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Ridehalgh C, Fundaun J, Bremner S, Cercignani M, Koushesh S, Young R, Novak A, Greening J, Schmid AB, Dilley A. Evidence for peripheral neuroinflammation after acute whiplash. Pain 2025:00006396-990000000-00842. [PMID: 40035629 DOI: 10.1097/j.pain.0000000000003560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 01/09/2025] [Indexed: 03/05/2025]
Abstract
ABSTRACT Whiplash injury is associated with high socioeconomic costs and poor prognosis. Most people are classified as having whiplash-associated disorder grade II (WADII), with neck complaints and musculoskeletal signs, in the absence of frank neurological signs. However, evidence suggests that there is a subgroup with underlying nerve involvement in WADII, such as peripheral neuroinflammation. This study aimed to investigate the presence of neuroinflammation in acute WADII using T2-weighted magnetic resonance imaging of the brachial plexus, dorsal root ganglia and median nerve, and clinical surrogates of neuroinflammation: heightened nerve mechanosensitivity (HNM), raised serum inflammatory mediators, and somatosensory hyperalgesia. One hundred twenty-two WADII participants within 4 weeks of whiplash and 43 healthy controls (HCs) were recruited. Magnetic resonance imaging T2 signal ratio was increased in the C5 root of the brachial plexus and the C5-C8 dorsal root ganglia in WADII participants compared with HCs but not in the distal median nerve trunk. Fifty-five percent of WADII participants had signs of HNM. Inflammatory mediators were also raised compared with HCs, and 47% of WADII participants had somatosensory changes on quantitative sensory testing. In those WADII individuals with HNM, there was hyperalgesia to cold and pressure and an increased proportion of neuropathic pain. Many people with WADII had multiple indicators of neuroinflammation. Overall, our results present a complex phenotypic profile for acute WADII and provide evidence suggestive of peripheral neuroinflammation in a subgroup of individuals. The results suggest that there is a need to reconsider the management of people with WADII.
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Affiliation(s)
- Colette Ridehalgh
- Department of Clinical Neuroscience, Brighton and Sussex Medical School, Trafford Centre, University of Sussex, Falmer, Brighton, United Kingdom
- School of Life Course and Population Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom
| | - Joel Fundaun
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Palo Alto, CA, United States
| | - Stephen Bremner
- Department of Primary Care and Public Health, Brighton and Sussex Medical School, Brighton, United Kingdom
| | - Mara Cercignani
- Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, United Kingdom
| | - Soraya Koushesh
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Rupert Young
- School of Engineering and Informatics, University of Sussex, Brighton, United Kingdom
| | - Alex Novak
- Emergency Medicine Research Oxford (EMROx), Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
| | - Jane Greening
- Department of Clinical Neuroscience, Brighton and Sussex Medical School, Trafford Centre, University of Sussex, Falmer, Brighton, United Kingdom
| | - Annina B Schmid
- Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Andrew Dilley
- Department of Clinical Neuroscience, Brighton and Sussex Medical School, Trafford Centre, University of Sussex, Falmer, Brighton, United Kingdom
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Yin W, Noguchi CT. The Role of Erythropoietin in Metabolic Regulation. Cells 2025; 14:280. [PMID: 39996752 PMCID: PMC11853986 DOI: 10.3390/cells14040280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 02/05/2025] [Accepted: 02/12/2025] [Indexed: 02/26/2025] Open
Abstract
Erythropoietin (EPO) is a key regulator of erythrocyte production, promoting erythroid progenitor cell survival, division, and differentiation in the fetal liver and adult bone marrow. Mice lacking EPO or its receptor (EPOR) die in utero due to severe anemia. Beyond hematopoiesis, EPO influences non-hematopoietic tissues, including glucose and fat metabolism in adipose tissue, skeletal muscle, and the liver. EPO is used to treat anemia associated with chronic kidney disease clinically and plays a role in maintaining metabolic homeostasis and regulating fat mass. EPO enhances lipolysis while inhibiting lipogenic gene expression in white adipose tissue, brown adipose tissue, skeletal muscle, and the liver, acting through the EPO-EPOR-RUNX1 axis. The non-erythroid EPOR agonist ARA290 also improves diet-induced obesity and glucose tolerance providing evidence for EPO regulation of fat metabolism independent of EPO stimulated erythropoiesis. Therefore, in addition to the primary role of EPO to stimulate erythropoiesis, EPO contributes significantly to EPOR-dependent whole-body metabolic response.
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Affiliation(s)
| | - Constance T. Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA;
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3
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Motafeghi F, Fakhri B MS, Ghassemi Barghi N. Mechanisms of ARA290 in counteracting cadmium-triggered neurotoxicity in PC12 cells. Toxicol Res (Camb) 2025; 14:tfaf023. [PMID: 39968520 PMCID: PMC11831023 DOI: 10.1093/toxres/tfaf023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 01/27/2025] [Accepted: 02/06/2025] [Indexed: 02/20/2025] Open
Abstract
Erythropoietin (EPO) is known for its role in hematopoiesis and also exhibits anti-inflammatory, anti-apoptotic, antioxidant, and cytoprotective properties. However, its clinical application is limited by hematopoietic side effects. ARA290, a non-hematopoietic derivative of EPO, selectively activates the innate repair receptor (IRR) and replicates these protective effects without the associated hematopoietic complications. Cadmium (Cd), a prevalent environmental toxin, causes neurotoxic damage through mechanisms such as oxidative stress, genotoxicity, apoptosis, and inflammation. This study explored ARA290's neuroprotective effects against cadmium-induced toxicity in PC12 cells, an in vitro model for neuronal health. PC12 cells pretreated with ARA290 showed significantly improved cell viability in the MTT assay, indicating reduced cytotoxicity. The comet assay revealed decreased DNA damage, suggesting reduced genotoxicity. ARA290 also alleviated oxidative stress, as evidenced by reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), alongside increased glutathione (GSH), total antioxidant capacity (TAC), and superoxide dismutase (SOD) activities. A marker of apoptosis, TUNEL-positive cells, was significantly reduced. Additionally, ARA290 decreased inflammatory markers such as TNF alpha, IL1ß and IL 6. These findings demonstrate that ARA290, via IRR activation, provides robust neuroprotection against cadmium-induced toxicity, suggesting a multi-faceted protective mechanism. This highlights ARA290's potential therapeutic role in managing heavy metal-induced neurotoxicity and supports further research into its long-term effects and applications in other neurodegenerative diseases or conditions involving environmental toxins. Highlights ARA290 as a Neuroprotective Agent: ARA290, a modified form of erythropoietin that doesn't affect blood production, shows promising neuroprotective effects. It helps counteract the harmful effects of cadmium exposure on nerve cells by reducing oxidative stress, inflammation, cell death, and DNA damage.Reducing Oxidative Stress: ARA290 plays a key role in lowering oxidative stress by cutting down on harmful molecules like reactive oxygen species (ROS) and malondialdehyde (MDA). At the same time, it boosts the body's natural antioxidant defenses, including glutathione (GSH), superoxide dismutase (SOD), and overall antioxidant capacity.Protecting DNA Integrity: By reducing DNA damage caused by cadmium, ARA290 helps preserve the genetic stability of nerve cells. This protective effect is evident in laboratory tests, where it lowers the extent of DNA damage seen in the comet assay.Fighting Inflammation and Cell Death: ARA290 also has strong anti-inflammatory and anti-apoptotic effects. It reduces levels of inflammation markers like TNF-α, IL-1β, and IL-6, and significantly cuts down on nerve cell death, as seen in fewer TUNEL-positive cells in experiments.A Therapeutic Promise: Overall, these findings underscore ARA290's ability to protect the nervous system through multiple pathways. This makes it a promising candidate for treating cadmium-induced nerve damage and potentially other neurodegenerative conditions.
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Affiliation(s)
- Farzaneh Motafeghi
- Reproductive Endocrinology Research Center, Research Institute for Endocrine Molecular Biology, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tajrish, Taleqani St, No. 24, P.O. Box 19395-4763, Tehran, Iran
| | - Maryam S Fakhri B
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, District 6, Pour Sina St, P94+V8MF, Tehran Province, Tehran, Iran
- Department of Internal Medicine, School of Medicine, Tehran University of Medical Science, (TUMS), District 6, Pour Sina St, P94V+8MF, Tehran Province, Tehran, Iran
| | - Nasrin Ghassemi Barghi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, District 6, Pour Sina St, P94+V8MF, Tehran Province, Tehran, Iran
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4
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Moor CC, Obi ON, Kahlmann V, Buschulte K, Wijsenbeek MS. Quality of life in sarcoidosis. J Autoimmun 2024; 149:103123. [PMID: 37813805 DOI: 10.1016/j.jaut.2023.103123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 10/04/2023] [Indexed: 10/11/2023]
Abstract
Having sarcoidosis often has a major impact on quality of life of patients and their families. Improving quality of life is prioritized as most important treatment aim by many patients with sarcoidosis, but current evidence and treatment options are limited. In this narrative review, we describe the impact of sarcoidosis on various aspects of daily life, evaluate determinants of health-related quality of life (HRQoL), and provide an overview of the different patient-reported outcome measures to assess HRQoL in sarcoidosis. Moreover, we review the current evidence for pharmacological and non-pharmacological interventions to improve quality of life for people with sarcoidosis.
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Affiliation(s)
- Catharina C Moor
- Department of Respiratory Medicine, Centre of Excellence for Interstitial Lung Diseases and Sarcoidosis, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Ogugua Ndili Obi
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA
| | - Vivienne Kahlmann
- Department of Respiratory Medicine, Centre of Excellence for Interstitial Lung Diseases and Sarcoidosis, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Katharina Buschulte
- Center for Interstitial and Rare Lung Diseases, Pneumology and Respiratory Critical Care Medicine, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
| | - Marlies S Wijsenbeek
- Department of Respiratory Medicine, Centre of Excellence for Interstitial Lung Diseases and Sarcoidosis, Erasmus Medical Center, Rotterdam, the Netherlands.
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Obi ON, Saketkoo LA, Maier LA, Baughman RP. Developmental drugs for sarcoidosis. J Autoimmun 2024; 149:103179. [PMID: 38548579 DOI: 10.1016/j.jaut.2024.103179] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Revised: 12/04/2023] [Accepted: 02/08/2024] [Indexed: 12/15/2024]
Abstract
Sarcoidosis is a multi-organ granulomatous inflammatory disease of unknown etiology. Over 50% of patients will require treatment at some point in their disease and 10%-30% will develop a chronic progressive disease with pulmonary fibrosis leading to significant morbidity and mortality. Recently published guidelines recommend immunosuppressive therapy for sarcoidosis patients at risk of increased disease-related morbidity and mortality, and in whom disease has negatively impacted quality of life. Prednisone the currently recommended first line therapy is associated with significant toxicity however none of the other guideline recommended steroid sparing therapy is approved by regulatory agencies for use in sarcoidosis, and data in support of their use is weak. For patients with severe refractory disease requiring prolonged therapy, treatment options are limited. The need for expanding treatment options in sarcoidosis has been emphasized. Well conducted large, randomized trials evaluating currently available therapeutic options as well as novel pathways for targeting disease are necessary to better guide treatment decisions. These trials will not be without significant challenges. Sarcoidosis is a rare disease with heterogenous presentation and variable progression and clinical outcome. There are no universally agreed upon biomarkers of disease activity and measurement of outcomes is confounded by the need to balance patient centric measures and objective measures of disease activity. Our paper provides an update on developmental drugs in sarcoidosis and outlines several novel pathways that may be targeted for future drug development. Currently available trials are highlighted and ongoing challenges to drug development and clinical trial design are briefly discussed.
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Affiliation(s)
- Ogugua Ndili Obi
- Division of Pulmonary Critical Care and Sleep Medicine, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
| | - Lesley Ann Saketkoo
- New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans, USA; University Medical Center - Comprehensive Pulmonary Hypertension Center and Interstitial Lung Disease Clinic Programs, New Orleans, USA; Louisiana State University School of Medicine, Section of Pulmonary Medicine, New Orleans, LA, USA; Tulane University School of Medicine, Undergraduate Honors Department, New Orleans, LA, USA
| | - Lisa A Maier
- Division of Environmental and Occupational Health Sciences, Department of Medicine, National Jewish Health, Denver, CO, USA; Division of Pulmonary and Critical Care Sciences, Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA
| | - Robert P Baughman
- Emeritus Professor of Medicine, Department of Medicine, University of Cincinnati, Cincinnati, OH, USA
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6
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Zhao B, Zhao Y, Sun X. Mechanism and therapeutic targets of circulating immune cells in diabetic retinopathy. Pharmacol Res 2024; 210:107505. [PMID: 39547465 DOI: 10.1016/j.phrs.2024.107505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 11/17/2024]
Abstract
Diabetic retinopathy (DR) continues to be the leading cause of preventable vision loss among working-aged adults, marked by immune dysregulation within the retinal microenvironment. Typically, the retina is considered as an immune-privileged organ, where circulating immune cells are restricted from entry under normal conditions. However, during the progression of DR, this immune privilege is compromised as circulating immune cells breach the barrier and infiltrate the retina. Increasing evidence suggests that vascular and neuronal degeneration in DR is largely driven by the infiltration of immune cells, particularly neutrophils, monocyte-derived macrophages, and lymphocytes. This review delves into the mechanisms and therapeutic targets associated with these immune cell populations in DR, offering a promising and innovative approach to managing the disease.
