Antioxidant and Anti-Inflammatory Properties of Incretin-Based Therapies—Implications for Acute and Chronic Disease

A special issue of Antioxidants (ISSN 2076-3921). This special issue belongs to the section "Health Outcomes of Antioxidants and Oxidative Stress".

Deadline for manuscript submissions: closed (30 June 2021) | Viewed by 21789

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Department of Cardiology 1, University Medical Center Mainz, Mainz, Germany

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Guest Editor
Department of Cardiology 1, University Medical Center Mainz, Mainz, Germany

Special Issue Information

Glucagon-like peptide (GLP-1) is an incretin hormone released from L-cells in the intestine after food uptake. Circulating GLP-1 binds to its receptor, which is expressed on pancreatic beta-cells, but also on various other cell types such as cardiomyocytes, endothelial cells, and inflammatory cells. The GLP-1 receptor belongs to the family of G-protein-coupled receptors and largely contributes to glucose homeostasis. In beta-cells of the pancreas, activation of the GLP-1 receptor increases intracellular cAMP levels, which stimulates insulin release and reduces glucagon release from alpha-cells. Based on these physiological actions of GLP-1 in glycemic control, GLP-1 analogs such as liraglutide, semaglutide, and dulaglutide (synthetic peptides with an almost similar chemical structure but significantly increased biological half-life) represent a new therapeutic option treating Type 2 diabetes. Similarly, inhibitors of the exopeptidase dipeptidyl peptidase-4 (DPP-4, also known as CD26) comprise the new drug class of gliptins for the treatment of diabetes, as they prevent the proteolytic degradation of GLP-1 by DPP-4 and thereby increase the half-life and bioavailability of GLP-1. Both drug classes, GLP-1 analogs and gliptins, are meanwhile a successful mainstay in modern antidiabetic therapeutic management. Importantly, GLP-1 analogs and gliptins have potent anti-inflammatory and antioxidant as well as other pleiotropic beneficial effects (e.g., direct vasodilation) that may indicate their use also in other chronic inflammatory, metabolic, cardiovascular, and neurodegenerative diseases (e.g., atherosclerosis, thrombosis, sepsis, non-alcoholic steatohepatitis, Alzheimer’s disease). In this Special Issue, we invite the submission of manuscripts that cover the following topics, preferably through in vivo studies at the preclinical (animal) and clinical (human) level combining functional and mechanistic data:

  • Improvement of the pathophysiology of the abovementioned chronic diseases in either animal models or patients by treatment with one of the mentioned drug classes—preferably phenotypic characterization with mechanistic insight into the mode of action of the drugs;
  • Proof-of-concept studies showing that GLP-1 analogs and gliptins act as anti-inflammatory and antioxidant or by another mechanism via well-characterized pleiotropic effects; these studies should use well accepted markers of inflammation or oxidative stress (or another process) that are assessed by state-of-the-art techniques, preferably using at least two complementary methods;
  • Cell culture studies will only be considered if they provide deep mechanistic insights and data from at least two different cell types; these studies should use superior techniques, not only ELISA and other descriptive biomarkers.

Dr. Sebastian Steven
Prof. Dr. Andreas Daiber
Guest Editors

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Published Papers (5 papers)

