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Singh H, Singh R, Singh A, Singh H, Singh G, Kaur S, Singh B. Role of oxidative stress in diabetes-induced complications and their management with antioxidants. Arch Physiol Biochem 2024; 130:616-641. [PMID: 37571852 DOI: 10.1080/13813455.2023.2243651] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/30/2023] [Accepted: 06/02/2023] [Indexed: 08/13/2023]
Abstract
Diabetes mellitus (DM) is a huge global health issue and one of the most studied diseases, with a large global prevalence. Oxidative stress is a cytotoxic consequence of the excessive development of ROS and suppression of the antioxidant defense system for ROS elimination, which accelerates the progression of diabetes complications such as diabetic neuropathy, retinopathy, and nephropathy. Hyperglycaemia induced oxidative stress causes the activation of seven major pathways implicated in the pathogenesis of diabetic complications. These pathways increase the production of ROS and RNS, which contributes to dysregulated autophagy, gene expression changes, and the development of numerous pro-inflammatory mediators which may eventually lead to diabetic complications. This review will illustrate that oxidative stress plays a vital role in the pathogenesis of diabetic complications, and the use of antioxidants will help to reduce oxidative stress and thus may alleviate diabetic complications.
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Affiliation(s)
- Hasandeep Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Rajanpreet Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Arshdeep Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Harshbir Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Gurpreet Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Sarabjit Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
| | - Balbir Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, 143005, India
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Abd Razak NH, Idris J, Hassan NH, Zaini F, Muhamad N, Daud MF. Unveiling the Role of Schwann Cell Plasticity in the Pathogenesis of Diabetic Peripheral Neuropathy. Int J Mol Sci 2024; 25:10785. [PMID: 39409114 PMCID: PMC11476695 DOI: 10.3390/ijms251910785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 08/23/2024] [Accepted: 08/24/2024] [Indexed: 10/20/2024] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes that affects a significant proportion of diabetic patients worldwide. Although the pathogenesis of DPN involves axonal atrophy and demyelination, the exact mechanisms remain elusive. Current research has predominantly focused on neuronal damage, overlooking the potential contributions of Schwann cells, which are the predominant glial cells in the peripheral nervous system. Schwann cells play a critical role in neurodevelopment, neurophysiology, and nerve regeneration. This review highlights the emerging understanding of the involvement of Schwann cells in DPN pathogenesis. This review explores the potential role of Schwann cell plasticity as an underlying cellular and molecular mechanism in the development of DPN. Understanding the interplay between Schwann cell plasticity and diabetes could reveal novel strategies for the treatment and management of DPN.
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Affiliation(s)
- Nurul Husna Abd Razak
- Institute of Medical Science Technology, Universiti Kuala Lumpur (UniKL), A1-1, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia; (N.H.A.R.); (J.I.); (N.H.H.)
| | - Jalilah Idris
- Institute of Medical Science Technology, Universiti Kuala Lumpur (UniKL), A1-1, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia; (N.H.A.R.); (J.I.); (N.H.H.)
| | - Nur Hidayah Hassan
- Institute of Medical Science Technology, Universiti Kuala Lumpur (UniKL), A1-1, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia; (N.H.A.R.); (J.I.); (N.H.H.)
| | - Fazlin Zaini
- Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL), No. 3, Jalan Greentown, Ipoh 30450, Perak, Malaysia; (F.Z.); (N.M.)
| | - Noorzaid Muhamad
- Royal College of Medicine Perak, Universiti Kuala Lumpur (UniKL), No. 3, Jalan Greentown, Ipoh 30450, Perak, Malaysia; (F.Z.); (N.M.)
| | - Muhammad Fauzi Daud
- Institute of Medical Science Technology, Universiti Kuala Lumpur (UniKL), A1-1, Jalan TKS 1, Taman Kajang Sentral, Kajang 43000, Selangor, Malaysia; (N.H.A.R.); (J.I.); (N.H.H.)
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Donoiu I, Târtea G, Sfredel V, Raicea V, Țucă AM, Preda AN, Cozma D, Vătășescu R. Dapagliflozin Ameliorates Neural Damage in the Heart and Kidney of Diabetic Mice. Biomedicines 2023; 11:3324. [PMID: 38137545 PMCID: PMC10741899 DOI: 10.3390/biomedicines11123324] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2023] [Revised: 12/12/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
(1) Background: Measures for the control of diabetes mellitus (DM) and, especially, for the control of its complications represent a main objective of the research carried out on this disease, since both mortality and morbidity relating to DM represent real problems for the health system worldwide. The aim of our study was to evaluate nervous tissue from the heart and kidneys of mice with diabetes induced by streptozotocin (STZ) in the presence or absence of dapagliflozin (DAPA) treatment. (2) Methods: For this purpose, we used 24 C 57Bl/6 male mice, aged between 8 and 10 weeks. The mice were divided into three groups: sham (DM-), control (DM+), and treated (DM+). Diabetes mellitus was induced by injecting a single intraperitoneal dose of STZ. The duration of diabetes in the mice included in our study was 12 weeks after STZ administration; then, the heart and kidneys were sampled, and nervous tissue (using the primary antibody PGP 9.5) from the whole heart, from the atrioventricular node, and from the kidneys was analyzed. (3) Results: The density of nerve tissue registered a significant decrease in animals from the control group (DM+), to a value of 0.0122 ± 0.005 mm2 nerve tissue/mm2 cardiac tissue, compared with the sham group (DM-), wherein the value was 0.022 ± 0.006 mm2 nervous tissue/mm2 cardiac tissue (p = 0.004). Treatment with dapagliflozin reduced the nerve tissue damage in the treated (DM+DAPA) group of animals, resulting in a nerve tissue density of 0.019 ± 0.004 mm2 nerve tissue/mm2 cardiac tissue; a statistically significant difference was noted between the control (DM+) and treated (DM+DAPA) groups (p = 0.046). The same trends of improvement in nerve fiber damage in DM after treatment with DAPA were observed both in the atrioventricular node and in the kidneys. (4) Conclusions. These data suggest that dapagliflozin, when used in streptozotocin-induced diabetes in mice, reduces the alteration of the nervous system in the kidneys and in the heart, thus highlighting better preservation of cardiac and renal homeostasis, independent of any reduction in the effects of hyperglycemia produced in this disease.