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Affiliation(s)
- Bowen Zhao
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yin Zhao
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Xufang Sun
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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7
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Yin W, Rajvanshi PK, Rogers HM, Yoshida T, Kopp JB, An X, Gassmann M, Noguchi CT. Erythropoietin regulates energy metabolism through EPO-EpoR-RUNX1 axis. Nat Commun 2024; 15:8114. [PMID: 39284834 PMCID: PMC11405798 DOI: 10.1038/s41467-024-52352-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 09/02/2024] [Indexed: 09/20/2024] Open
Abstract
Erythropoietin (EPO) plays a key role in energy metabolism, with EPO receptor (EpoR) expression in white adipose tissue (WAT) mediating its metabolic activity. Here, we show that male mice lacking EpoR in adipose tissue exhibit increased fat mass and susceptibility to diet-induced obesity. Our findings indicate that EpoR is present in WAT, brown adipose tissue, and skeletal muscle. Elevated EPO in male mice improves glucose tolerance and insulin sensitivity while reducing expression of lipogenic-associated genes in WAT, which is linked to an increase in transcription factor RUNX1 that directly inhibits lipogenic genes expression. EPO treatment in wild-type male mice decreases fat mass and lipogenic gene expression and increase in RUNX1 protein in adipose tissue which is not observed in adipose tissue EpoR ablation mice. EPO treatment decreases WAT ubiquitin ligase FBXW7 expression and increases RUNX1 stability, providing evidence that EPO regulates energy metabolism in male mice through the EPO-EpoR-RUNX1 axis.
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Affiliation(s)
- Weiqin Yin
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Praveen Kumar Rajvanshi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Heather M Rogers
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Teruhiko Yoshida
- Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Jeffrey B Kopp
- Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Xiuli An
- Laboratory of Membrane Biology, New York Blood Center, New York, NY, USA
| | - Max Gassmann
- Institute of Veterinary Physiology and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Constance T Noguchi
- Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
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8
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Røikjer J, Borbjerg MK, Andresen T, Giordano R, Hviid CVB, Mørch CD, Karlsson P, Klonoff DC, Arendt-Nielsen L, Ejskjaer N. Diabetic Peripheral Neuropathy: Emerging Treatments of Neuropathic Pain and Novel Diagnostic Methods. J Diabetes Sci Technol 2024:19322968241279553. [PMID: 39282925 PMCID: PMC11571639 DOI: 10.1177/19322968241279553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2024]
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is a prevalent and debilitating complication of diabetes, often leading to severe neuropathic pain. Although other diabetes-related complications have witnessed a surge of emerging treatments in recent years, DPN has seen minimal progression. This stagnation stems from various factors, including insensitive diagnostic methods and inadequate treatment options for neuropathic pain. METHODS In this comprehensive review, we highlight promising novel diagnostic techniques for assessing DPN, elucidating their development, strengths, and limitations, and assessing their potential as future reliable clinical biomarkers and endpoints. In addition, we delve into the most promising emerging pharmacological and mechanistic treatments for managing neuropathic pain, an area currently characterized by inadequate pain relief and a notable burden of side effects. RESULTS Skin biopsies, corneal confocal microscopy, transcutaneous electrical stimulation, blood-derived biomarkers, and multi-omics emerge as some of the most promising new techniques, while low-dose naltrexone, selective sodium-channel blockers, calcitonin gene-related peptide antibodies, and angiotensin type 2 receptor antagonists emerge as some of the most promising new drug candidates. CONCLUSION Our review concludes that although several promising diagnostic modalities and emerging treatments exist, an ongoing need persists for the further development of sensitive diagnostic tools and mechanism-based, personalized treatment approaches.
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Affiliation(s)
- Johan Røikjer
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Integrative Neuroscience, Aalborg University, Aalborg, Denmark
- Department Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Mette Krabsmark Borbjerg
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Integrative Neuroscience, Aalborg University, Aalborg, Denmark
| | - Trine Andresen
- Integrative Neuroscience, Aalborg University, Aalborg, Denmark
- Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
| | - Rocco Giordano
- Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
| | - Claus Vinter Bødker Hviid
- Department of Biochemistry, Aalborg University Hospital, Aalborg, Denmark
- Department Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Carsten Dahl Mørch
- Integrative Neuroscience, Aalborg University, Aalborg, Denmark
- Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
| | - Pall Karlsson
- Danish Pain Research Center, Aarhus University, Aarhus, Denmark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
| | | | - Lars Arendt-Nielsen
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Center for Neuroplasticity and Pain, Aalborg University, Aalborg, Denmark
- Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | - Niels Ejskjaer
- Steno Diabetes Center North Denmark, Aalborg University Hospital, Aalborg, Denmark
- Department Clinical Medicine, Aalborg University, Aalborg, Denmark
- Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
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9
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Liu G, Liang J, Li W, Jiang S, Song M, Xu S, Du Q, Wang L, Wang X, Liu X, Tang L, Yang Z, Zhou M, Meng H, Zhang L, Yang Y, Zhang B. The protective effect of erythropoietin and its novel derived peptides in peripheral nerve injury. Int Immunopharmacol 2024; 138:112452. [PMID: 38943972 DOI: 10.1016/j.intimp.2024.112452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/23/2024] [Accepted: 06/07/2024] [Indexed: 07/01/2024]
Abstract
Peripheral nerve injury seriously endangers human life and health, but there is no clinical drug for the treatment of peripheral nerve injury, so it is imperative to develop drugs to promote the repair of peripheral nerve injury. Erythropoietin (EPO) not only has the traditional role of promoting erythropoiesis, but also has a tissue-protective effect. Over the past few decades, researchers have confirmed that EPO has neuroprotective effects. However, side effects caused by long-term use of EPO limited its clinical application. Therefore, EPO derivatives with low side effects have been explored. Among them, ARA290 has shown significant protective effects on the nervous system, but the biggest disadvantage of ARA290, its short half-life, limits its application. To address the short half-life issue, the researchers modified ARA290 with thioether cyclization to generate a thioether cyclized helical B peptide (CHBP). ARA290 and CHBP have promising applications as peptide drugs. The neuroprotective effects they exhibit have attracted continuous exploration of their mechanisms of action. This article will review the research on the role of EPO, ARA290 and CHBP in the nervous system around this developmental process, and provide a certain reference for the subsequent research.
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Affiliation(s)
- Guixian Liu
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Jie Liang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Wei Li
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Suli Jiang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Meiying Song
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Shuo Xu
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Qiaochu Du
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Luoyang Wang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Xiao Wang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Xiaoli Liu
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Lei Tang
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Zijie Yang
- Department of Special Medicine, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Mengting Zhou
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Haining Meng
- Department of Emergency Medicine, Medical College of Qingdao University, Qingdao, Shandong 266071, PR China
| | - Li Zhang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Yanyan Yang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China
| | - Bei Zhang
- Department of Immunology, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, PR China.
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10
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Gad H, Elgassim E, Lebbe A, MacDonald RS, Baraka A, Petropoulos IN, Ponirakis G, Ibrahim NO, Malik RA. Corneal confocal microscopy detects early nerve regeneration after pharmacological and surgical interventions: Systematic review and meta-analysis. J Peripher Nerv Syst 2024; 29:173-184. [PMID: 38887985 DOI: 10.1111/jns.12641] [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: 04/23/2024] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/20/2024]
Abstract
Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that enables the identification of corneal nerve fibre degeneration and regeneration. To undertake a systematic review and meta-analysis of studies utilizing CCM to assess for corneal nerve regeneration after pharmacological and surgical interventions in patients with peripheral neuropathy. Databases (EMBASE [Ovid], PubMed, CENTRAL and Web of Science) were searched to summarize the evidence from randomized and non-randomized studies using CCM to detect corneal nerve regeneration after pharmacological and surgical interventions. Data synthesis was undertaken using RevMan web. Eighteen studies including 958 patients were included. CCM identified an early (1-8 months) and longer term (1-5 years) increase in corneal nerve measures in patients with peripheral neuropathy after pharmacological and surgical interventions. This meta-analysis confirms the utility of CCM to identify nerve regeneration following pharmacological and surgical interventions. It could be utilized to show a benefit in clinical trials of disease modifying therapies for peripheral neuropathy.
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Affiliation(s)
- Hoda Gad
- Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Einas Elgassim
- Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Ahamed Lebbe
- Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | - Areej Baraka
- Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | | | - Nada O Ibrahim
- Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Rayaz A Malik
- Research Department, Weill Cornell Medicine-Qatar, Doha, Qatar
- Institute of Cardiovascular Medicine, University of Manchester, Manchester, UK
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11
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Sher EK, Džidić-Krivić A, Karahmet A, Beća-Zećo M, Farhat EK, Softić A, Sher F. Novel therapeutical approaches based on neurobiological and genetic strategies for diabetic polyneuropathy - A review. Diabetes Metab Syndr 2023; 17:102901. [PMID: 37951098 DOI: 10.1016/j.dsx.2023.102901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 11/13/2023]
Abstract
BACKGROUND Neuropathy is among the most often reported consequences of diabetes and the biggest cause of morbidity and mortality in people suffering from this life-long disease. Although different therapeutic methods are available for diabetic neuropathy, it is still the leading cause of limb amputations, and it significantly decreases patients' quality of life. AIM This study investigates potential novel therapeutic options that could ameliorate symptoms of DN. METHODOLOGY Research and review papers from the last 10 years were taken into consideration. RESULTS There are various traditional drugs and non-pharmacological methods used to treat this health condition. However, the research in the area of pathogenic-oriented drugs in the treatment of DN showed no recent breakthroughs, mostly due to the limited evidence about their effectiveness and safety obtained through clinical trials. Consequently, there is an urgent demand for the development of novel therapeutic options for diabetic neuropathy. CONCLUSION Some of the latest novel diagnostic methods for diagnosing diabetic neuropathy are discussed as well as the new therapeutic approaches, such as the fusion of neuronal cells with stem cells, targeting gene delivery and novel drugs.
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Affiliation(s)
- Emina Karahmet Sher
- Department of Biosciences, School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS, United Kingdom.
| | - Amina Džidić-Krivić
- International Society of Engineering Science and Technology, Nottingham, United Kingdom; Department of Neurology, Clinical Hospital Zenica, Zenica, 72000, Bosnia and Herzegovina
| | - Alma Karahmet
- International Society of Engineering Science and Technology, Nottingham, United Kingdom
| | - Merima Beća-Zećo
- International Society of Engineering Science and Technology, Nottingham, United Kingdom; Department of Pharmacy, Faculty of Health Sciences, Victoria International University, Mostar, 88000, Bosnia and Herzegovina
| | - Esma Karahmet Farhat
- International Society of Engineering Science and Technology, Nottingham, United Kingdom; Faculty of Food Technology, Juraj Strossmayer University of Osijek, Osijek, 31000, Croatia
| | - Adaleta Softić
- Department of Biochemistry, Faculty of Pharmacy, University of Tuzla, Tuzla, 75000, Bosnia and Herzegovina
| | - Farooq Sher
- Department of Engineering, School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS, United Kingdom.
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12
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Guldiken YC, Malik A, Petropoulos IN, Gad H, Elgassim E, Salivon I, Ponirakis G, Alam U, Malik RA. Where Art Thou O treatment for diabetic neuropathy: the sequel. Expert Rev Neurother 2023; 23:845-851. [PMID: 37602687 DOI: 10.1080/14737175.2023.2247163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 08/08/2023] [Indexed: 08/22/2023]
Abstract
INTRODUCTION Having lived through a pandemic and witnessed how regulatory approval processes can evolve rapidly; it is lamentable how we continue to rely on symptoms/signs and nerve conduction as primary endpoints for clinical trials in DPN. AREAS COVERED Small (Aδ and C) fibers are key to the genesis of pain, regulate skin blood flow, and play an integral role in the development of diabetic foot ulceration but continue to be ignored. This article challenges the rationale for the FDA insisting on symptoms/signs and nerve conduction as primary endpoints for clinical trials in DPN. EXPERT OPINION Quantitative sensory testing, intraepidermal nerve fiber density, and especially corneal confocal microscopy remain an after-thought, demoted at best to exploratory secondary endpoints in clinical trials of diabetic neuropathy. If pharma are to be given a fighting chance to secure approval for a new therapy for diabetic neuropathy, the FDA needs to reassess the evidence rather than rely on 'opinion' for the most suitable endpoint(s) in clinical trials of diabetic neuropathy.
