions.
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Affiliation(s)
- Yoko Kikumoto
- Department of Medicine and Clinical Science, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
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Ardestani A, Yazdanparast R, Jamshidi S. Therapeutic effects of Teucrium polium extract on oxidative stress in pancreas of streptozotocin-induced diabetic rats. J Med Food 2009; 11:525-32. [PMID: 18800902 DOI: 10.1089/jmf.2006.0230] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Increased oxidative stress is a widely accepted factor in the development and progression of diabetes and its complications. In this study, we evaluated the antioxidative potential of Teucrium polium (Family Lamiaceae) aqueous extract for protecting rat pancreatic tissue against streptozotocin (STZ)-induced oxidative stress. Diabetes was induced in rats by intraperitoneal injections of at a single dose of STZ at 40 mg/kg. The crude extract (equivalent to 0.5 g of plant powder/kg of body weight) was administered orally (intragastrically) to a group of STZ diabetic rats for 30 consecutive days. Changes in antioxidant status were evaluated by determining catalase (CAT) and superoxide dismutase (SOD) activities and the level of reduced glutathione (GSH) in pancreatic tissue. In addition, serum nitric oxide (NO) concentration, pancreatic tissue malondialdehyde (MDA) (an index of lipid peroxidation) level, and reliable markers of protein oxidation such as protein carbonyl content (PCO) and advanced oxidation protein products (AOPP) were also determined. Under diabetic conditions, blood glucose level, serum NO concentration, and pancreatic MDA, PCO, and AOPP levels were all increased. The diabetic rats also exhibited pancreatic GSH depletion along with significant reductions in activities of CAT and SOD. Rats treated with T. polium extract had significantly higher GSH levels along with enhanced CAT and SOD activities in pancreatic tissue. In addition to suppressed blood glucose levels, serum NO, pancreatic MDA, PCO, and AOPP levels were all lower than in the diabetic group. Our results strongly support the proposal that antioxidative activity of T. polium occurs by quenching the extent of lipid and protein oxidation. Based on these observations, it is concluded that T. polium may have protective effect(s) on pancreatic tissue in STZ-induced oxidative stress due to its high antioxidative potential.
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Affiliation(s)
- A Ardestani
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
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