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Affiliation(s)
- Ionuț Donoiu
- Department of Cardiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (I.D.); (V.R.)
| | - Georgică Târtea
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.S.); (A.M.Ț.)
| | - Veronica Sfredel
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.S.); (A.M.Ț.)
| | - Victor Raicea
- Department of Cardiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (I.D.); (V.R.)
| | - Anca Maria Țucă
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.S.); (A.M.Ț.)
| | - Alexandra Nicoleta Preda
- Department of Physiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.S.); (A.M.Ț.)
| | - Dragoş Cozma
- Department of Cardiology, “Victor Babes” University of Medicine and Pharmacy, 2 Eftimie Murgu Sq., 300041 Timisoara, Romania;
| | - Radu Vătășescu
- Cardio-Thoracic Pathology Department, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
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Shahani P, Mahadevan A, Mondal K, Waghmare G, Datta I. Repeat intramuscular transplantation of human dental pulp stromal cells is more effective in sustaining Schwann cell survival and myelination for functional recovery after onset of diabetic neuropathy. Cytotherapy 2023; 25:1200-1211. [PMID: 37642606 DOI: 10.1016/j.jcyt.2023.07.011] [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: 06/06/2022] [Revised: 07/30/2023] [Accepted: 07/30/2023] [Indexed: 08/31/2023]
Abstract
BACKGROUND AIMS Mesenchymal stromal cell (MSC) therapy for diabetic neuropathy (DN) has been extensively researched in vitro and in pre-clinical studies; however, the clinical scenario thus far has been disappointing. Temporary recovery, a common feature of these studies, indicates that either the retention of transplanted cells deteriorates with time or recovery of supportive endogenous cells, such as bone marrow-derived MSCs (BM-MSCs), does not occur, requiring further replenishment. In DN, BM-MSCs are recognized mediators of Schwann cell regeneration, and we have earlier shown that they suffer impairment in the pre-neuropathy stage. In this study, we attempted to further elucidate the mechanisms of functional recovery by focusing on changes occurring at the cellular level in the sciatic nerve, in conjunction with the biodistribution and movement patterns of the transplanted cells, to define the interval between doses. METHOD & RESULTS We found that two doses of 1 × 106 dental pulp stromal cells (DPSCs) transplanted intramuscularly at an interval of 4 weeks effectively improved nerve conduction velocity (NCV) and restored motor coordination through improving sciatic nerve architecture, Schwann cell survival and myelination. Despite very minimal recovery of endogenous BM-MSCs, a temporary restoration of NCV and motor function was achieved with the first dose of DPSC transplantation. However, this did not persist, and a repeat dose was needed to consolidate functional improvement and rehabilitate the sciatic nerve architecture. CONCLUSION Thus, repeat intramuscular transplantation of DPSCs is more effective for maintenance of Schwann cell survival and myelination for functional recovery after onset of DN.
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Affiliation(s)
- Pradnya Shahani
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Anita Mahadevan
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Kallolika Mondal
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Girish Waghmare
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Bengaluru, India
| | - Indrani Datta
- Department of Biophysics, National Institute of Mental Health and Neurosciences, Bengaluru, India.
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Zaino B, Goel R, Devaragudi S, Prakash A, Vaghamashi Y, Sethi Y, Patel N, Kaka N. Diabetic neuropathy: Pathogenesis and evolving principles of management. Dis Mon 2023; 69:101582. [PMID: 37164794 DOI: 10.1016/j.disamonth.2023.101582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/12/2023]
Abstract
The global rise of prediabetes and diabetes has spawned an epidemic of complications associated with these conditions. Neuropathy is the most common consequence, with distal symmetric polyneuropathy (DSP) being the most prevalent. Diabetic neuropathy (DN) is a debilitating consequence of diabetes mellitus resulting in the highest morbidity and death, besides imposing a substantial financial burden on the patient. Loss of sensory function commencing distally in the lower limbs, accompanied by discomfort and considerable morbidity, characterizes diabetic neuropathy. The clinical evaluation and therapeutic options for diabetic peripheral neuropathy are multifaceted. At least fifty percent of people with diabetes acquire diabetic neuropathy over time. Good glycemic control halts the evolution in individuals with Type 1 diabetes mellitus. These results have prompted fresh attempts to comprehend the origin and develop new guidelines for prevention and treatment. New recommendations have also been established for the treatment of painful DN using separate classes of medications, with an emphasis on avoiding the use of opioids. Although our comprehension of the intricacies of diabetic neuropathy has progressed significantly over the past decade, the unique processes driving the neuropathy in type 1 and type 2 diabetes remain unexplained. Currently, glycemic control and pain management are the only effective therapies. While glucose management significantly reduces neuropathy development in type 1 diabetics, the effect is considerably lower in type 2 diabetics. Evidence supports the use of anticonvulsants and antidepressants for diabetic peripheral neuropathy pain treatment. However, the absence of disease-modifying medications for diabetic DSP necessitates the identification of unrecognized modifiable risk factors. It is imperative to identify the 'missed' risk factors and targets, allowing comprehensive, individualized care for patients.
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Affiliation(s)
- Basem Zaino
- Tishreen University, Syria; PearResearch, India
| | - Rashika Goel
- Punjab Institute of Medical Sciences, India; PearResearch, India
| | - Sanjana Devaragudi
- Apollo Institute of Medical Sciences and Research, Hyderabad, India; PearResearch, India
| | - Ananya Prakash
- Narayana Institute of Cardiac Sciences, Bangalore, India; PearResearch, India
| | - Yogeshkumar Vaghamashi
- Bicol Christian College of Medicine, Legazpi city, Philippines; Narayana Institute of Cardiac Sciences, Bangalore, India
| | - Yashendra Sethi
- PearResearch, India; Government Doon Medical College, Dehradun, Uttarakhand, India
| | - Neil Patel
- PearResearch, India; GMERS Medical College Himmatnagar, India.
| | - Nirja Kaka
- PearResearch, India; GMERS Medical College Himmatnagar, India
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Wang X, Xu G, Liu H, Chen Z, Huang S, Yuan J, Xie C, Du L. Inhibiting apoptosis of Schwann cell under the high-glucose condition: A promising approach to treat diabetic peripheral neuropathy using Chinese herbal medicine. Biomed Pharmacother 2023; 157:114059. [PMID: 36462309 DOI: 10.1016/j.biopha.2022.114059] [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: 07/14/2022] [Revised: 11/15/2022] [Accepted: 11/27/2022] [Indexed: 12/05/2022] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes. Glycemic control and lifestyle alterations cannot prevent the development of DPN; therefore, investigating effective treatments for DPN is crucial. Schwann cells (SCs) maintain the physiological function of peripheral nerves and promote the repair and regeneration of injured nerves. Inhibiting the apoptosis of SCs through various pathological pathways in a high-glucose environment plays an important role in developing DPN. Therefore, inhibiting the apoptosis of SCs can be a novel treatment strategy for DPN. Previous studies have indicated the potential of Chinese herbal medicine (CHM) in treating DPN. In this study, we have reviewed the effects of CHM (both monomers and extracts) on the apoptosis of SCs by interfering with the production of advanced glycation end products, oxidative stress, and endoplasmic reticulum stress pathological pathways. This review will demonstrate the potentialities of CHM in inhibiting apoptosis in SCs, providing new insights and perspectives for treating DPN.