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Affiliation(s)
- Yigit Can Guldiken
- Department of Neurology, Kocaeli University Research and Application Hospital, İzmit/Kocaeli, Turkey
| | - Ayesha Malik
- Barts and The London School of Medicine and Dentistry - Medicine, London, UK
| | | | - Hoda Gad
- Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar
| | - Einas Elgassim
- Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar
| | - Iuliia Salivon
- Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar
| | | | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
| | - Rayaz A Malik
- Weill Cornell Medicine-Qatar, Qatar Foundation, Doha, Qatar
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13
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Preston FG, Riley DR, Azmi S, Alam U. Painful Diabetic Peripheral Neuropathy: Practical Guidance and Challenges for Clinical Management. Diabetes Metab Syndr Obes 2023; 16:1595-1612. [PMID: 37288250 PMCID: PMC10243347 DOI: 10.2147/dmso.s370050] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/16/2023] [Indexed: 06/09/2023] Open
Abstract
Painful diabetic peripheral neuropathy (PDPN) is present in nearly a quarter of people with diabetes. It is estimated to affect over 100 million people worldwide. PDPN is associated with impaired daily functioning, depression, sleep disturbance, financial instability, and a decreased quality of life. Despite its high prevalence and significant health burden, it remains an underdiagnosed and undertreated condition. PDPN is a complex pain phenomenon with the experience of pain associated with and exacerbated by poor sleep and low mood. A holistic approach to patient-centred care alongside the pharmacological therapy is required to maximise benefit. A key treatment challenge is managing patient expectation, as a good outcome from treatment is defined as a reduction in pain of 30-50%, with a complete pain-free outcome being rare. The future for the treatment of PDPN holds promise, despite a 20-year void in the licensing of new analgesic agents for neuropathic pain. There are over 50 new molecular entities reaching clinical development and several demonstrating benefit in early-stage clinical trials. We review the current approaches to its diagnosis, the tools, and questionnaires available to clinicians, international guidance on PDPN management, and existing pharmacological and non-pharmacological treatment options. We synthesise evidence and the guidance from the American Association of Clinical Endocrinology, American Academy of Neurology, American Diabetes Association, Diabetes Canada, German Diabetes Association, and the International Diabetes Federation into a practical guide to the treatment of PDPN and highlight the need for future research into mechanistic-based treatments in order to prioritise the development of personalised medicine.
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Affiliation(s)
- Frank G Preston
- Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool, Liverpool, UK
| | - David R Riley
- Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool, Liverpool, UK
| | - Shazli Azmi
- Institute of Cardiovascular Science, University of Manchester and Manchester Diabetes Centre, Manchester Foundation Trust, Manchester, UK
| | - Uazman Alam
- Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool, Liverpool, UK
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool, UK
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14
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Ghassemi-Barghi N, Ehsanfar Z, Mohammadrezakhani O, Ashari S, Ghiabi S, Bayrami Z. Mechanistic Approach for Protective Effect of ARA290, a Specific Ligand for the Erythropoietin/CD131 Heteroreceptor, against Cisplatin-Induced Nephrotoxicity, the Involvement of Apoptosis and Inflammation Pathways. Inflammation 2023; 46:342-358. [PMID: 36085231 DOI: 10.1007/s10753-022-01737-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/08/2022] [Accepted: 08/30/2022] [Indexed: 12/01/2022]
Abstract
ARA 290, an 11-amino acid linear nonhematopoietic peptide derived from the three-dimensional structure of helix B of the erythropoietin (EPO), interacts selectively with the innate repair receptor (IRR) that arbitrates tissue protection. The aim of this study was to investigate the protective effects of ARA290 against cisplatin-induced nephrotoxicity. For this purpose, HEK-293 and ACHN cells were treated with ARA290 (50-400 nM) and cisplatin (2.5 μM) in pretreatment condition. Then, cytotoxicity, genotoxicity, oxidative stress parameters (ROS, GPx, SOD, and MDA), and inflammatory markers (TNFα, IL6, and IL1β) were evaluated. Furthermore, apoptotic cell death was assessed via caspase-3 activity and tunnel assay. To determine the molecular mechanisms of the possible nephroprotective effects of ARA290, gene and protein expressions of TNFα, IL1β, IL6, Caspase-3, Bax, and Bcl2 were evaluated by real-time PCR and western blot assay, respectively. The findings indicated that ARA290 significantly reduced the DNA damage parameters of comet assay and the frequency of micronuclei induced by cisplatin. Besides, ARA290 improved cisplatin-induced oxidative stress by reducing MDA/ROS levels and enhancing antioxidant enzyme levels. In addition, reduced levels of pro-inflammatory cytokines indicated that cisplatin-induced renal inflammation was mitigated upon the treatment with ARA290. Besides, ARA290 ameliorates cisplatin-induced cell injury by antagonizing apoptosis. Furthermore, the molecular findings indicated that gene and protein levels of TNFα, IL1β, IL6, Caspase-3, and Bax were significantly decreased and gene and protein levels of Bcl2 significantly increased in the ARA290 plus cisplatin group compared with the cisplatin group. These findings revealed that ARA290 as a potent chemo-preventive agent exerted a protective effect on cisplatin-induced nephrotoxicity mostly through its anti-apoptotic, anti-inflammatory, and antioxidant potentials and also suggested that ARA290 might be a new therapeutic approach for patients with acute kidney injury.
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Affiliation(s)
- Nasrin Ghassemi-Barghi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
| | | | - Omid Mohammadrezakhani
- Student Research Committee, Ramsar Campus, Mazandaran University of Medical Sciences, Ramsar, Iran
| | - Sorour Ashari
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
| | - Shamim Ghiabi
- Department of Medical Chemistry, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Zahra Bayrami
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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15
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Winicki NM, Nanavati AP, Morrell CH, Moen JM, Axsom JE, Krawczyk M, Petrashevskaya NN, Beyman MG, Ramirez C, Alfaras I, Mitchell SJ, Juhaszova M, Riordon DR, Wang M, Zhang J, Cerami A, Brines M, Sollott SJ, de Cabo R, Lakatta EG. A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan. Front Cardiovasc Med 2023; 9:1096887. [PMID: 36741836 PMCID: PMC9889362 DOI: 10.3389/fcvm.2022.1096887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 12/28/2022] [Indexed: 01/20/2023] Open
Abstract
Background Aging is associated with increased levels of reactive oxygen species and inflammation that disrupt proteostasis and mitochondrial function and leads to organism-wide frailty later in life. ARA290 (cibinetide), an 11-aa non-hematopoietic peptide sequence within the cardioprotective domain of erythropoietin, mediates tissue protection by reducing inflammation and fibrosis. Age-associated cardiac inflammation is linked to structural and functional changes in the heart, including mitochondrial dysfunction, impaired proteostasis, hypertrophic cardiac remodeling, and contractile dysfunction. Can ARA290 ameliorate these age-associated cardiac changes and the severity of frailty in advanced age? Methods We conducted an integrated longitudinal (n = 48) and cross-sectional (n = 144) 15 months randomized controlled trial in which 18-month-old Fischer 344 x Brown Norway rats were randomly assigned to either receive chronic ARA290 treatment or saline. Serial echocardiography, tail blood pressure and body weight were evaluated repeatedly at 4-month intervals. A frailty index was calculated at the final timepoint (33 months of age). Tissues were harvested at 4-month intervals to define inflammatory markers and left ventricular tissue remodeling. Mitochondrial and myocardial cell health was assessed in isolated left ventricular myocytes. Kaplan-Meier survival curves were established. Mixed ANOVA tests and linear mixed regression analysis were employed to determine the effects of age, treatment, and age-treatment interactions. Results Chronic ARA290 treatment mitigated age-related increases in the cardiac non-myocyte to myocyte ratio, infiltrating leukocytes and monocytes, pro-inflammatory cytokines, total NF-κB, and p-NF-κB. Additionally, ARA290 treatment enhanced cardiomyocyte autophagy flux and reduced cellular accumulation of lipofuscin. The cardiomyocyte mitochondrial permeability transition pore response to oxidant stress was desensitized following chronic ARA290 treatment. Concurrently, ARA290 significantly blunted the age-associated elevation in blood pressure and preserved the LV ejection fraction. Finally, ARA290 preserved body weight and significantly reduced other markers of organism-wide frailty at the end of life. Conclusion Administration of ARA290 reduces cell and tissue inflammation, mitigates structural and functional changes within the cardiovascular system leading to amelioration of frailty and preserved healthspan.
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Affiliation(s)
- Nolan M. Winicki
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Alay P. Nanavati
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Christopher H. Morrell
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Jack M. Moen
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Jessie E. Axsom
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Melissa Krawczyk
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Natalia N. Petrashevskaya
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Max G. Beyman
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Christopher Ramirez
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Irene Alfaras
- Laboratory of Experimental Gerontology, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Sarah J. Mitchell
- Laboratory of Experimental Gerontology, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Magdalena Juhaszova
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Daniel R. Riordon
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Mingyi Wang
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Jing Zhang
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Anthony Cerami
- Araim Pharmaceuticals, Inc., Tarrytown, NY, United States
| | - Michael Brines
- Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Steven J. Sollott
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Rafael de Cabo
- Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States
| | - Edward G. Lakatta
- Laboratory of Experimental Gerontology, Intramural Research Program, National Institute on Aging, Baltimore, MD, United States,*Correspondence: Edward G. Lakatta,
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16
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Dennhardt S, Pirschel W, Wissuwa B, Imhof D, Daniel C, Kielstein JT, Hennig-Pauka I, Amann K, Gunzer F, Coldewey SM. Targeting the innate repair receptor axis via erythropoietin or pyroglutamate helix B surface peptide attenuates hemolytic-uremic syndrome in mice. Front Immunol 2022; 13:1010882. [PMID: 36211426 PMCID: PMC9537456 DOI: 10.3389/fimmu.2022.1010882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Accepted: 08/30/2022] [Indexed: 11/30/2022] Open
Abstract
Hemolytic-uremic syndrome (HUS) can occur as a systemic complication of infections with Shiga toxin (Stx)-producing Escherichia coli and is characterized by microangiopathic hemolytic anemia and acute kidney injury. Hitherto, therapy has been limited to organ-supportive strategies. Erythropoietin (EPO) stimulates erythropoiesis and is approved for the treatment of certain forms of anemia, but not for HUS-associated hemolytic anemia. EPO and its non-hematopoietic analog pyroglutamate helix B surface peptide (pHBSP) have been shown to mediate tissue protection via an innate repair receptor (IRR) that is pharmacologically distinct from the erythropoiesis-mediating receptor (EPO-R). Here, we investigated the changes in endogenous EPO levels in patients with HUS and in piglets and mice subjected to preclinical HUS models. We found that endogenous EPO was elevated in plasma of humans, piglets, and mice with HUS, regardless of species and degree of anemia, suggesting that EPO signaling plays a role in HUS pathology. Therefore, we aimed to examine the therapeutic potential of EPO and pHBSP in mice with Stx-induced HUS. Administration of EPO or pHBSP improved 7-day survival and attenuated renal oxidative stress but did not significantly reduce renal dysfunction and injury in the employed model. pHBSP, but not EPO, attenuated renal nitrosative stress and reduced tubular dedifferentiation. In conclusion, targeting the EPO-R/IRR axis reduced mortality and renal oxidative stress in murine HUS without occurrence of thromboembolic complications or other adverse side effects. We therefore suggest that repurposing EPO for the treatment of patients with hemolytic anemia in HUS should be systematically investigated in future clinical trials.
