35
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Therapeutic Options Targeting Oxidative Stress, Mitochondrial Dysfunction and Inflammation to Hinder the Progression of Vascular Complications of Diabetes

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Type 2 diabetes mellitus is a leading cause of morbidity and mortality worldwide, given its serious associated complications. Despite constant efforts and intensive research, an effective, ubiquitous treatment still eludes the scientific community. As such, the identification of novel avenues of research is key to the potential discovery of this evasive “silver bullet.” We focus on this review on the matter of diabetic injury to endothelial tissue and some of the pivotal underlying mechanisms, including hyperglycemia and hyperlipidemia evoked oxidative stress and inflammation. In this sense, we revisited the most promising therapeutic interventions (both non-pharmacological and antidiabetic drugs) targeting oxidative stress and inflammation to hinder progression of vascular complications of diabetes. This review article gives particular attention to the relevance of mitochondrial function, an often ignored and understudied organelle in the vascular endothelium. We highlight the importance of mitochondrial function and number homeostasis in diabetic conditions and discuss the work conducted to address the aforementioned issue by the use of various therapeutic strategies. We explore here the functional, biochemical and bioenergetic alterations provoked by hyperglycemia in the endothelium, from elevated oxidative stress to inflammation and cell death, as well as loss of tissue function. Furthermore, we synthetize the literature regarding the current and promising approaches into dealing with these alterations. We discuss how known agents and therapeutic behaviors (as, for example, metformin, dietary restriction or antioxidants) can restore normality to mitochondrial and endothelial function, preserving the tissue’s function and averting the aforementioned complications.

          Related collections

          Most cited references148

          • Record: found
          • Abstract: found
          • Article: not found

          Fatty acid carbon is essential for dNTP synthesis in endothelial cells

          The metabolism of endothelial cells (ECs) during vessel sprouting remains poorly studied. Here, we report that endothelial loss of CPT1a, a rate-limiting enzyme of fatty acid oxidation (FAO), caused vascular sprouting defects due to impaired proliferation, not migration of ECs. Reduction of FAO in ECs did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labeling studies in control ECs showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1a silencing reduced these processes and depleted EC stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1a-silenced ECs. Finally, CPT1 blockade inhibited pathological ocular angiogenesis, suggesting a novel strategy for blocking angiogenesis.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Endothelial dysfunction - a major mediator of diabetic vascular disease.

            The vascular endothelium is a multifunctional organ and is critically involved in modulating vascular tone and structure. Endothelial cells produce a wide range of factors that also regulate cellular adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. Thus, endothelial function is important for the homeostasis of the body and its dysfunction is associated with several pathophysiological conditions, including atherosclerosis, hypertension and diabetes. Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation. Therefore, understanding and treating endothelial dysfunction is a major focus in the prevention of vascular complications associated with all forms of diabetes mellitus. The mechanisms of endothelial dysfunction in diabetes may point to new management strategies for the prevention of cardiovascular disease in diabetes. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting. Mechanisms including altered glucose metabolism, impaired insulin signaling, low-grade inflammatory state, and increased reactive oxygen species generation will be discussed. The importance of developing new pharmacological approaches that upregulate endothelium-derived nitric oxide synthesis and target key vascular ROS-producing enzymes will be highlighted and new strategies that might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated vascular complications. © 2013.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation.

              Omega-3 fatty acids (ω-3 FAs) have potential anti-inflammatory activity in a variety of inflammatory human diseases, but the mechanisms remain poorly understood. Here we show that stimulation of macrophages with ω-3 FAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and other family members, abolished NLRP3 inflammasome activation and inhibited subsequent caspase-1 activation and IL-1β secretion. In addition, G protein-coupled receptor 120 (GPR120) and GPR40 and their downstream scaffold protein β-arrestin-2 were shown to be involved in inflammasome inhibition induced by ω-3 FAs. Importantly, ω-3 FAs also prevented NLRP3 inflammasome-dependent inflammation and metabolic disorder in a high-fat-diet-induced type 2 diabetes model. Our results reveal a mechanism through which ω-3 FAs repress inflammation and prevent inflammation-driven diseases and suggest the potential clinical use of ω-3 FAs in gout, autoinflammatory syndromes, or other NLRP3 inflammasome-driven inflammatory diseases. Copyright © 2013 Elsevier Inc. All rights reserved.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                17 January 2019
                2018
                : 9
                : 1857
                Affiliations
                [1] 1Center for Neurosciences and Cell Biology, Department of Life Sciences, University of Coimbra , Coimbra, Portugal
                [2] 2Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research, University of Coimbra , Coimbra, Portugal
                Author notes

                Edited by: Raquel M. Seiça, University of Coimbra, Portugal

                Reviewed by: Marcos Lopez, University of Chicago, United States; Josef Finsterer, Krankenanstalt Rudolfstiftung, Austria

                *Correspondence: Flávio Reis, freis@ 123456fmed.uc.pt Carlos M. Palmeira, palmeira@ 123456ci.uc.pt ; palmeira@ 123456uc.pt

                These authors have contributed equally to this work

                This article was submitted to Oxidant Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2018.01857
                6344610
                30705633
                480d320d-3095-4382-b1fd-d732683db1de
                Copyright © 2019 Teodoro, Nunes, Rolo, Reis and Palmeira.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 20 April 2018
                : 11 December 2018
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 208, Pages: 18, Words: 0
                Funding
                Funded by: Fundação para a Ciência e a Tecnologia 10.13039/501100001871
                Award ID: POCI-01-0145-FEDER-007440
                Award ID: PTDC/BIM-MEC/6911/2014
                Award ID: SFRH/BPD/94036/2013
                Funded by: European Regional Development Fund 10.13039/501100008530
                Award ID: CENTRO-01-0145-FEDER-000012-HealthyAging2020
                Categories
                Physiology
                Review

                Anatomy & Physiology
                type 2 diabetes mellitus,oxidative stress,mitochondrial dysfunction,inflammation,diabetic vascular complications,therapeutics

                Comments

                Comment on this article