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Affiliation(s)
- Xueru Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China.
| | - Gang Xu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China.
| | - Hanyu Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China.
| | - Zhengtao Chen
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China.
| | - Susu Huang
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China.
| | - Jiushu Yuan
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China.
| | - Chunguang Xie
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu610072, Sichuan, China; TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Chengdu, 610072, Sichuan, China.
| | - Lian Du
- College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China.
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Drug repurposing – A search for novel therapy for the treatment of diabetic neuropathy. Biomed Pharmacother 2022; 156:113846. [DOI: 10.1016/j.biopha.2022.113846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 09/27/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022] Open
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Curcumin protect Schwann cells from inflammation response and apoptosis induced by high glucose through the NF-κB pathway. Tissue Cell 2022; 77:101873. [PMID: 35868051 DOI: 10.1016/j.tice.2022.101873] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 07/14/2022] [Accepted: 07/15/2022] [Indexed: 12/18/2022]
Abstract
Demyelination disease as diabetes mellitus (DM) complication is characterized by apoptosis of Schwann cells (SCs) and several reports have demonstrated that high glucose content can induce an inflammation response and lead to the apoptosis of SCs. For NF-κB plays a pivotal role in the inflammatory response, hence we hypothesized that high glucose content can induce inflammation though the NF-κB pathway. First we verified that 150 mM high glucose can increase the expression of cleaved caspase 3, interleukin (IL)- 1β, Cyto-C and NF-κB with time through Western blot and increase the apoptosis of RSC96s through Flow Cytometry. Then we found that high glucose can increase the nuclear translocation NF-κB through confocal system which can promote the expression of inflammation genes such as IL-1β. Curcumin has been reported to possess anti-inflammation activities to protect cells. In this study, we found that application with 25 μM curcumin could alleviate the inflammation response and protect the cells from apoptosis. We revealed that the expression of NF-κB and p-NF-κB was decreased and the translocation was also inhibited after curcumin application. Accordingly, the secretion of IL-1β and the apoptosis of RSC96s induce by high glucose was suppressed. Our cumulative findings suggest that curcumin can protect SCs from apoptosis through the inhibition of the inflammatory response though the NF-κB pathway.
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A Comparative Study of Xi’s Tendon Gangrene (Nonischemic Type of Diabetic Foot) and Gangrene (Diabetic Foot Ischemic Type). COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:8114073. [PMID: 35799637 PMCID: PMC9256357 DOI: 10.1155/2022/8114073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/10/2022] [Accepted: 06/03/2022] [Indexed: 11/18/2022]
Abstract
Background. Diabetic foot gangrene refers to a lesion in which the tissue of the foot or lower extremities of diabetic patients is damaged, and the cause is the infection of peripheral blood vessels and neuropathy caused by diabetes. Objective. To compare the related indexes of blood glucose, inflammation, blood viscosity, and peripheral neuropathy between the nonischemic diabetic foot and ischemic diabetic foot, the same and different characteristics of the two different types of diabetic foot in pathogenesis were discussed and studied. Methods. A total of 122 patients with diabetic foot were selected from the Department of Vascular Medicine, Shanghai Hospital of Integrated Traditional Chinese and Western Medicine, including 61 cases of ischemic type and 61 cases of nonischemic type. The differences in blood glucose, inflammation, blood supply, and peripheral neuropathy between the nonischemic diabetic foot and ischemic diabetic foot were compared to explore their different characteristics. Results. The blood glucose index, inflammatory index, and plasma fibrinogen in patients with nonischemic diabetic foot were significantly higher than those in patients with ischemic diabetic foot (
). The patients with ischemic diabetic foot were higher in age and blood lipid index than those with the nonischemic diabetic foot (
), while having no significant difference in platelet count, plasma viscosity, hematocrit, and end products of glycation (AGEs). Conclusion. The nonischemic diabetic foot is mainly infective necrosis, and the ischemic type is ischemic necrosis. The former occurs in the middle-aged and elderly with good blood supply between 40 and 60 years old, while the latter occurs in the elderly with the severe vascular disease over 60 years old. The blood glucose level of nonischemic patients is significantly higher than that of ischemic patients, but it has little to do with the course of diabetes.
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Shinouchi R, Shibata K, Jono S, Hasumi K, Nobe K. SMTP-44D Exerts Antioxidant and Anti-Inflammatory Effects through Its Soluble Epoxide Hydrolase Inhibitory Action in Immortalized Mouse Schwann Cells upon High Glucose Treatment. Int J Mol Sci 2022; 23:5187. [PMID: 35563575 PMCID: PMC9104197 DOI: 10.3390/ijms23095187] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/30/2022] [Accepted: 05/04/2022] [Indexed: 11/29/2022] Open
Abstract
Diabetic neuropathy (DN) is a major complication of diabetes mellitus. We have previously reported the efficacy of Stachybotrys microspora triprenyl phenol-44D (SMTP-44D) for DN through its potential antioxidant and anti-inflammatory activities. However, the mechanisms underlying the antioxidant and anti-inflammatory activities of SMTP-44D remain unclear. The present study aimed to explore the mechanism of these effects of SMTP-44D in regard to its inhibition of soluble epoxide hydrolase (sEH) in immortalized mouse Schwann cells (IMS32) following high glucose treatment. IMS32 cells were incubated in a high glucose medium for 48 h and then treated with SMTP-44D for 48 h. After incubation, the ratio of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), oxidative stress markers, such as NADPH oxidase-1 and malondialdehyde, inflammatory factors, such as the ratio of nuclear to cytosolic levels of NF-κB and the levels of IL-6, MCP-1, MMP-9, the receptor for the advanced glycation end product (RAGE), and apoptosis, were evaluated. SMTP-44D treatment considerably increased the ratio of EETs to DHETs and mitigated oxidative stress, inflammation, RAGE induction, and apoptosis after high glucose treatment. In conclusion, SMTP-44D can suppress the induction of apoptosis by exerting antioxidant and anti-inflammatory effects, possibly through sEH inhibition. SMTP-44D can be a potential therapeutic agent against DN.