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Affiliation(s)
- Sophie Dennhardt
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Wiebke Pirschel
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Bianka Wissuwa
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
| | - Diana Imhof
- Pharmaceutical Biochemistry and Bioanalytics, Pharmaceutical Institute, University of Bonn, Bonn, Germany
| | - Christoph Daniel
- Department of Nephropathology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Jan T. Kielstein
- Medical Clinic V, Nephrology | Rheumatology | Blood Purification, Academic Teaching Hospital Braunschweig, Braunschweig, Germany
| | - Isabel Hennig-Pauka
- Field Station for Epidemiology, University of Veterinary Medicine Hannover, Bakum, Germany
| | - Kerstin Amann
- Department of Nephropathology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Florian Gunzer
- Department of Hospital Infection Control, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Sina M. Coldewey
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany
- Septomics Research Center, Jena University Hospital, Jena, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- *Correspondence: Sina M. Coldewey,
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17
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Multi-analyte screening of small peptides by alkaline pre-activated solid phase extraction coupled with liquid chromatography-high resolution mass spectrometry in doping controls. J Chromatogr A 2022; 1676:463272. [DOI: 10.1016/j.chroma.2022.463272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/16/2022] [Accepted: 06/20/2022] [Indexed: 11/19/2022]
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18
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Jolivalt CG, Han MM, Nguyen A, Desmond F, Alves Jesus CH, Vasconselos DC, Pedneault A, Sandlin N, Dunne-Cerami S, Frizzi KE, Calcutt NA. Using Corneal Confocal Microscopy to Identify Therapeutic Agents for Diabetic Neuropathy. J Clin Med 2022; 11:jcm11092307. [PMID: 35566433 PMCID: PMC9104226 DOI: 10.3390/jcm11092307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/19/2022] [Accepted: 04/19/2022] [Indexed: 02/04/2023] Open
Abstract
Corneal confocal microscopy (CCM) is emerging as a tool for identifying small fiber neuropathy in both peripheral neuropathies and neurodegenerative disease of the central nervous system (CNS). The value of corneal nerves as biomarkers for efficacy of clinical interventions against small fiber neuropathy and neurodegenerative disease is less clear but may be supported by preclinical studies of investigational agents. We, therefore, used diverse investigational agents to assess concordance of efficacy against corneal nerve loss and peripheral neuropathy in a mouse model of diabetes. Ocular delivery of the peptides ciliary neurotrophic factor (CNTF) or the glucagon-like peptide (GLP) analog exendin-4, both of which prevent diabetic neuropathy when given systemically, restored corneal nerve density within 2 weeks. Similarly, ocular delivery of the muscarinic receptor antagonist cyclopentolate protected corneal nerve density while concurrently reversing indices of systemic peripheral neuropathy. Conversely, systemic delivery of the muscarinic antagonist glycopyrrolate, but not gallamine, prevented multiple indices of systemic peripheral neuropathy and concurrently protected against corneal nerve loss. These data highlight the potential for use of corneal nerve quantification by confocal microscopy as a bridging assay between in vitro and whole animal assays in drug development programs for neuroprotectants and support its use as a biomarker of efficacy against peripheral neuropathy.
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Corneal Confocal Microscopy Identifies People with Type 1 Diabetes with More Rapid Corneal Nerve Fibre Loss and Progression of Neuropathy. J Clin Med 2022; 11:jcm11082249. [PMID: 35456342 PMCID: PMC9030140 DOI: 10.3390/jcm11082249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/03/2022] [Accepted: 04/05/2022] [Indexed: 11/23/2022] Open
Abstract
There is a need to accurately identify patients with diabetes at higher risk of developing and progressing diabetic peripheral neuropathy (DPN). Fifty subjects with Type 1 Diabetes Mellitus (T1DM) and sixteen age matched healthy controls underwent detailed neuropathy assessments including symptoms, signs, quantitative sensory testing (QST), nerve conduction studies (NCS), intra epidermal nerve fiber density (IENFD) and corneal confocal microscopy (CCM) at baseline and after 2 years of follow-up. Overall, people with type 1 diabetes mellitus showed no significant change in HbA1c, blood pressure, lipids or neuropathic symptoms, signs, QST, neurophysiology, IENFD and CCM over 2 years. However, a sub-group (n = 11, 22%) referred to as progressors, demonstrated rapid corneal nerve fiber loss (RCNFL) with a reduction in corneal nerve fiber density (CNFD) (p = 0.0006), branch density (CNBD) (p = 0.0002), fiber length (CNFL) (p = 0.0002) and sural (p = 0.04) and peroneal (p = 0.05) nerve conduction velocities, which was not related to a change in HbA1c or cardiovascular risk factors. The majority of people with T1DM and good risk factor control do not show worsening of neuropathy over 2 years. However, CCM identifies a sub-group of people with T1DM who show a more rapid decline in corneal nerve fibers and nerve conduction velocity.
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20
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Tavee J. Peripheral neuropathy in sarcoidosis. J Neuroimmunol 2022; 368:577864. [DOI: 10.1016/j.jneuroim.2022.577864] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/28/2022] [Accepted: 04/06/2022] [Indexed: 12/19/2022]
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21
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Petropoulos IN, Bitirgen G, Ferdousi M, Kalteniece A, Azmi S, D'Onofrio L, Lim SH, Ponirakis G, Khan A, Gad H, Mohammed I, Mohammadi YE, Malik A, Gosal D, Kobylecki C, Silverdale M, Soran H, Alam U, Malik RA. Corneal Confocal Microscopy to Image Small Nerve Fiber Degeneration: Ophthalmology Meets Neurology. FRONTIERS IN PAIN RESEARCH 2022; 2:725363. [PMID: 35295436 PMCID: PMC8915697 DOI: 10.3389/fpain.2021.725363] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 07/26/2021] [Indexed: 12/13/2022] Open
Abstract
Neuropathic pain has multiple etiologies, but a major feature is small fiber dysfunction or damage. Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that can image small nerve fibers in the cornea and has been utilized to show small nerve fiber loss in patients with diabetic and other neuropathies. CCM has comparable diagnostic utility to intraepidermal nerve fiber density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fiber loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease and dementia. We conclude that corneal confocal microscopy has good diagnostic and prognostic capability and fulfills the FDA criteria as a surrogate end point for clinical trials in peripheral and central neurodegenerative diseases.
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Affiliation(s)
| | - Gulfidan Bitirgen
- Department of Ophthalmology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Maryam Ferdousi
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Alise Kalteniece
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Shazli Azmi
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom.,Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Luca D'Onofrio
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Sze Hway Lim
- Department of Neurology, Salford Royal National Health System (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
| | | | - Adnan Khan
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Hoda Gad
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Ibrahim Mohammed
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | | | - Ayesha Malik
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - David Gosal
- Department of Neurology, Salford Royal National Health System (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
| | - Christopher Kobylecki
- Department of Neurology, Salford Royal National Health System (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
| | - Monty Silverdale
- Department of Neurology, Salford Royal National Health System (NHS) Foundation Trust, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, United Kingdom
| | - Handrean Soran
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine, Clinical Sciences Centre, Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool University Hospital National Health System (NHS) Foundation Trust, Liverpool, United Kingdom
| | - Rayaz A Malik
- Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar.,Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
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22
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Al-Bazz DY, Nelson AJ, Burgess J, Petropoulos IN, Nizza J, Marshall A, Brown E, Cuthbertson DJ, Marshall AG, Malik RA, Alam U. Is Nerve Electrophysiology a Robust Primary Endpoint in Clinical Trials of Treatments for Diabetic Peripheral Neuropathy? Diagnostics (Basel) 2022; 12:731. [PMID: 35328284 PMCID: PMC8947384 DOI: 10.3390/diagnostics12030731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 12/10/2022] Open
Abstract
There is currently no FDA-approved disease-modifying therapy for diabetic peripheral neuropathy (DPN). Nerve conduction velocity (NCV) is an established primary endpoint of disease-modifying therapies in DPN and clinical trials have been powered with an assumed decline of 0.5 m/s/year. This paper sought to establish the time-dependent change in NCV associated with a placebo, compared to that observed in the active intervention group. A literature search identified twenty-one double-blind, randomised controlled trials in DPN of ≥1 year duration conducted between 1971 and 2021. We evaluated changes in neurophysiology, with a focus on peroneal motor and sural sensory NCV and amplitude in the placebo and treatment groups. There was significant variability in the change and direction of change (reduction/increase) in NCV in the placebo arm, as well as variability influenced by the anatomical site of neurophysiological measurement within a given clinical trial. A critical re-evaluation of efficacy trials should consider placebo-adjusted effects and present the placebo-subtracted change in NCV rather than assume a universal annual decline of 0.5 m/s/year. Importantly, endpoints such as corneal confocal microscopy (CCM) have demonstrated early nerve repair, whilst symptoms and NCV have not changed, and should thus be considered as a viable alternative.
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Affiliation(s)
- Dalal Y. Al-Bazz
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Andrew J. Nelson
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Jamie Burgess
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Ioannis N. Petropoulos
- Research Division, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha 24144, Qatar; (I.N.P.); (R.A.M.)
| | - Jael Nizza
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Anne Marshall
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
| | - Emily Brown
- Obesity and Endocrinology Research Group, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (E.B.); (D.J.C.)
| | - Daniel J. Cuthbertson
- Obesity and Endocrinology Research Group, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (E.B.); (D.J.C.)
| | - Andrew G. Marshall
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
- Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, Manchester M13 9WL, UK
| | - Rayaz A. Malik
- Research Division, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha 24144, Qatar; (I.N.P.); (R.A.M.)
- Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, University of Manchester and NIHR/Wellcome Trust Clinical Research Facility, Manchester M13 9WL, UK
| | - Uazman Alam
- Institute of Life Course and Medical Sciences and the Pain Research Institute, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool L9 7AL, UK; (A.J.N.); (J.B.); (J.N.); (A.M.); (A.G.M.)
- Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester M13 9PL, UK
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23
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Zhou T, Lee A, Lo ACY, Kwok JSWJ. Diabetic Corneal Neuropathy: Pathogenic Mechanisms and Therapeutic Strategies. Front Pharmacol 2022; 13:816062. [PMID: 35281903 PMCID: PMC8905431 DOI: 10.3389/fphar.2022.816062] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 01/27/2022] [Indexed: 12/27/2022] Open
Abstract
Diabetes mellitus (DM) is a major global public health problem that can cause complications such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy. Besides the reporting of reduction in corneal nerve density and decrease in corneal sensitivity in diabetic patients, there may be a subsequent result in delayed corneal wound healing and increased corneal infections. Despite being a potential cause of blindness, these corneal nerve changes have not gained enough attention. It has been proposed that corneal nerve changes may be an indicator for diabetic neuropathy, which can provide a window for early diagnosis and treatment. In this review, the authors aimed to give an overview of the relationship between corneal nerves and diabetic neuropathy as well as the underlying pathophysiological mechanisms of corneal nerve fiber changes caused by DM for improved prediction and prevention of diabetic neuropathy. In addition, the authors summarized current and novel therapeutic methods for delayed corneal wound healing, nerve protection and regeneration in the diabetic cornea.
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Affiliation(s)
- Ting Zhou
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Allie Lee
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Amy Cheuk Yin Lo
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
| | - Jeremy Sze Wai John Kwok
- Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China
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24
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Malik RA, Efron N. Corneal Confocal Microscopy and the Nervous System: Introduction to the Special Issue. J Clin Med 2022; 11:jcm11061475. [PMID: 35329801 PMCID: PMC8953792 DOI: 10.3390/jcm11061475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 03/05/2022] [Indexed: 12/07/2022] Open
Affiliation(s)
- Rayaz A. Malik
- Weill Cornell Medicine-Qatar, Research Division, Qatar Foundation, Education City, Doha 24144, Qatar;
| | - Nathan Efron
- School of Optometry and Vision Science, Queensland University of Technology, Kelvin Grove, QLD 4059, Australia
- Correspondence:
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25
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Bunch KL, Abdelrahman AA, Caldwell RB, Caldwell RW. Novel Therapeutics for Diabetic Retinopathy and Diabetic Macular Edema: A Pathophysiologic Perspective. Front Physiol 2022; 13:831616. [PMID: 35250632 PMCID: PMC8894892 DOI: 10.3389/fphys.2022.831616] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 01/17/2022] [Indexed: 12/12/2022] Open
Abstract
Diabetic retinopathy (DR) and diabetic macular edema (DME) are retinal complications of diabetes that can lead to loss of vision and impaired quality of life. The current gold standard therapies for treatment of DR and DME focus on advanced disease, are invasive, expensive, and can trigger adverse side-effects, necessitating the development of more effective, affordable, and accessible therapies that can target early stage disease. The pathogenesis and pathophysiology of DR is complex and multifactorial, involving the interplay between the effects of hyperglycemia, hyperlipidemia, hypoxia, and production of reactive oxygen species (ROS) in the promotion of neurovascular dysfunction and immune cell polarization to a proinflammatory state. The pathophysiology of DR provides several therapeutic targets that have the potential to attenuate disease progression. Current novel DR and DME therapies under investigation include erythropoietin-derived peptides, inducers of antioxidant gene expression, activators of nitric oxide/cyclic GMP signaling pathways, and manipulation of arginase activity. This review aims to aid understanding of DR and DME pathophysiology and explore novel therapies that capitalize on our knowledge of these diabetic retinal complications.