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Research

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13 pages, 1927 KiB  
Article
Teneligliptin Exerts Antinociceptive Effects in Rat Model of Partial Sciatic Nerve Transection Induced Neuropathic Pain
by Yaswanth Kuthati, Vaikar Navakanth Rao, Prabhakar Busa and Chih-Shung Wong
Antioxidants 2021, 10(9), 1438; https://doi.org/10.3390/antiox10091438 - 9 Sep 2021
Cited by 7 | Viewed by 2533
Abstract
Neuropathic pain (NP), is a chronic pain resulting from nerve injury, with limited treatment options. Teneligliptin (TEN) is a dipeptidyl peptidase-4 inhibitor (DPP-4i) approved to treat type 2 diabetes. DPP-4is prevent the degradation of the incretin hormone glucagon-like peptide 1 (GLP-1) and prolong [...] Read more.
Neuropathic pain (NP), is a chronic pain resulting from nerve injury, with limited treatment options. Teneligliptin (TEN) is a dipeptidyl peptidase-4 inhibitor (DPP-4i) approved to treat type 2 diabetes. DPP-4is prevent the degradation of the incretin hormone glucagon-like peptide 1 (GLP-1) and prolong its circulation. Apart from glycemic control, GLP-1 is known to have antinociceptive and anti-inflammatory effects. Herein, we investigated the antinociceptive properties of TEN on acute pain, and partial sciatic nerve transection (PSNT)-induced NP in Wistar rats. Seven days post PSNT, allodynia and hyperalgesia were confirmed as NP, and intrathecal (i.t) catheters were implanted and connected to an osmotic pump for the vehicle (1 μL/h) or TEN (5 μg/1 μL/h) or TEN (5 μg) + GLP-1R antagonist Exendin-3 (9–39) amide (EXE) 0.1 μg/1 μL/h infusion. The tail-flick response, mechanical allodynia, and thermal hyperalgesia were measured for 7 more days. On day 14, the dorsal horn was harvested and used for Western blotting and immunofluorescence assays. The results showed that TEN had mild antinociceptive effects against acute pain but remarkable analgesic effects against NP. Furthermore, co-infusion of GLP-1R antagonist EXE with TEN partially reversed allodynia but not tail-flick latency. Immunofluorescence examination of the spinal cord revealed that TEN decreased the immunoreactivity of glial fibrillary acidic protein (GFAP). Taken together, our findings suggest that TEN is efficient in attenuation of PSNT-induced NP. Hence, the pleiotropic effects of TEN open a new avenue for NP management. Full article
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15 pages, 2472 KiB  
Article
GLP-1 Analog Liraglutide Improves Vascular Function in Polymicrobial Sepsis by Reduction of Oxidative Stress and Inflammation
by Johanna Helmstädter, Karin Keppeler, Franziska Aust, Leonie Küster, Katie Frenis, Konstantina Filippou, Ksenija Vujacic-Mirski, Simeon Tsohataridis, Sanela Kalinovic, Swenja Kröller-Schön, Matthias Oelze, Markus Bosmann, Thomas Münzel, Andreas Daiber and Sebastian Steven
Antioxidants 2021, 10(8), 1175; https://doi.org/10.3390/antiox10081175 - 23 Jul 2021
Cited by 19 | Viewed by 3748
Abstract
Sepsis causes high mortality in the setting of septic shock. LEADER and other trials revealed cardioprotective and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) analogs like liraglutide (Lira). We previously demonstrated improved survival in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of GLP-1 degradation. Here we [...] Read more.
Sepsis causes high mortality in the setting of septic shock. LEADER and other trials revealed cardioprotective and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) analogs like liraglutide (Lira). We previously demonstrated improved survival in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of GLP-1 degradation. Here we investigate the effects of Lira in the polymicrobial sepsis model of cecal ligation and puncture (CLP). C57BL/6J mice were intraperitoneally injected with Lira (200 µg/kg/d; 3 days) and sepsis induced by CLP after one day of GLP-1 analog treatment. Survival and body temperature were monitored. Aortic vascular function (isometric tension recording), protein expression (immunohistochemistry and dot blot) and gene expression (qRT-PCR) were determined. Endothelium-dependent relaxation in the aorta was impaired by CLP and correlated with markers of inflammation (e.g., interleukin 6 and inducible nitric oxide synthase) and oxidative stress (e.g., 3-nitrotyrosine) was higher in septic mice, all of which was almost completely normalized by Lira therapy. We demonstrate that the GLP-1 analog Lira ameliorates sepsis-induced endothelial dysfunction by the reduction of vascular inflammation and oxidative stress. Accordingly, the findings suggest that the antioxidant and anti-inflammatory effects of GLP-1 analogs may be a valuable tool to protect the cardiovascular system from dysbalanced inflammation in polymicrobial sepsis. Full article
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21 pages, 4517 KiB  
Article
Role of Exendin-4 in Brain Insulin Resistance, Mitochondrial Function, and Neurite Outgrowth in Neurons under Palmitic Acid-Induced Oxidative Stress
by Danbi Jo, Gwangho Yoon and Juhyun Song
Antioxidants 2021, 10(1), 78; https://doi.org/10.3390/antiox10010078 - 9 Jan 2021
Cited by 10 | Viewed by 3370
Abstract
Glucagon like peptide 1 (GLP-1) is an incretin hormone produced by the gut and brain, and is currently being used as a therapeutic drug for type 2 diabetes and obesity, suggesting that it regulates abnormal appetite patterns, and ameliorates impaired glucose metabolism. Many [...] Read more.
Glucagon like peptide 1 (GLP-1) is an incretin hormone produced by the gut and brain, and is currently being used as a therapeutic drug for type 2 diabetes and obesity, suggesting that it regulates abnormal appetite patterns, and ameliorates impaired glucose metabolism. Many researchers have demonstrated that GLP-1 agonists and GLP-1 receptor agonists exert neuroprotective effects against brain damage. Palmitic acid (PA) is a saturated fatty acid, and increases the risk of neuroinflammation, lipotoxicity, impaired glucose metabolism, and cognitive decline. In this study, we investigated whether or not Exentin-4 (Ex-4; GLP-1 agonist) inhibits higher production of reactive oxygen species (ROS) in an SH-SY5Y neuronal cell line under PA-induced apoptosis conditions. Moreover, pre-treatment with Ex-4 in SH-SY5Y neuronal cells prevents neural apoptosis and mitochondrial dysfunction through several cellular signal pathways. In addition, insulin sensitivity in neurons is improved by Ex-4 treatment under PA-induced insulin resistance. Additionally, our imaging data showed that neuronal morphology is improved by EX-4 treatment, in spite of PA-induced neuronal damage. Furthermore, we identified that Ex-4 inhibits neuronal damage and enhanced neural complexity, such as neurite length, secondary branches, and number of neurites from soma in PA-treated SH-SY5Y. We observed that Ex-4 significantly increases neural complexity, dendritic spine morphogenesis, and development in PA treated primary cortical neurons. Hence, we suggest that GLP-1 administration may be a crucial therapeutic solution for improving neuropathology in the obese brain. Full article
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Review