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Affiliation(s)
- Ryosuke Shinouchi
- Division of Pharmacology, Department of Pharmacology, Toxicology & Therapeutics, School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Keita Shibata
- Division of Pharmacology, Department of Pharmacology, Toxicology & Therapeutics, School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Shiori Jono
- Division of Pharmacology, Department of Pharmacology, Toxicology & Therapeutics, School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
| | - Keiji Hasumi
- Department of Applied Biological Science, Tokyo University of Agriculture and Technology, 3-5-8 Saiwaicho, Fuchu-shi, Tokyo 183-8509, Japan
- Division of Research and Development, TMS Co., Ltd., 1-23-3-501 Miyamachi, Fuchu-shi, Tokyo 183-0023, Japan
| | - Koji Nobe
- Division of Pharmacology, Department of Pharmacology, Toxicology & Therapeutics, School of Pharmacy, Pharmacology Research Center, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
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11
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Olson LC, Redden JT, Schwartz Z, Cohen DJ, McClure MJ. Advanced Glycation End-Products in Skeletal Muscle Aging. Bioengineering (Basel) 2021; 8:bioengineering8110168. [PMID: 34821734 PMCID: PMC8614898 DOI: 10.3390/bioengineering8110168] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/26/2021] [Accepted: 10/28/2021] [Indexed: 12/17/2022] Open
Abstract
Advanced age causes skeletal muscle to undergo deleterious changes including muscle atrophy, fast-to-slow muscle fiber transition, and an increase in collagenous material that culminates in the age-dependent muscle wasting disease known as sarcopenia. Advanced glycation end-products (AGEs) non-enzymatically accumulate on the muscular collagens in old age via the Maillard reaction, potentiating the accumulation of intramuscular collagen and stiffening the microenvironment through collagen cross-linking. This review contextualizes known aspects of skeletal muscle extracellular matrix (ECM) aging, especially the role of collagens and AGE cross-linking, and underpins the motor nerve’s role in this aging process. Specific directions for future research are also discussed, with the understudied role of AGEs in skeletal muscle aging highlighted. Despite more than a half century of research, the role that intramuscular collagen aggregation and cross-linking plays in sarcopenia is well accepted yet not well integrated with current knowledge of AGE’s effects on muscle physiology. Furthermore, the possible impact that motor nerve aging has on intramuscular cross-linking and muscular AGE levels is posited.
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Affiliation(s)
- Lucas C. Olson
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.C.O.); (J.T.R.); (Z.S.); (D.J.C.)
- Department of Gerontology, College of Health Professions, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - James T. Redden
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.C.O.); (J.T.R.); (Z.S.); (D.J.C.)
| | - Zvi Schwartz
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.C.O.); (J.T.R.); (Z.S.); (D.J.C.)
- Department of Periodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - David J. Cohen
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.C.O.); (J.T.R.); (Z.S.); (D.J.C.)
| | - Michael J. McClure
- Department of Biomedical Engineering, College of Engineering, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.C.O.); (J.T.R.); (Z.S.); (D.J.C.)
- Correspondence:
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12
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Dimova R, Chakarova N, Grozeva G, Tankova T. The relationship between endogenous secretory RAGE and cardiac autonomic function in prediabetes. Int J Clin Pract 2021; 75:e14769. [PMID: 34473880 DOI: 10.1111/ijcp.14769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 08/30/2021] [Indexed: 11/26/2022] Open
Abstract
AIMS The putative protective role of esRAGE for cardiac autonomic function (CAF) remains unclear. To address this question, the present study has assessed the relationship of serum AGEs, sRAGE and esRAGE, and tissue AGEs with CAF in a high-risk population without diabetes. MATERIAL AND METHODS This study enrolled 48 subjects of mean age 52.7 ± 11.2 years and mean BMI 28.4 ± 6.3 kg/m2 , divided into two groups according to glucose tolerance: 16 with normal glucose tolerance (NGT) and 24 with prediabetes. A standard oral glucose tolerance test (OGTT) was performed. The glucose tolerance was defined according to 2006 WHO criteria. Fasting, 120-minutes glucose, lipids, creatinine, and HbA1c were measured. eGFR was calculated (CKD-EPI). Fasting, 120-minutes insulin (ECLIA method), advanced glycation end products (AGEs), plasma-soluble receptor for AGE (sRAGE), and endogenous secreted isoform of the receptor for AGE (esRAGE), (ELISA method) were assessed. HOMA-IR was calculated. Tissue AGEs were assessed by skin autofluorescence (AGE-Reader, DiagnOpticsTM). CAF was evaluated with ANX 3.0 autonomic nervous-monitoring system (ANSAR), applying deep breathing, Valsalva, and standing. RESULTS There was a significant decline in CAF in prediabetes in comparison with NGT. Serum and tissue AGEs, sRAGE, and esRAGE levels were similar between groups. On the matrix analysis, both sympathetic and parasympathetic activities at baseline and after standing and sympathetic tone during Valsalva were positively related to esRAGE in prediabetes. Multivariate regression analysis showed that esRAGE is an independent contributor to sympathetic, parasympathetic, and total autonomic tone in prediabetes accounting for about 28%, 34%, and 35% of their variances, respectively. CONCLUSION Our results have demonstrated that CAF is decreased in prediabetes. esRAGE, but not sRAGE, is reciprocally related to CAF, probably opposing the negative effects of glycation.