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Affiliation(s)
- Katharine L. Bunch
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Ammar A. Abdelrahman
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - Ruth B. Caldwell
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA, United States
- Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA, United States
| | - R. William Caldwell
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, United States
- James and Jean Culver Vision Discovery Institute, Medical College of Georgia, Augusta University, Augusta, GA, United States
- *Correspondence: R. William Caldwell,
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Al-Onaizi MA, Thériault P, Lecordier S, Prefontaine P, Rivest S, ElAli A. Early monocyte modulation by the non-erythropoietic peptide ARA 290 decelerates AD-like pathology progression. Brain Behav Immun 2022; 99:363-382. [PMID: 34343617 DOI: 10.1016/j.bbi.2021.07.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 07/06/2021] [Accepted: 07/24/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) pathology is characterized by amyloid-β (Aβ) deposition and tau hyper-phosphorylation, accompanied by a progressive cognitive decline. Monocytes have been recently shown to play a major role in modulating Aβ pathology, and thereby have been pointed as potential therapeutic targets. However, the main challenge remains in identifying clinically relevant interventions that could modulate monocyte immune functions in absence of undesired off-target effects. Erythropoietin (EPO), a key regulator of erythrocyte production, has been shown to possess immunomodulatory potential and to provide beneficial effects in preclinical models of AD. However, the transition to use recombinant human EPO in clinical trials was hindered by unwanted erythropoietic effects that could lead to thrombosis. Here, we used a recently identified non-erythropoietic analogue of EPO, ARA 290, to evaluate its therapeutic potential in AD therapy. We first evaluated the effects of early systemic ARA 290 administration on AD-like pathology in an early-onset model, represented by young APP/PS1 mice. Our findings indicate that ARA 290 early treatment decelerated Aβ pathology progression in APP/PS1 mice while improving cognitive functions. ARA 290 potently increased the levels of total monocytes by specifically stimulating the generation of Ly6CLow patrolling subset, which are implicated in clearing Aβ from the cerebral vasculature, and subsequently reducing overall Aβ burden in the brain. Moreover, ARA 290 increased the levels of monocyte progenitors in the bone marrow. Using chimeric APP/PS1 mice in which Ly6CLow patrolling subset are selectively depleted, ARA 290 was inefficient in attenuating Aβ pathology and ameliorating cognitive functions in young animals. Interestingly, ARA 290 effects were compromised when delivered in a late-onset model, represented by aged APP1/PS1. In aged APP/PS1 mice in which AD-like pathology is at advanced stages, ARA 290 failed to reverse Aβ pathology and to increase the levels of circulating monocytes. Our study suggests that ARA 290 early systemic treatment could prevent AD-like progression via modulation of monocyte functions by specifically increasing the ratio of patrolling monocytes.
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Affiliation(s)
- Mohammed A Al-Onaizi
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
| | - Peter Thériault
- Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
| | - Sarah Lecordier
- Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada; Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
| | - Paul Prefontaine
- Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
| | - Serge Rivest
- Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC, Canada
| | - Ayman ElAli
- Neuroscience Axis, Research Center of CHU de Québec - Université Laval, Quebec City, QC, Canada; Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Quebec City, QC, Canada.
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27
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Sloan G, Alam U, Selvarajah D, Tesfaye S. The Treatment of Painful Diabetic Neuropathy. Curr Diabetes Rev 2022; 18:e070721194556. [PMID: 34238163 DOI: 10.2174/1573399817666210707112413] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/18/2021] [Accepted: 03/08/2021] [Indexed: 11/22/2022]
Abstract
Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine and the Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, and Liverpool University Hospital, NHS Foundation Trust, Liverpool, UK
- Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
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28
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El-Abassi RN, Soliman M, Levy MH, England JD. Treatment and Management of Autoimmune Neuropathies. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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29
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James CF, Tripathi S, Karampatou K, Gladston DV, Pappachan JM. Pharmacotherapy of Painful Diabetic Neuropathy: A Clinical Update. SISLI ETFAL HASTANESI TIP BULTENI 2022; 56:1-20. [PMID: 35515975 PMCID: PMC9040305 DOI: 10.14744/semb.2021.54670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 12/30/2021] [Indexed: 02/08/2023]
Abstract
The rising prevalence of diabetes mellitus (DM) leads on to an increase in chronic diabetic complications. Diabetic peripheral neuropathies (DPNs) are common chronic complications of diabetes. Distal symmetric polyneuropathy is the most prevalent form. Most patients with DPN will remain pain-free; however, painful DPN (PDPN) occurs in 6-34% of all DM patients and is associated with reduced health-related-quality-of-life and substantial economic burden. Symptomatic treatment of PDPN and diabetic autonomic neuropathy is the key treatment goals. Using certain patient related characteristics, subjects with PDPN can be stratified and assigned targeted therapies to produce better pain outcomes. The aim of this review is to discuss the various pathogenetic mechanisms of DPN with special reference to the mechanisms leading to PDPN and the various pharmacological and non-pharmacological therapies available for its management. Recommended pharmacological therapies include anticonvulsants, antidepressants, opioid analgesics, and topical medications.
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Affiliation(s)
- Cornelius Fernandez James
- Department of Endocrinology & Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, United Kingdom
| | - Shiva Tripathi
- Department of Anaesthesia & Pain Management, Lancashire Teaching Hospitals NHS Trust, United Kingdom
| | - Kyriaki Karampatou
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, United Kingdom
| | - Divya V Gladston
- Department of Anaesthesiology, Regional Cancer Centre, Thiruvananthapuram, India
| | - Joseph M Pappachan
- Department of Endocrinology & Metabolism, Lancashire Teaching Hospitals NHS Trust, United Kingdom; The University of Manchester, Manchester, UK; Manchester Metropolitan University, Manchester, UK
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30
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The Non-Erythropoietic EPO Analogue Cibinetide Inhibits Osteoclastogenesis In Vitro and Increases Bone Mineral Density in Mice. Int J Mol Sci 2021; 23:ijms23010055. [PMID: 35008482 PMCID: PMC8744753 DOI: 10.3390/ijms23010055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/17/2021] [Accepted: 12/18/2021] [Indexed: 01/21/2023] Open
Abstract
The two erythropoietin (EPO) receptor forms mediate different cellular responses to erythropoietin. While hematopoiesis is mediated via the homodimeric EPO receptor (EPOR), tissue protection is conferred via a heteromer composed of EPOR and CD131. In the skeletal system, EPO stimulates osteoclast precursors and induces bone loss. However, the underlying molecular mechanisms are still elusive. Here, we evaluated the role of the heteromeric complex in bone metabolism in vivo and in vitro by using Cibinetide (CIB), a non-erythropoietic EPO analogue that exclusively binds the heteromeric receptor. CIB is administered either alone or in combination with EPO. One month of CIB treatment significantly increased the cortical (~5.8%) and trabecular (~5.2%) bone mineral density in C57BL/6J WT female mice. Similarly, administration of CIB for five consecutive days to female mice that concurrently received EPO on days one and four, reduced the number of osteoclast progenitors, defined by flow cytometry as Lin−CD11b−Ly6Chi CD115+, by 42.8% compared to treatment with EPO alone. In addition, CIB alone or in combination with EPO inhibited osteoclastogenesis in vitro. Our findings introduce CIB either as a stand-alone treatment, or in combination with EPO, as an appealing candidate for the treatment of the bone loss that accompanies EPO treatment.
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31
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Burgess J, Petropoulos I, Gad H, Nevitt SJ, Ponirakis G, Ferdousi M, Kalteniece A, Azmi S, Kaye S, Malik RA, Alam U. Corneal confocal microscopy for the diagnosis of diabetic sensorimotor polyneuropathy in people with type 1 and 2 diabetes mellitus. Hippokratia 2021. [DOI: 10.1002/14651858.cd014675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Jamie Burgess
- Department of Cardiovascular & Metabolic Medicine and the Pain Research Institute, Institute of Life Course and Medical Sciences; University of Liverpool and Liverpool University Hospital NHS Trust; Liverpool UK
| | - Ioannis Petropoulos
- Weill Cornell Medicine-Qatar, Research Division; Qatar Foundation, Education City; Doha Qatar
| | - Hoda Gad
- Weill Cornell Medicine-Qatar, Research Division; Qatar Foundation, Education City; Doha Qatar
| | - Sarah J Nevitt
- Department of Health Data Science; University of Liverpool; Liverpool UK
| | - Georgios Ponirakis
- Weill Cornell Medicine-Qatar, Research Division; Qatar Foundation, Education City; Doha Qatar
| | - Maryam Ferdousi
- Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health; The University of Manchester; Manchester UK
| | - Alise Kalteniece
- Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health; The University of Manchester; Manchester UK
| | - Shazli Azmi
- Division of Cardiovascular Sciences, Cardiac Centre, Faculty of Biology, Medicine and Health; The University of Manchester; Manchester UK
| | - Stephen Kaye
- Department of Ophthalmology; Royal Liverpool University Hospital Trust and University of Liverpool; Liverpool UK
| | - Rayaz A Malik
- Weill Cornell Medicine-Qatar, Research Division; Qatar Foundation, Education City; Doha Qatar
- Institute of Cardiovascular Sciences; University of Manchester; Manchester UK
| | - Uazman Alam
- Department of Ophthalmology; Royal Liverpool University Hospital Trust and University of Liverpool; Liverpool UK
- Division of Endocrinology, Diabetes and Gastroenterology; University of Manchester; Manchester UK
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32
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Ponirakis G, Abdul‐Ghani MA, Jayyousi A, Zirie MA, Al‐Mohannadi S, Almuhannadi H, Petropoulos IN, Khan A, Gad H, Migahid O, Megahed A, Qazi M, AlMarri F, Al‐Khayat F, Mahfoud Z, DeFronzo R, Malik RA. Insulin resistance limits corneal nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control. J Diabetes Investig 2021; 12:2002-2009. [PMID: 34002953 PMCID: PMC8565403 DOI: 10.1111/jdi.13582] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 03/22/2021] [Accepted: 04/15/2021] [Indexed: 01/04/2023] Open
Abstract
AIMS/INTRODUCTION This study aimed to investigate whether insulin resistance (IR) in individuals with type 2 diabetes undergoing intensive glycemic control determines the extent of improvement in neuropathy. MATERIALS AND METHODS This was an exploratory substudy of an open-label, randomized controlled trial of individuals with poorly controlled type 2 diabetes treated with exenatide and pioglitazone or insulin to achieve a glycated hemoglobin <7.0% (<53 mmol/mol). Baseline IR was defined using homeostasis model assessment of IR, and change in neuropathy was assessed using corneal confocal microscopy. RESULTS A total of 38 individuals with type 2 diabetes aged 50.2 ± 8.5 years with (n = 25, 66%) and without (n = 13, 34%) IR were studied. There was a significant decrease in glycated hemoglobin (P < 0.0001), diastolic blood pressure (P < 0.0001), total cholesterol (P < 0.01) and low-density lipoprotein (P = 0.05), and an increase in bodyweight (P < 0.0001) with treatment. Individuals with homeostasis model assessment of IR <1.9 showed a significant increase in corneal nerve fiber density (P ≤ 0.01), length (P ≤ 0.01) and branch density (P ≤ 0.01), whereas individuals with homeostasis model assessment of IR ≥1.9 showed no change. IR was negatively associated with change in corneal nerve fiber density after adjusting for change in bodyweight (P < 0.05). CONCLUSIONS Nerve regeneration might be limited in individuals with type 2 diabetes and IR undergoing treatment with pioglitazone plus exenatide or insulin to improve glycemic control.