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30 pages, 1177 KiB  
Review
Nonalcoholic Steatohepatitis (NASH) and Atherosclerosis: Explaining Their Pathophysiology, Association and the Role of Incretin-Based Drugs
by Eleftheria Galatou, Elena Mourelatou, Sophia Hatziantoniou and Ioannis S. Vizirianakis
Antioxidants 2022, 11(6), 1060; https://doi.org/10.3390/antiox11061060 - 27 May 2022
Cited by 4 | Viewed by 3563
Abstract
Nonalcoholic steatohepatitis (NASH) is the most severe manifestation of nonalcoholic fatty liver disease (NAFLD), a common complication of type 2 diabetes, and may lead to cirrhosis and hepatocellular carcinoma. Oxidative stress and liver cell damage are the major triggers of the severe hepatic [...] Read more.
Nonalcoholic steatohepatitis (NASH) is the most severe manifestation of nonalcoholic fatty liver disease (NAFLD), a common complication of type 2 diabetes, and may lead to cirrhosis and hepatocellular carcinoma. Oxidative stress and liver cell damage are the major triggers of the severe hepatic inflammation that characterizes NASH, which is highly correlated with atherosclerosis and coronary artery disease. Regarding drug therapy, research on the role of GLP-1 analogues and DPP4 inhibitors, novel classes of antidiabetic drugs, is growing. In this review, we outline the association between NASH and atherosclerosis, the underlying molecular mechanisms, and the effects of incretin-based drugs, especially GLP-1 RAs, for the therapeutic management of these conditions. Full article
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17 pages, 627 KiB  
Review
Renoprotective Effects of DPP-4 Inhibitors
by Daiji Kawanami, Yuichi Takashi, Hiroyuki Takahashi, Ryoko Motonaga and Makito Tanabe
Antioxidants 2021, 10(2), 246; https://doi.org/10.3390/antiox10020246 - 5 Feb 2021
Cited by 20 | Viewed by 7455
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Dipeptidyl peptidase (DPP)-4 inhibitors are widely used in the treatment of patients with type 2 diabetes (T2D). DPP-4 inhibitors reduce glucose levels by inhibiting degradation of incretins. DPP-4 is [...] Read more.
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) worldwide. Dipeptidyl peptidase (DPP)-4 inhibitors are widely used in the treatment of patients with type 2 diabetes (T2D). DPP-4 inhibitors reduce glucose levels by inhibiting degradation of incretins. DPP-4 is a ubiquitous protein with exopeptidase activity that exists in cell membrane-bound and soluble forms. It has been shown that an increased renal DPP-4 activity is associated with the development of DKD. A series of clinical and experimental studies showed that DPP-4 inhibitors have beneficial effects on DKD, independent of their glucose-lowering abilities, which are mediated by anti-fibrotic, anti-inflammatory, and anti-oxidative stress properties. In this review article, we highlight the current understanding of the clinical efficacy and the mechanisms underlying renoprotection by DPP-4 inhibitors under diabetic conditions. Full article
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