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Affiliation(s)
- Rumyana Dimova
- Division of Diabetology, Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria
| | - Nevena Chakarova
- Division of Diabetology, Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria
| | - Greta Grozeva
- Division of Diabetology, Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria
| | - Tsvetalina Tankova
- Division of Diabetology, Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria
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Luna R, Talanki Manjunatha R, Bollu B, Jhaveri S, Avanthika C, Reddy N, Saha T, Gandhi F. A Comprehensive Review of Neuronal Changes in Diabetics. Cureus 2021; 13:e19142. [PMID: 34868777 PMCID: PMC8628358 DOI: 10.7759/cureus.19142] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2021] [Indexed: 12/11/2022] Open
Abstract
There has been an exponential rise in diabetes mellitus (DM) cases on a global scale. Diabetes affects almost every system of the body, and the nervous system is no exception. Although the brain is dependent on glucose, providing it with the energy required for optimal functionality, glucose also plays a key role in the regulation of oxidative stress, cell death, among others, which furthermore contribute to the pathophysiology of neurological disorders. The variety of biochemical processes engaged in this process is only matched by the multitude of clinical consequences resulting from it. The wide-ranging effects on the central and peripheral nervous system include, but are not limited to axonopathies, neurodegenerative diseases, neurovascular diseases, and general cognitive impairment. All language search was conducted on MEDLINE, COCHRANE, EMBASE, and GOOGLE SCHOLAR till September 2021. The following search strings and Medical Subject Headings (MeSH terms) were used: "Diabetes Mellitus," "CNS," "Diabetic Neuropathy," and "Insulin." We explored the literature on diabetic neuropathy, covering its epidemiology, pathophysiology with the respective molecular pathways, clinical consequences with a special focus on the central nervous system and finally, measures to prevent and treat neuronal changes. Diabetes is slowly becoming an epidemic, rapidly increasing the clinical burden on account of its wide-ranging complications. This review focuses on the neuronal changes occurring in diabetes such as the impact of hyperglycemia on brain function and structure, its association with various neurological disorders, and a few diabetes-induced peripheral neuropathic changes. It is an attempt to summarize the relevant literature about neuronal consequences of DM as treatment options available today are mostly focused on achieving better glycemic control; further research on novel treatment options to prevent or delay the progression of neuronal changes is still needed.
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Affiliation(s)
- Rudy Luna
- Neurofisiología, Instituto Nacional de Neurologia y Neurocirugia, CDMX, MEX
| | | | | | | | - Chaithanya Avanthika
- Medicine and Surgery; Pediatrics, Karnataka Institute of Medical Sciences, Hubli, IND
| | - Nikhil Reddy
- Internal Medicine, Kamineni Academy of Medical Science and Research Centre, Hyderabad, IND
| | - Tias Saha
- Internal Medicine, Diabetic Association Medical College, Faridpur, BGD
| | - Fenil Gandhi
- Medicine, Shree Krishna Hospital, Anand, IND
- Research Project Associate, Memorial Sloan Kettering Cancer Center, New York, USA
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14
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Cutaneous innervation in impaired diabetic wound healing. Transl Res 2021; 236:87-108. [PMID: 34029747 PMCID: PMC8380642 DOI: 10.1016/j.trsl.2021.05.003] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022]
Abstract
Type 2 diabetes is associated with several potential comorbidities, among them impaired wound healing, chronic ulcerations, and the requirement for lower extremity amputation. Disease-associated abnormal cellular responses, infection, immunological and microvascular dysfunction, and peripheral neuropathy are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory nerve afferents and nerve-derived modulators, which communicate with epidermal keratinocytes and dermal fibroblasts bidirectionally to effect normal wound healing after trauma. However, the mechanisms through which cutaneous innervation modulates wound healing are poorly understood, especially in humans. Better understanding of these mechanisms may provide the basis for targeted treatments for chronic diabetic wounds. This review provides an overview of wound healing pathophysiology with a focus on neural involvement in normal and diabetic wound healing, as well as future therapeutic perspectives to address the unmet needs of diabetic patients with chronic wounds.
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15
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Takino JI, Sato T, Nagamine K, Sakasai-Sakai A, Takeuchi M, Hori T. Suppression of Hepatic Stellate Cell Death by Toxic Advanced Glycation End-Products. Biol Pharm Bull 2021; 44:112-117. [PMID: 33390537 DOI: 10.1248/bpb.b20-00708] [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] [Indexed: 11/22/2022]
Abstract
Advanced glycation end-products (AGEs) are produced by the non-enzymatic reaction of sugars with proteins. It has been revealed that glyceraldehyde-derived toxic AGEs (TAGE) are elevated in the serum of non-alcoholic steatohepatitis (NASH) patients. NASH causes liver fibrosis and progresses to cirrhosis and hepatocellular carcinoma. However, the impact of TAGE in liver fibrosis caused by extracellular matrix accumulation remains poorly understood. In this study, we examined the effect of TAGE on the activation of hepatic stellate cells that are involved in liver fibrosis. LX-2 cells treated with transforming growth factor-β1 (TGF-β1) significantly reduced cell viability by apoptosis. However, the decrease in cell viability with TGF-β1 treatment was significantly suppressed by TAGE co-treatment. The levels of α-smooth muscle actin (α-SMA) and platelet-derived growth factor (PDGF)-Rβ and its ligand PDGF-B were increased in LX-2 cells following TGF-β1 treatment, suggesting that these cells were activated; however, these increases were unaffected by TAGE co-treatment. Moreover, collagen I level was increased with TGF-β1 treatment, and this increase was further increased by TAGE co-treatment. These results suggested that the suppression of apoptosis in activated LX-2 cells by TGF-β1 and TAGE co-treatment is related to an increase in the production of the extracellular matrix such as collagen I. Therefore, it was suggested that TAGE might aggravate the liver fibrosis of chronic hepatitis, such as NASH.
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Affiliation(s)
- Jun-Ichi Takino
- Faculty of Pharmaceutical Sciences, Hiroshima International University
| | - Takuma Sato
- Faculty of Pharmaceutical Sciences, Hiroshima International University
| | | | | | | | - Takamitsu Hori
- Faculty of Pharmaceutical Sciences, Hiroshima International University
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16
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Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems. Int J Mol Sci 2021; 22:ijms22031031. [PMID: 33494154 PMCID: PMC7864348 DOI: 10.3390/ijms22031031] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/13/2021] [Accepted: 01/19/2021] [Indexed: 12/13/2022] Open
Abstract
Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.