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Affiliation(s)
- Georgios Ponirakis
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
- Faculty of Science and EngineeringManchester Metropolitan UniversityManchesterUK
| | - Muhammad A Abdul‐Ghani
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
- Division of DiabetesUniversity of Texas Health Science CenterSan AntonioTexasUSA
| | - Amin Jayyousi
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
| | - Mahmoud A Zirie
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
| | - Salma Al‐Mohannadi
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
| | - Hamad Almuhannadi
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
| | | | - Adnan Khan
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
| | - Hoda Gad
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
| | - Osama Migahid
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
- Division of DiabetesUniversity of Texas Health Science CenterSan AntonioTexasUSA
| | - Ayman Megahed
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
| | - Murtaza Qazi
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
| | - Fatema AlMarri
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
| | - Fatima Al‐Khayat
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
| | - Ziyad Mahfoud
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
| | - Ralph DeFronzo
- Division of DiabetesUniversity of Texas Health Science CenterSan AntonioTexasUSA
| | - Rayaz A Malik
- Weill Cornell Medicine in QatarQatar FoundationEducation City, DohaQatar
- Faculty of Science and EngineeringManchester Metropolitan UniversityManchesterUK
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
- Institute of Cardiovascular ScienceUniversity of ManchesterManchesterUK
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33
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Antsiferov OV, Cherevatenko RF, Korokin MV, Gureev VV, Gureeva AV, Zatolokina MA, Avdeyeva EV, Zhilinkova LA, Kolesnik IM. A new EPOR/CD131 heteroreceptor agonist EP-11-1: a neuroprotective effect in experimental traumatic brain injury. RESEARCH RESULTS IN PHARMACOLOGY 2021. [DOI: 10.3897/rrpharmacology.7.75301] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Introduction: EP-11-1 (UEHLERALNSS) is a short-chain erythropoietin derivative without have erythropoietic activity. It was created by modifying a peptide mimicking the spatial structure of the erythropoietin a-helix B pHBSP. One of the promising directions of its administration is the correction of morphofunctional disorders that occur in traumatic brain injury (TBI).
Materials and methods: The study was performed in 160 male Wistar rats, weighing 180–200 g.TBI was simulated using the drop-weight method. To assess the emerging morphofunctional disorders and a degree of their correction, we used the severity of neurological deficit, indicators of locomotor activity and exploration, a marker of brain injury S100B and morphological examination.
Results and discussion: The combined administration of a new EPOR/CD131 heteroreceptor agonist EP-11-1 with citicoline and trimetazidine led to a more pronounced correction of the neurological deficit when compared not only to the group of the ”untreated” animals, but also to the groups of animals to which these drugs had been administered as monotherapy (p < 0.05). The same tendency was also observed in the study of locomotor activity and exploration. A biochemical study showed that the administration of all three combinations led to a statistically significant (p < 0.05) decrease in the S-100B concentration compared not only to the group of “untreated” animals, but also to the groups of animals to which these drugs had been administered as a monotherapy.
Conclusion: The results of the conducted experiments prove the most pronounced positive dynamics in the combined administration of the new EPOR/CD131 heteroreceptor agonist EP-11-1with citicoline and trimetazidine.
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Yao M, Domogatskaya A, Ågren N, Watanabe M, Tokodai K, Brines M, Cerami A, Ericzon BG, Kumagai-Braesch M, Lundgren T. Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation. Cell Transplant 2021; 30:9636897211039739. [PMID: 34498509 PMCID: PMC8436319 DOI: 10.1177/09636897211039739] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
During intra-portal pancreatic islet transplantation (PITx), innate immune reactions such as the instant blood mediated inflammatory reaction (IBMIR) cause an immediate loss of islets. The non-hematopoietic erythropoietin analogue cibinetide has previously shown islet-protective effects in mouse PITx. Herein, we aimed to confirm cibinetide's efficacy on human islets, and to characterize its effect on IBMIR. We cultured human islets with pro-inflammatory cytokines for 18 hours with or without cibinetide. ATP content and caspase 3/7 activity were measured. Dynamic glucose perfusion assay was used to evaluate islet function. To evaluate cibinetides effect on IBMIR, human islets were incubated in heparinized polyvinyl chloride tubing system with ABO compatible blood and rotated for 60 minutes to mimic the portal vein system. Moreover, human islets were transplanted into athymic mice livers via the portal vein with or without perioperative cibinetide treatment. The mice were sacrificed six days following transplantation and the livers were analyzed for human insulin and serum for human C-peptide levels. Histological examination of recipient livers to evaluate islet graft infiltration by CD11b+ cells was performed. Our results show that cibinetide maintained human islet ATP levels and reduced the caspase 3/7 activity during culture with pro-inflammatory cytokines and improved their insulin secreting capacity. In the PVC loop system, administration of cibinetide reduced the IBMIR-induced platelet consumption. In human islet to athymic mice PITx, cibinetide treatment showed an increased amount of human insulin in the livers and higher serum human C-peptide, while histological examination of the livers showed reduced infiltration of pro-inflammatory CD11b+ cells around islets grafts compared to the controls. In summary, Cibinetide protected isolated human islets in a pro-inflammatory milieu and reduced IBMIR related platelet consumption. It improved engraftment of human islets in athymic mice. The study confirms that cibinetide is a promising agent to be used in clinical PITx.
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Affiliation(s)
- Ming Yao
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
| | - Anna Domogatskaya
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
| | - Nils Ågren
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
| | - Masaaki Watanabe
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
| | - Kazuaki Tokodai
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
| | | | | | - Bo-Göran Ericzon
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
| | - Makiko Kumagai-Braesch
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
| | - Torbjörn Lundgren
- Division of Transplantation Surgery, CLINTEC, Karolinska Institutet, and Department of Transplantation Surgery, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
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Ponirakis G, Abdul‐Ghani MA, Jayyousi A, Zirie MA, Qazi M, Almuhannadi H, Petropoulos IN, Khan A, Gad H, Migahid O, Megahed A, Al‐Mohannadi S, AlMarri F, Al‐Khayat F, Mahfoud Z, Al Hamad H, Ramadan M, DeFronzo R, Malik RA. Painful diabetic neuropathy is associated with increased nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control. J Diabetes Investig 2021; 12:1642-1650. [PMID: 33714226 PMCID: PMC8409832 DOI: 10.1111/jdi.13544] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/24/2021] [Accepted: 03/09/2021] [Indexed: 12/13/2022] Open
Abstract
AIMS/INTRODUCTION Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control. MATERIALS AND METHODS This exploratory substudy of an open-label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal-bolus insulin at baseline and 1-year follow up, and 18 controls at baseline only. RESULTS Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain. CONCLUSIONS This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy.
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Affiliation(s)
- Georgios Ponirakis
- Weill Cornell Medicine‐QatarQatar FoundationEducation CityDohaQatar
- Faculty of Science and EngineeringManchester Metropolitan UniversityManchesterUK
| | - Muhammad A Abdul‐Ghani
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
- Division of DiabetesUniversity of Texas Health Science CenterSan AntonioTexasUSA
| | - Amin Jayyousi
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
| | - Mahmoud A Zirie
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
| | - Murtaza Qazi
- Weill Cornell Medicine‐QatarQatar FoundationEducation CityDohaQatar
| | | | | | - Adnan Khan
- Weill Cornell Medicine‐QatarQatar FoundationEducation CityDohaQatar
| | - Hoda Gad
- Weill Cornell Medicine‐QatarQatar FoundationEducation CityDohaQatar
| | - Osama Migahid
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
- Division of DiabetesUniversity of Texas Health Science CenterSan AntonioTexasUSA
| | - Ayman Megahed
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
| | | | - Fatema AlMarri
- Weill Cornell Medicine‐QatarQatar FoundationEducation CityDohaQatar
| | - Fatima Al‐Khayat
- Weill Cornell Medicine‐QatarQatar FoundationEducation CityDohaQatar
| | - Ziyad Mahfoud
- Weill Cornell Medicine‐QatarQatar FoundationEducation CityDohaQatar
| | | | | | - Ralph DeFronzo
- Division of DiabetesUniversity of Texas Health Science CenterSan AntonioTexasUSA
| | - Rayaz A Malik
- Weill Cornell Medicine‐QatarQatar FoundationEducation CityDohaQatar
- Faculty of Science and EngineeringManchester Metropolitan UniversityManchesterUK
- National Diabetes CenterHamad General HospitalHamad Medical CorporationDohaQatar
- Institute of Cardiovascular ScienceUniversity of ManchesterManchesterUK
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Vittori DC, Chamorro ME, Hernández YV, Maltaneri RE, Nesse AB. Erythropoietin and derivatives: Potential beneficial effects on the brain. J Neurochem 2021; 158:1032-1057. [PMID: 34278579 DOI: 10.1111/jnc.15475] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 06/24/2021] [Accepted: 07/14/2021] [Indexed: 12/16/2022]
Abstract
Erythropoietin (Epo), the main erythropoiesis-stimulating factor widely prescribed to overcome anemia, is also known nowadays for its cytoprotective action on non-hematopoietic tissues. In this context, Epo showed not only its ability to cross the blood-brain barrier, but also its expression in the brain of mammals. In clinical trials, recombinant Epo treatment has been shown to stimulate neurogenesis; improve cognition; and activate antiapoptotic, antioxidant, and anti-inflammatory signaling pathways. These mechanisms, proposed to characterize a neuroprotective property, opened new perspectives on the Epo pharmacological potencies. However, many questions arise about a possible physiological role of Epo in the central nervous system (CNS) and the factors or environmental conditions that induce its expression. Although Epo may be considered a strong candidate to be used against neuronal damage, long-term treatments, particularly when high Epo doses are needed, may induce thromboembolic complications associated with increases in hematocrit and blood viscosity. To avoid these adverse effects, different Epo analogs without erythropoietic activity but maintaining neuroprotection ability are currently being investigated. Carbamylated erythropoietin, as well as alternative molecules like Epo fusion proteins and partial peptides of Epo, seems to match this profile. This review will focus on the discussion of experimental evidence reported in recent years linking erythropoietin and CNS function through investigations aimed at finding benefits in the treatment of neurodegenerative diseases. In addition, it will review the proposed mechanisms for novel derivatives which may clarify and, eventually, improve the neuroprotective action of Epo.
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Affiliation(s)
- Daniela C Vittori
- Department of Biological Chemistry, National Scientific and Technical Research Council, Institute of Biological Chemistry (IQUIBICEN), School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
| | - María E Chamorro
- Department of Biological Chemistry, National Scientific and Technical Research Council, Institute of Biological Chemistry (IQUIBICEN), School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
| | - Yender V Hernández
- Department of Biological Chemistry, National Scientific and Technical Research Council, Institute of Biological Chemistry (IQUIBICEN), School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
| | - Romina E Maltaneri
- Department of Biological Chemistry, National Scientific and Technical Research Council, Institute of Biological Chemistry (IQUIBICEN), School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
| | - Alcira B Nesse
- Department of Biological Chemistry, National Scientific and Technical Research Council, Institute of Biological Chemistry (IQUIBICEN), School of Exact and Natural Sciences, University of Buenos Aires, Buenos Aires, Argentina
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Zhang Y, Fan D, Zhang Y, Zhang S, Wang H, Liu Z, Wang H. Using corneal confocal microscopy to compare Mecobalamin intramuscular injections vs oral tablets in treating diabetic peripheral neuropathy: a RCT. Sci Rep 2021; 11:14697. [PMID: 34282267 PMCID: PMC8290034 DOI: 10.1038/s41598-021-94284-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/18/2021] [Indexed: 02/04/2023] Open
Abstract
This randomized controlled study used corneal confocal microscopy (CCM) to compare the efficacy of Mecobalamin intramuscular injections vs oral tablets in treating mild to moderate diabetic peripheral neuropathy (DPN) by detecting early nerve fiber repair. Enrolled patients were randomized approximately 1:1 to receive Mecobalamin intramuscular injections (0.5 mg/day, 3 times/week) or Mecobalamin oral tablets (1.5 mg/day) for 8 weeks. Primary outcome was change of inferior whorl length (IWL) from baseline. Secondary outcomes included changes of corneal nerve fibre length (CNFL), corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD) and the Survey of Autonomic Symptoms (SAS). 15 (93.75%) patients in the injection group and 17 (89.47%) patients in the tablet group completed the study. The injection treatment significantly improved patients' IWL from baseline (21.64 ± 3.00 mm/mm2 vs 17.64 ± 4.83 mm/mm2, P < 0.01) while the tablet treatment didn't. Additionally, the injection treatment led to significantly improved CNFL, CNBD and SAS from baseline (all P < 0.05) while the tablet treatment did not. No patient experienced any adverse events. In conclusion, CCM is sensitive enough to detect the superior efficacy of 8-week Mecobalamin intramuscular injection treatment for DPN compared to the oral tablet treatment.ClinicalTrials.gov registration number: NCT04372316 (30/04/2020).
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Affiliation(s)
- Yuanjin Zhang
- Neurology Department, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, 100191, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Disease, Beijing, China
| | - Dongsheng Fan
- Neurology Department, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, 100191, China.
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Disease, Beijing, China.
| | - Yixuan Zhang
- Neurology Department, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, 100191, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Disease, Beijing, China
| | - Shuo Zhang
- Neurology Department, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, 100191, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Disease, Beijing, China
| | - Haikun Wang
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Ziyuan Liu
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Hongli Wang
- Neurology Department, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, 100191, China
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Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 2021; 17:400-420. [PMID: 34050323 DOI: 10.1038/s41574-021-00496-z] [Citation(s) in RCA: 210] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 02/08/2023]
Abstract
Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
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ERS clinical practice guidelines on treatment of sarcoidosis. Eur Respir J 2021; 58:13993003.04079-2020. [PMID: 34140301 DOI: 10.1183/13993003.04079-2020] [Citation(s) in RCA: 256] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 05/04/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The major reasons to treat sarcoidosis are to lower the morbidity and mortality risk or to improve quality of life (QoL). The indication for treatment varies depending on which manifestation is the cause of symptoms: lungs, heart, brain, skin, or other manifestations. While glucocorticoids (GC) remain the first choice for initial treatment of symptomatic disease, prolonged use is associated with significant toxicity. GC-sparing alternatives are available. The presented treatment guideline aims to provide guidance to physicians treating the very heterogenous sarcoidosis manifestations. MATERIALS AND METHODS A European Respiratory Society Task Force (TF) committee composed of clinicians, methodologists, and patients with experience in sarcoidosis developed recommendations based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology. The committee developed eight PICO (Patients, Intervention, Comparison, Outcomes) questions and these were used to make specific evidence-based recommendations. RESULTS The TF committee delivered twelve recommendations for seven PICOs. These included treatment of pulmonary, cutaneous, cardiac, and neurologic disease as well as fatigue. One PICO question regarding small fiber neuropathy had insufficient evidence to support a recommendation. In addition to the recommendations, the committee provided information on how they use alternative treatments, when there was insufficient evidence to support a recommendation. CONCLUSIONS There are many treatments available to treat sarcoidosis. Given the diverse nature of the disease, treatment decisions require an assessment of organ involvement, risk for significant morbidity, and impact on QoL of the disease and treatment. MESSAGE An evidence based guideline for treatment of sarcoidosis is presented. The panel used the GRADE approach and specific recommendations are made. A major factor in treating patients is the risk of loss of organ function or impairment of quality of life.
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Iqbal Z, Kalteniece A, Ferdousi M, Adam S, D'Onofrio L, Ho JH, Rao AP, Dhage S, Azmi S, Liu Y, Donn R, Malik RA, Soran H. Corneal Keratocyte Density and Corneal Nerves Are Reduced in Patients With Severe Obesity and Improve After Bariatric Surgery. Invest Ophthalmol Vis Sci 2021; 62:20. [PMID: 33475689 PMCID: PMC7817877 DOI: 10.1167/iovs.62.1.20] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Purpose Obesity is associated with peripheral neuropathy, which bariatric surgery may ameliorate. The aim of this study was to assess whether corneal confocal microscopy can show a change in corneal nerve morphology and keratocyte density in subjects with severe obesity after bariatric surgery. Methods Twenty obese patients with diabetes (n = 13) and without diabetes (n = 7) underwent assessment of hemoglobin A1c (HbA1c), lipids, IL-6, highly sensitive C-reactive protein (hsCRP), and corneal confocal microscopy before and 12 months after bariatric surgery. Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and keratocyte density (KD) from the anterior, middle, and posterior stroma were quantified. Twenty-two controls underwent assessment at baseline only. Results CNFL (P < 0.001), CNBD (P < 0.05), and anterior (P < 0.001), middle (P < 0.001), and posterior (P < 0.001) keratocyte densities were significantly lower in obese patients compared to controls, and anterior keratocyte density (AKD) correlated with CNFL. Twelve months after bariatric surgery, there were significant improvements in body mass index (BMI; P < 0.001), HDL cholesterol (P < 0.05), hsCRP (P < 0.001), and IL-6 (P < 0.01). There were significant increases in CNFD (P < 0.05), CNBD (P < 0.05), CNFL (P < 0.05), and anterior (P < 0.05) and middle (P < 0.001) keratocyte densities. The increase in AKD correlated with a decrease in BMI (r = -0.55, P < 0.05) and triglycerides (r = -0.85, P < 0.001). There were no significant correlations between the change in keratocyte densities and corneal nerve fiber or other neuropathy measures. Conclusions Corneal confocal microscopy demonstrates early small fiber damage and reduced keratocyte density in obese patients. Bariatric surgery leads to weight reduction and improvement in lipids and inflammation and an improvement in keratocyte density and corneal nerve regeneration.
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Affiliation(s)
- Zohaib Iqbal
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Alise Kalteniece
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Maryam Ferdousi
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Safwaan Adam
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Luca D'Onofrio
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Jan H Ho
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Anoop Prasanna Rao
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Shaishav Dhage
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Shazli Azmi
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Yifen Liu
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Rachelle Donn
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
| | - Rayaz A Malik
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Department of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Handrean Soran
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.,Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
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Malik RA, Calcutt NA. Translating diabetic peripheral neuropathy. J Peripher Nerv Syst 2021; 25:64-65. [PMID: 32394617 DOI: 10.1111/jns.12384] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 01/27/2023]
Affiliation(s)
- Rayaz A Malik
- Department of Medicine, Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar
| | - Nigel A Calcutt
- Department of Pathology, University of California, San Diego, California, USA
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Petropoulos IN, Ponirakis G, Ferdousi M, Azmi S, Kalteniece A, Khan A, Gad H, Bashir B, Marshall A, Boulton AJM, Soran H, Malik RA. Corneal Confocal Microscopy: A Biomarker for Diabetic Peripheral Neuropathy. Clin Ther 2021; 43:1457-1475. [PMID: 33965237 DOI: 10.1016/j.clinthera.2021.04.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/05/2021] [Accepted: 04/08/2021] [Indexed: 02/08/2023]
Abstract
PURPOSE Diagnosing early diabetic peripheral neuropathy remains a challenge due to deficiencies in currently advocated end points. The cornea is densely innervated with small sensory fibers, which are structurally and functionally comparable to intraepidermal nerve fibers. Corneal confocal microscopy is a method for rapid, noninvasive scanning of the living cornea with high resolution and magnification. METHODS This narrative review presents the framework for the development of biomarkers and the literature on the use and adoption of corneal confocal microscopy as an objective, diagnostic biomarker in experimental and clinical studies of diabetic peripheral neuropathy. A search was performed on PubMed and Google Scholar based on the terms "corneal confocal microscopy," "diabetic neuropathy," "corneal sensitivity," and "clinical trials." FINDINGS A substantial body of evidence underpins the thesis that corneal nerve loss predicts incident neuropathy and progresses with the severity of diabetic peripheral neuropathy. Corneal confocal microscopy also identifies early corneal nerve regeneration, strongly arguing for its inclusion as a surrogate end point in clinical trials of disease-modifying therapies. IMPLICATIONS There are sufficient diagnostic and prospective validation studies to fulfill the US Food and Drug Administration criteria for a biomarker to support the inclusion of corneal confocal microscopy as a primary end point in clinical trials of disease-modifying therapies in diabetic neuropathy.
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Affiliation(s)
| | | | - Maryam Ferdousi
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Shazli Azmi
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Alise Kalteniece
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Adnan Khan
- Research Division, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Hoda Gad
- Research Division, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Bilal Bashir
- Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Andrew Marshall
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom; Clinical Neurophysiology, The Walton Centre, Liverpool, United Kingdom; Division of Neuroscience and Experimental Psychology, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
| | - Andrew J M Boulton
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom; Centre for Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Handrean Soran
- Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Rayaz A Malik
- Research Division, Weill Cornell Medicine-Qatar, Doha, Qatar; Faculty of Biology, Medicine and Health, University of Manchester, Cardiovascular Trials Unit, Manchester University NHS Foundation Trust, Manchester, United Kingdom.
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Silva I, Alípio C, Pinto R, Mateus V. Potential anti-inflammatory effect of erythropoietin in non-clinical studies in vivo: A systematic review. Biomed Pharmacother 2021; 139:111558. [PMID: 33894624 DOI: 10.1016/j.biopha.2021.111558] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/19/2021] [Accepted: 03/23/2021] [Indexed: 02/07/2023] Open
Abstract
Erythropoietin (EPO) is a hypoxia-induced hormone produced in adult kidneys with erythropoietic and non-erythropoietic effects. In vivo studies represent an important role to comprehend the efficacy and safety in the early phase of repurposing drugs. The aim is to evaluate the potential anti-inflammatory effect of EPO observed in animal models of disease. Following PRISMA statements, electronic database Medline via PubMed platform was used to search articles with the research expression ((erythropoietin [MeSH Terms]) AND (inflammation [MeSH Terms]) AND (disease models, animal [MeSH Terms])). The inclusion criteria were original articles, studies where EPO was administered, studies where inflammation was studied and/or evaluated, non-clinical studies in vivo with rodents, and articles published in English. Thirty-six articles met the criteria for qualitative analysis. Exogenous EPO was used in models of sepsis, traumatic brain injury, and autoimmune neuritis, with an average of 3000 IU/Kg for single and multiple doses, using mice and rats. Biomarkers such as immune-related effectors, cytokines, reactive oxygen species, prostaglandins, and other biomarkers were assessed. EPO has been recognized as a multifunctional cytokine with anti-inflammatory properties, showing its significant effect both in acute and chronic models of inflammation. Further non-clinical studies are suggested for the enlightenment of anti-inflammatory mechanisms of EPO in lower doses, allowing us to understand the translational data for humans.
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Affiliation(s)
- Inês Silva
- H&TRC-Health and Technology Research Center, ESTeSL-Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal
| | - Carolina Alípio
- H&TRC-Health and Technology Research Center, ESTeSL-Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal
| | - Rui Pinto
- iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal; JCS, Dr. Joaquim Chaves, Laboratório de Análises Clínicas, Miraflores, 1495-069 Algés, Portugal
| | - Vanessa Mateus
- H&TRC-Health and Technology Research Center, ESTeSL-Lisbon School of Health Technology, Instituto Politécnico de Lisboa, 1990-096 Lisbon, Portugal; iMed.ULisboa, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.
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Abstract
Neuropathy is a common complication of long-term diabetes that impairs quality of life by producing pain, sensory loss and limb amputation. The presence of neuropathy in both insulin-deficient (type 1) and insulin resistant (type 2) diabetes along with the slowing of progression of neuropathy by improved glycemic control in type 1 diabetes has caused the majority of preclinical and clinical investigations to focus on hyperglycemia as the initiating pathogenic lesion. Studies in animal models of diabetes have identified multiple plausible mechanisms of glucotoxicity to the nervous system including post-translational modification of proteins by glucose and increased glucose metabolism by aldose reductase, glycolysis and other catabolic pathways. However, it is becoming increasingly apparent that factors not necessarily downstream of hyperglycemia can also contribute to the incidence, progression and severity of neuropathy and neuropathic pain. For example, peripheral nerve contains insulin receptors that transduce the neurotrophic and neurosupportive properties of insulin, independent of systemic glucose regulation, while the detection of neuropathy and neuropathic pain in patients with metabolic syndrome and failure of improved glycemic control to protect against neuropathy in cohorts of type 2 diabetic patients has placed a focus on the pathogenic role of dyslipidemia. This review provides an overview of current understanding of potential initiating lesions for diabetic neuropathy and the multiple downstream mechanisms identified in cell and animal models of diabetes that may contribute to the pathogenesis of diabetic neuropathy and neuropathic pain.
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Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand. Transplantation 2021; 104:2048-2058. [PMID: 32345869 DOI: 10.1097/tp.0000000000003284] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND During intraportal pancreatic islet transplantation (PITx), early inflammatory reactions cause an immediate loss of more than half of the transplanted graft and potentiate subsequent allograft rejection. Previous findings suggest that cibinetide, a selective innate repair receptor agonist, exerts islet protective and antiinflammatory properties and improved transplant efficacy in syngeneic mouse PITx model. In a stepwise approach toward a clinical application, we have here investigated the short- and long-term effects of cibinetide in an allogeneic mouse PITx model. METHODS Streptozotocin-induced diabetic C57BL/6N (H-2) mice were transplanted with 320 (marginal) or 450 (standard) islets from BALB/c (H-2) mice via the portal vein. Recipients were treated perioperative and thereafter daily during 14 d with cibinetide (120 µg/kg), with or without tacrolimus injection (0.4 mg/kg/d) during days 4-14 after transplantation. Graft function was assessed using nonfasting glucose measurements. Relative gene expressions of proinflammatory cytokines and proinsulin of the graft-bearing liver were assessed by quantitative polymerase chain reaction. Cibinetide's effects on dendritic cell maturation were investigated in vitro. RESULTS Cibinetide ameliorated the local inflammatory responses in the liver and improved glycemic control immediately after allogeneic PITx and significantly delayed the onset of allograft loss. Combination treatment with cibinetide and low-dose tacrolimus significantly improved long-term graft survival following allogeneic PITx. In vitro experiments indicated that cibinetide lowered bone-marrow-derived-immature-dendritic cell maturation and subsequently reduced allogeneic T-cell response. CONCLUSIONS Cibinetide reduced the initial transplantation-related severe inflammation and delayed the subsequent alloreactivity. Cibinetide, in combination with low-dose tacrolimus, could significantly improve long-term graft survival in allogeneic PITx.