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17
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Waghela BN, Vaidya FU, Ranjan K, Chhipa AS, Tiwari BS, Pathak C. AGE-RAGE synergy influences programmed cell death signaling to promote cancer. Mol Cell Biochem 2020; 476:585-598. [PMID: 33025314 DOI: 10.1007/s11010-020-03928-y] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/23/2020] [Indexed: 12/11/2022]
Abstract
Advanced glycation end products (AGEs) are formed as a result of non-enzymatic reaction between the free reducing sugars and proteins, lipids, or nucleic acids. AGEs are predominantly synthesized during chronic hyperglycemic conditions or aging. AGEs interact with their receptor RAGE and activate various sets of genes and proteins of the signal transduction pathway. Accumulation of AGEs and upregulated expression of RAGE is associated with various pathological conditions including diabetes, cardiovascular diseases, neurodegenerative disorders, and cancer. The role of AGE-RAGE signaling has been demonstrated in the progression of various types of cancer and other pathological disorders. The expression of RAGE increases manifold during cancer progression. The activation of AGE-RAGE signaling also perturbs the cellular redox balance and modulates various cell death pathways. The programmed cell death signaling often altered during the progression of malignancies. The cellular reprogramming of AGE-RAGE signaling with cell death machinery during tumorigenesis is interesting to understand the complex signaling mechanism of cancer cells. The present review focus on multiple molecular paradigms relevant to cell death particularly Apoptosis, Autophagy, and Necroptosis that are considerably influenced by the AGE-RAGE signaling in the cancer cells. Furthermore, the review also attempts to shed light on the provenience of AGE-RAGE signaling on oxidative stress and consequences of cell survival mechanism of cancer cells.
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Affiliation(s)
- Bhargav N Waghela
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Foram U Vaidya
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Kishu Ranjan
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, 06519, USA
| | - Abu Sufiyan Chhipa
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Budhi Sagar Tiwari
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India
| | - Chandramani Pathak
- Cell Biology Laboratory, School of Biological Sciences & Biotechnology, Indian Institute of Advanced Research, Koba Institutional Area, Gandhinagar, Gujarat, 382426, India.
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18
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Suzuki A, Yabu A, Nakamura H. Advanced glycation end products in musculoskeletal system and disorders. Methods 2020; 203:179-186. [PMID: 32987130 DOI: 10.1016/j.ymeth.2020.09.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/18/2020] [Accepted: 09/23/2020] [Indexed: 02/06/2023] Open
Abstract
The human population is ageing globally, and the number of old people is increasing yearly. Diabetes is common in the elderly, and the number of diabetic patients is also increasing. Elderly and diabetic patients often have musculoskeletal disorder, which are associated with advanced glycation end products (AGEs). AGEs are heterogeneous molecules derived from non-enzymatic products of the reaction of glucose or other sugar derivatives with proteins or lipids, and many different types of AGEs have been identified. AGEs are a biomarker for ageing and for evaluating disease conditions. Fluorescence, spectroscopy, mass spectrometry, chromatography, and immunological methods are commonly used to measure AGEs, but there is no standardized evaluation method because of the heterogeneity of AGEs. The formation of AGEs is irreversible, and they accumulate in tissue, eventually causing damage. AGE accumulation has been confirmed in neuromusculoskeletal tissues, including bones, cartilage, muscles, tendons, ligaments, and nerves, where they adversely affect biomechanical properties by causing charge changes and forming cross-linkages. AGEs also bind to receptors, such as the receptor for AGEs (RAGE), and induce inflammation by intracellular signal transduction. These mechanisms cause many varied aging and diabetes-related pathological conditions, such as osteoporosis, osteoarthritis, sarcopenia, tendinopathy, and neuropathy. Understanding of AGEs related pathomechanism may lead to develop novel methods for the prevention and therapy of such disorders which affect patients' quality of life. Herein, we critically review the current methodology used for detecting AGEs, and present potential mechanisms by which AGEs cause or exacerbate musculoskeletal disorders.
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Affiliation(s)
- Akinobu Suzuki
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan.
| | - Akito Yabu
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan
| | - Hiroaki Nakamura
- Department of Orthopedic Surgery, Osaka City University Graduate School of Medicine, Japan
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19
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Enhanced carbonyl stress and disrupted white matter integrity in schizophrenia. Schizophr Res 2020; 223:242-248. [PMID: 32843203 DOI: 10.1016/j.schres.2020.08.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 04/30/2020] [Accepted: 08/11/2020] [Indexed: 11/19/2022]
Abstract
Carbonyl stress is a state caused by an increase in rich reactive carbonyl compounds (RCOs); RCOs facilitate the formation of advanced glycation end products (AGEs), which are associated with various age-related illnesses. Recently, enhanced carbonyl stress and lower levels of pyridoxal, a kind of vitamin B6 that scavenges RCOs, have been shown to be associated with schizophrenia. Meanwhile, lower levels of pyridoxal have been reported to decrease myelination through the biochemical process of carbonyl stress. Despite a number of reports on white matter disruption in schizophrenia, it is unclear whether this disruption is related to enhanced carbonyl stress. Therefore, we investigated the relationship between carbonyl stress and white matter integrity in schizophrenia using diffusion tensor imaging. A total of 53 patients with schizophrenia and 83 age- and gender-matched healthy controls were recruited. We used plasma pentosidine, an AGE, and serum pyridoxal as carbonyl stress markers. Between-group differences in these carbonyl stress markers and their relationships with white matter integrity were investigated using Tract-Based Spatial Statistics. In the schizophrenia group, plasma pentosidine level was significantly higher and serum pyridoxal level was lower than those of controls. There was a significant negative correlation between plasma pentosidine and white matter integrity in the schizophrenia group, but not in the control group. Our findings suggest that enhanced carbonyl stress is a possible underlying mechanism of white matter microstructural disruption in schizophrenia.
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20
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Shoaib A, Siddiqui HH, Dixit RK, Siddiqui S, Deen B, Khan A, Alrokayan SH, Khan HA, Ahmad P. Neuroprotective Effects of Dried Tubers of Aconitum napellus. PLANTS (BASEL, SWITZERLAND) 2020; 9:356. [PMID: 32168878 PMCID: PMC7154901 DOI: 10.3390/plants9030356] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 02/15/2020] [Accepted: 02/18/2020] [Indexed: 02/07/2023]
Abstract
The present study was designed to explore the neuroprotective properties of Aconitum napellus (Ranunculaceae). The plant detoxification was done using either water, or cow or goat milk as per the Ayurvedic shodhana method. The evaluation of the neuroprotective role of A. napellus was performed on diabetic neuropathy induced by streptozotocin in Sprague Dawley (SD) rats. Body mass, blood sugar level, oral glucose tolerance test, hyperalgesia, cold allodynia, motor co-ordination test, and locomotor activity, oxidative biomarkers (TBARS, reduced glutathione, catalase and superoxide dismutase) and sciatic nerve histomorphology were assessed. The in vitro studies were done on human neuroblastoma cell line SHSY-5Y and used an MTT assay to assess the antiproliferative activity of different extracts. Results suggest that the goat milk treated chloroform extract has less percentage of aconitine. After administration of the detoxified chloroform extract to the diabetic animals, there was a significant improvement in the myelination and degenerative changes of the nerve fibers along with behavioral changes (p < 0.05 as compared with diabetic control group). The findings of the in vitro research show an effective neuroprotective role of A. napellus. This suggests that A. napellus should be further investigated for its effect in diabetic pathology.
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Affiliation(s)
- Ambreen Shoaib
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow 226026, India;
| | | | - Rakesh Kumar Dixit
- Department of Pharmacology, King George Medical University, Lucknow, Uttar Pradesh 226003, India;
| | - Sahabjada Siddiqui
- Department of Biotechnology, Era’s Lucknow Medical College & Hospital, Era University, Lucknow 226003, India;
| | - Badrud Deen
- Department of Pharmacology, Faculty of Pharmacy, Integral University, Lucknow 226026, India;
| | - Andleeb Khan
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia;
| | - Salman H. Alrokayan
- Department of Biochemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (S.H.A.); (H.A.K.)
| | - Haseeb A. Khan
- Department of Biochemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (S.H.A.); (H.A.K.)
| | - Parvaiz Ahmad
- Botany and Microbiology Department, College of Science, King Saudi University, Riyadh 11451, Saudi Arabia
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21
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Araki T. Regulatory Mechanism of Peripheral Nerve Myelination by Glutamate-Induced Signaling. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1190:23-31. [PMID: 31760635 DOI: 10.1007/978-981-32-9636-7_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/12/2023]
Abstract
Regulation of differentiation and proliferation of Schwann cells is an essential part of the regulation of peripheral nerve development, degeneration, and regeneration. ZNRF1, a ubiquitin ligase, is expressed in undifferentiated/repair Schwann cells, directs glutamine synthetase to proteasomal degradation, and thereby increase glutamate levels in Schwann cell environment. Glutamate elicits subcellular signaling in Schwann cells via mGluR2 to modulate Neuregulin-1/ErbB2/3 signaling and thereby promote undifferentiated phenotype of Schwann cell.
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Affiliation(s)
- Toshiyuki Araki
- Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
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22
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Glycolaldehyde induces sensory neuron death through activation of the c-Jun N-terminal kinase and p-38 MAP kinase pathways. Histochem Cell Biol 2019; 153:111-119. [DOI: 10.1007/s00418-019-01830-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/06/2019] [Indexed: 02/04/2023]
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Tang HY, Jiang AJ, Ma JL, Wang FJ, Shen GM. Understanding the Signaling Pathways Related to the Mechanism and Treatment of Diabetic Peripheral Neuropathy. Endocrinology 2019; 160:2119-2127. [PMID: 31318414 DOI: 10.1210/en.2019-00311] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 07/11/2019] [Indexed: 12/13/2022]
Abstract
Worldwide, the most prevalent metabolic disorder is diabetes mellitus (DM), an important condition that has been widely studied. Diabetic peripheral neuropathy (DPN), a complication that can occur with DM, is associated with pain and can result in foot ulcers and even amputation. DPN treatments are limited and mainly focus on pain management. There is a clear need to develop treatments for DPN at all stages. To make this progress, it is necessary to understand the molecular signaling pathways related to DPN. For this review, we aimed to concentrate on the main signaling cascades that contribute to DPN. In addition, we provide information with regard to treatments that are being explored.
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Affiliation(s)
- He-Yong Tang
- Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Ai-Juan Jiang
- Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Jun-Long Ma
- Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Fan-Jing Wang
- Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Guo-Ming Shen
- Anhui University of Chinese Medicine, Hefei, Anhui, China
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Impellizzeri D, Peritore AF, Cordaro M, Gugliandolo E, Siracusa R, Crupi R, D'Amico R, Fusco R, Evangelista M, Cuzzocrea S, Di Paola R. The neuroprotective effects of micronized PEA (PEA-m) formulation on diabetic peripheral neuropathy in mice. FASEB J 2019; 33:11364-11380. [PMID: 31344333 DOI: 10.1096/fj.201900538r] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Diabetic peripheral neuropathy (DPN) is a complication of diabetes connected with morbidity and mortality. DPN presents deterioration of peripheral nerves with pain, feebleness, and loss of sensation. Particular medications might display their remedial potential by controlling neuroinflammation. Palmitoylethanolamide (PEA) is an autacoid local injury antagonist distinguished for its neuroprotective, analgesic, and anti-inflammatory properties in numerous experimental models of neuroinflammation. Based on these findings, the goal of this work was to better test the neuroprotective effects of a formulation of micronized PEA (PEA-m) and the probable mechanism of action in a mouse model of DPN induced by streptozotocin (STZ) injection. Diabetic and control animals received PEA-m (10 mg/kg) by oral gavage daily starting 2 wk from STZ injection. After 16 wk, the animals were euthanized, and blood, urine, spinal cord, and sciatic nerve tissues were collected. Our results demonstrated that after diabetes induction, PEA-m was able to reduce mechanical, thermal hyperalgesia, and motor alterations as well as reduce mast cell activation and nerve growth factor expression. In addition, PEA-m decreased neural histologic damage, oxidative and nitrosative stress, cytokine release, angiogenesis, and apoptosis. Moreover, spinal microglia activation (IBA-1), phospho-P38 MAPK, and nuclear factor NF-κB inflammatory pathways were also inhibited. The protective effects of PEA-m could be correlated at least in part to peroxisome proliferator-activated receptor-α activation. In summary, we demonstrated that PEA-m represents a new therapeutic strategy for neuroinflammation pain associated with mixed neuropathies.-Impellizzeri, D., Peritore, A. F., Cordaro, M., Gugliandolo, E., Siracusa, R., Crupi, R., D'Amico, R., Fusco, R., Evangelista, M., Cuzzocrea, S., Di Paola, R. The neuroprotective effects of micronized PEA (PEA-m) formulation on diabetic peripheral neuropathy in mice.