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Adam S, Azmi S, Ho JH, Liu Y, Ferdousi M, Siahmansur T, Kalteniece A, Marshall A, Dhage SS, Iqbal Z, D'Souza Y, Natha S, Kalra PA, Donn R, Ammori BJ, Syed AA, Durrington PN, Malik RA, Soran H. Improvements in Diabetic Neuropathy and Nephropathy After Bariatric Surgery: a Prospective Cohort Study. Obes Surg 2021; 31:554-563. [PMID: 33104989 PMCID: PMC7847862 DOI: 10.1007/s11695-020-05052-8] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 10/10/2020] [Accepted: 10/13/2020] [Indexed: 02/08/2023]
Abstract
PURPOSE There are limited data on the impact of bariatric surgery on microvascular complications of type 2 diabetes (T2D), particularly diabetic neuropathy. We assessed microvascular complications (especially neuropathy) in obese patients with T2D before and 12 months after bariatric surgery. MATERIALS AND METHODS This was a prospective observational cohort study. Measurements of neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration (VPT), cold (CPT) and warm (WPT) perception thresholds, nerve conduction studies (NCS) and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), branch density (CNBD) and fibre length (CNFL); urinary albumin/creatinine ratio (uACR), estimated glomerular filtration rate (eGFRcyst-creat) and retinal grading were taken. RESULTS Twenty-six (62% female; median age 52 years) obese patients with T2D were recruited. Body mass index (BMI) (47.2 to 34.5 kg/m2; p < 0.001) decreased post-operatively. There were improvements in CNFD (27.1 to 29.2/mm2; p = 0.005), CNBD (63.4 to 77.8/mm2; p = 0.008), CNFL (20.0 to 20.2/mm2; p = 0.001), NSP (3 to 0/38; p < 0.001) and eGFRcyst-creat (128 to 120 ml/min; p = 0.015) post-bariatric surgery. Changes in (Δ) triglycerides were independently associated with ΔCNFL (β = - 0.53; p = 0.024) and Δsystolic blood pressure (β = 0.62;p = 0.017), and %excess BMI loss (β = - 0.004; p = 0.018) were associated with ΔeGFRcyst-creat. There was no significant change in NDS, VPT, CPT, WPT, NCS, uACR or retinopathy status. Glomerular hyperfiltration resolved in 42% of the 12 patients with this condition pre-operatively. CONCLUSION Bariatric surgery results in improvements in small nerve fibres and glomerular hyperfiltration in obese people with T2D, which were associated with weight loss, triglycerides and systolic blood pressure, but with no change in retinopathy or uACR at 12 months.
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Affiliation(s)
- Safwaan Adam
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- The Christie NHS Foundation Trust, Manchester, UK
| | - Shazli Azmi
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Manchester University NHS Foundation Trust, Manchester, UK
| | - Jan H Ho
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Manchester University NHS Foundation Trust, Manchester, UK
| | - Yifen Liu
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Maryam Ferdousi
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Manchester University NHS Foundation Trust, Manchester, UK
| | - Tarza Siahmansur
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Alise Kalteniece
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Andrew Marshall
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Manchester University NHS Foundation Trust, Manchester, UK
| | - Shaishav S Dhage
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- The Christie NHS Foundation Trust, Manchester, UK
| | - Zohaib Iqbal
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Manchester University NHS Foundation Trust, Manchester, UK
| | - Yvonne D'Souza
- Manchester University NHS Foundation Trust, Manchester, UK
| | - Salim Natha
- Wrightington, Wigan and Leigh NHS Foundation Trust, Wigan, UK
| | - Philip A Kalra
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Salford Royal NHS Foundation Trust, Salford, UK
| | - Rachelle Donn
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Basil J Ammori
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Salford Royal NHS Foundation Trust, Salford, UK
| | - Akheel A Syed
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Salford Royal NHS Foundation Trust, Salford, UK
| | - Paul N Durrington
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Rayaz A Malik
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Weill-Cornell Medicine-Qatar, Doha, Qatar
| | - Handrean Soran
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
- Manchester University NHS Foundation Trust, Manchester, UK.
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Hemani S, Lane O, Agarwal S, Yu SP, Woodbury A. Systematic Review of Erythropoietin (EPO) for Neuroprotection in Human Studies. Neurochem Res 2021; 46:732-739. [PMID: 33521906 DOI: 10.1007/s11064-021-03242-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 01/04/2021] [Accepted: 01/07/2021] [Indexed: 11/29/2022]
Abstract
Erythropoietin (EPO) is an exciting neurotherapeutic option. Despite its potential, concerns exist regarding the potential for thrombosis and adverse events with EPO administration in normonemic adults. Systematic review of literature using PRISMA guidelines to examine the application and risks of EPO as a treatment option for neuroprotection in normonemic adults. Independent, systematic searches were performed in July 2019. PubMed (1960-2019) and the Cochrane Controlled Trials Register (1960-2019) were screened. Search terms included erythropoietin, neuroprotection, and humans. The PubMed search resulted in the following search strategy: ("erythropoietin" [MeSH Terms] OR "erythropoietin" [All Fields] OR "epoetin alfa" [MeSH Terms] OR ("epoetin" [All Fields] AND "alfa" [All Fields]) OR "epoetin alfa" [All Fields]) AND ("neuroprotection" [MeSH Terms] OR "neuroprotection" [All Fields]) AND "humans" [MeSH Terms]. PubMed, Cochrane Controlled Trials Register, and articles based on prior searches yielded 388 citations. 50 studies were included, comprising of 4351 patients. There were 13 studies that noted adverse effects from EPO. Three attributed serious adverse effects to EPO and complications were statistically significant. Two of these studies related the adverse events to the co-administration of EPO with tPA. Minor adverse effects associated with the EPO group included nausea, pyrexia, headache, generalized weakness and superficial phlebitis. Most published studies focus on spinal cord injury, peri-surgical outcomes and central effects of EPO. We found no studies to date evaluating the role of EPO in post-operative pain. Future trials could evaluate this application in persistent post-surgical pain and in the peri-operative period.
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Affiliation(s)
- Salman Hemani
- Division of Pain Medicine, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Olabisi Lane
- Division of Pain Medicine, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
| | - Sunil Agarwal
- Division of Pain Medicine, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Shan Ping Yu
- Division of Pain Medicine, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Atlanta Veterans Affairs Healthcare System, Decatur, GA, 30033, USA
| | - Anna Woodbury
- Division of Pain Medicine, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA.,Atlanta Veterans Affairs Healthcare System, Decatur, GA, 30033, USA
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Abstract
BACKGROUND Diabetic neuropathy is a multifaceted condition affecting up to 50% of individuals with long standing diabetes. The most common presentation is peripheral diabetic sensory neuropathy (DPN). METHODS We carried out a systematic review of papers dealing with diabetic neuropathy on Pubmed in addition to a targeted Google search.Search terms included small fiber neuropathy,diffuse peripheral neuropathy, quantitative sensory testing, nerve conduction testing, intra-epidermal nerve fiber density, corneal confocal reflectance microscopy, aldose reductase inhbitors, nerve growth factor, alpha-lipoic acid, ruboxistaurin, nerve growth factor antibody, and cibinetide. RESULTS Over the past half century, there have been a number of agents undergoing unsuccessful trials for treatment of DPN.There are several approved agents for relief of pain caused by diabetic neuropathy, but these do not affect the pathologic process. EXPERT OPINION The failure to find treatments for diabetic neuropathy can be ascribed to (1) the complexity of design of studies and (2) the slow progression of the condition, necessitating long duration trials to prove efficacy.We propose a modification of the regulatory process to permit early introduction of agents with demonstrated safety and suggestion of benefit as well as prolongation of marketing exclusivity while long term trials are in progress to prove efficacy.
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Affiliation(s)
- Marc S Rendell
- The Association for Diabetes Investigators , Newport Coast, California. USA
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Tiwari R, Wal P, Singh P, Tiwari G, Rai A. A Review on Mechanistic and Pharmacological Findings of Diabetic Peripheral Neuropathy including Pharmacotherapy. Curr Diabetes Rev 2021; 17:247-258. [PMID: 32928092 DOI: 10.2174/1573399816666200914141558] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/01/2020] [Accepted: 08/18/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Chronic hyperglycemia and related complications involving peripheral nerves in diabetes are one of the most severe microvascular complications with an average prevalence of 50-60%. Diabetic neuropathy is among the vascular disorders of diabetes, the most debilitating and crippled, lethal condition impacting patients's quality of life. METHODS In the present review article, several hypotheses associated with the pathogenesis of Diabetic Peripheral Neuropathy (DPN) have been introduced, among them metabolic pathways associated with polyol pathway, oxidative stress, production of reactive oxygen species (ROS) amplified under chronic hyperglycemic conditions and activation of transcription factor Nuclear factor-κB (NF- κB). The review article also possesses pathogenetic and pharmacologic treatments along with others, including acupressure, lidocaine, and capsaicin for DPN. CONCLUSION It may be concluded that we can combat the pathogenesis of DPN with different suggested treatments.
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Affiliation(s)
- Ruchi Tiwari
- Department of Pharmacy, Pranveer Singh Institute Of Technology, Kanpur - Agra - Delhi National Highway - 2 , Bhauti - Kanpur - 209305, India
| | - Pranay Wal
- Department of Pharmacy, Pranveer Singh Institute Of Technology, Kanpur - Agra - Delhi National Highway - 2 , Bhauti - Kanpur - 209305, India
| | - Priya Singh
- Department of Pharmacy, Pranveer Singh Institute Of Technology, Kanpur - Agra - Delhi National Highway - 2 , Bhauti - Kanpur - 209305, India
| | - Gaurav Tiwari
- Department of Pharmacy, Pranveer Singh Institute Of Technology, Kanpur - Agra - Delhi National Highway - 2 , Bhauti - Kanpur - 209305, India
| | - Awani Rai
- Department of Pharmacy, Pranveer Singh Institute Of Technology, Kanpur - Agra - Delhi National Highway - 2 , Bhauti - Kanpur - 209305, India
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Carmichael J, Fadavi H, Ishibashi F, Shore AC, Tavakoli M. Advances in Screening, Early Diagnosis and Accurate Staging of Diabetic Neuropathy. Front Endocrinol (Lausanne) 2021; 12:671257. [PMID: 34122344 PMCID: PMC8188984 DOI: 10.3389/fendo.2021.671257] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 03/17/2021] [Indexed: 12/14/2022] Open
Abstract
The incidence of both type 1 and type 2 diabetes is increasing worldwide. Diabetic peripheral neuropathy (DPN) is among the most distressing and costly of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life. This incurs a significant burden on health care costs and society, especially as these young people enter their peak working and earning capacity at the time when diabetes-related complications most often first occur. DPN is often asymptomatic during the early stages; however, once symptoms and overt deficits have developed, it cannot be reversed. Therefore, early diagnosis and timely intervention are essential to prevent the development and progression of diabetic neuropathy. The diagnosis of DPN, the determination of the global prevalence, and incidence rates of DPN remain challenging. The opinions vary about the effectiveness of the expansion of screenings to enable early diagnosis and treatment initiation before disease onset and progression. Although research has evolved over the years, DPN still represents an enormous burden for clinicians and health systems worldwide due to its difficult diagnosis, high costs related to treatment, and the multidisciplinary approach required for effective management. Therefore, there is an unmet need for reliable surrogate biomarkers to monitor the onset and progression of early neuropathic changes in DPN and facilitate drug discovery. In this review paper, the aim was to assess the currently available tests for DPN's sensitivity and performance.
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Affiliation(s)
- Josie Carmichael
- Diabetes and Vascular Research Centre, National Institute for Health Research, Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom
| | - Hassan Fadavi
- Peripheral Neuropathy Group, Imperial College, London, United Kingdom
| | - Fukashi Ishibashi
- Internal Medicine, Ishibashi Medical and Diabetes Centre, Hiroshima, Japan
| | - Angela C Shore
- Diabetes and Vascular Research Centre, National Institute for Health Research, Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom
| | - Mitra Tavakoli
- Diabetes and Vascular Research Centre, National Institute for Health Research, Exeter Clinical Research Facility, University of Exeter Medical School, Exeter, United Kingdom
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