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Affiliation(s)
- Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
| | - Alessio Filippo Peritore
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
| | - Marika Cordaro
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
| | - Enrico Gugliandolo
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
| | - Rosalia Crupi
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
| | - Ramona D'Amico
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
| | - Roberta Fusco
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
| | - Maurizio Evangelista
- Institute of Anaesthesiology and Reanimation, Catholic University of the Sacred Heart, Rome, Italy
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy.,Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri, USA
| | - Rosanna Di Paola
- Department of Chemical, Biological, Pharmaceutical, and Environmental Science, University of Messina, Messina, Italy
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Shaikh-Kader A, Houreld NN, Rajendran NK, Abrahamse H. The link between advanced glycation end products and apoptosis in delayed wound healing. Cell Biochem Funct 2019; 37:432-442. [PMID: 31318458 DOI: 10.1002/cbf.3424] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 06/05/2018] [Accepted: 06/05/2019] [Indexed: 01/26/2023]
Abstract
Advanced glycation end products (AGEs) are naturally occurring molecules that start to accumulate from embryonic developmental stages and form as part of normal ageing. When reducing sugars interact with and modify proteins or lipids, AGE production occurs. AGE formation accelerates in chronic hyperglycemic conditions, and high AGE levels have been associated with the pathogenesis of various diseases. In addition, enhanced levels of AGEs have been linked to delayed wound healing as seen in patients with diabetes mellitus. Research has provided numerous ways in which a high AGE concentration results in impaired wound healing, including oxidative stress, structural and functional changes to proteins important in wound repair, an enhanced inflammatory response by activation of transcription factors, and possible exaggerated apoptosis of cells necessary to the wound repair process. Apoptosis is a naturally occurring cell death process that is significant for normal tissue functioning and plays an important role in wound repair by preventing a prolonged inflammatory response and excessive scar formation. Abnormal apoptosis affects wound healing, resulting in slow healing wounds. This review will summarize the role of AGEs in wound healing, focusing on the mechanisms by which AGEs lead to apoptosis in various cell types. The review provides the way forward for medical research and molecular studies as it focuses on the mechanisms by which AGEs induce apoptosis in various cell types, including fibroblasts, osteoblasts, neuronal cells, and endothelial cells. Reviewing the mechanisms of AGE-linked apoptosis is important in understanding the impact of high AGE levels in delayed wound healing in diabetic patients due to abnormal apoptosis of cells necessary to the wound healing process.
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Affiliation(s)
- Asma Shaikh-Kader
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
| | - Nicolette Nadene Houreld
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
| | - Naresh Kumar Rajendran
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
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Xu S, Li J, Zhai M, Yao X, Liu H, Deng T, Cai H, Zhang W, Zhang W, Lou J, Peng L. 1,25-(OH) 2D 3 protects Schwann cells against advanced glycation end products-induced apoptosis through PKA-NF-κB pathway. Life Sci 2019; 225:107-116. [PMID: 30928409 DOI: 10.1016/j.lfs.2019.03.068] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 03/21/2019] [Accepted: 03/27/2019] [Indexed: 11/28/2022]
Abstract
AIMS To explore the effect and mechanism of 1, 25-(OH)2D3 on Schwann cell apoptosis induced by advanced glycation end products. MAIN METHODS Schwann cells, isolated from rodent sciatic nerve were incubated with AGE-modified bovine serum albumin(AGE) to mimic diabetic conditions and 1,25-(OH)2D3 was used as protector. Cell apoptosis was detected by PI/Annexin-V staining, caspase 3 activity assay and western blotting for caspase 3 and PARP. The activation of protein kinase A (PKA) and nuclear factor kappa-B (NF-κB) was evaluated by western blot. Immunofluorescent staining was used for intercellular location of NF-κB. Cytokine secretion was evaluated by enzyme-linked immunosorbent assay. KEY FINDINGS Schwann cell apoptosis accelerated after incubating with AGE. However, if combining 1,25-(OH)2D3 with AGE, apoptosis decreased significantly. 1,25-(OH)2D3 enhanced PKA activity, but inhibited AGE-induced nuclear translocation of NF-κB. Furthermore, PKA activator (8-bromoadenoside cyclic adenoside monophosphate, 8-Br-cAMP) or NF-κB inhibitor (caffeic acid phenethyl ester, CAPE) could reduce the apoptosis, decreased cleaved caspase 3 and cleaved PARP, suggesting the involvement of PKA and NF-κB pathways in the protection of 1,25-(OH)2D3 on Schwann cells. Moreover, 8-Br-cAMP and CAPE could inhibit AGE-induced secretion of interleukin(IL)-1β, prostaglandin E2(PEG2) and cyclooxygenase 2(COX2). Interestingly, 8-Br-cAMP decreased phospho-NF-κB and inhibited nucleus translocation of NF-κB. It hinted at the regulation of PKA to NF-κB. Finally, a pre-treatment of H-89 (an inhibitor of PKA) could block the protection of 1,25-(OH)2D3 on cell apoptosis. In conclusion, 1,25-(OH)2D3 could protect Schwann cell against AGE-induced apoptosis through PKA/NF-κB pathway. SIGNIFICANCE These findings provide experimental rationales for using vitamin D for diabetic neuropathy.
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Affiliation(s)
- Shiqing Xu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Jing Li
- Department of Stomatology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Min Zhai
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiaoqi Yao
- Department of Ultrasonic Diagnosis, China-Japan Friendship Hospital, Beijing 100029, China
| | - Honglin Liu
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Tingting Deng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China
| | - Hanqing Cai
- Department of Endocrinology, The Second Hospital of Jilin University, Changchun 130041, China
| | - Wan Zhang
- Department of Clinical Laboratory, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wenjian Zhang
- Suzhou Rely Bio-Tech Co., Ltd., Suzhou 215103, China
| | - Jinning Lou
- Suzhou Rely Bio-Tech Co., Ltd., Suzhou 215103, China
| | - Liang Peng
- Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing 100029, China.
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Fujimoto S, Murakami Y, Miyake H, Hayase F, Watanabe H. Identification of a novel advanced glycation end product derived from lactaldehyde. Biosci Biotechnol Biochem 2019; 83:1136-1145. [PMID: 30822216 DOI: 10.1080/09168451.2019.1585745] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Advanced glycation end products (AGEs) are implicated in the development of diabetic complications via the receptor for AGEs (RAGE). We have reported that the 3-hydroxypyridinium (3HP)-containing AGEs derived from α-hydroxyaldehydes physically interact with RAGE and show cytotoxicity. Lactaldehyde (LA) is formed from a reaction between threonine and myeloperoxidase, but no LA-derived AGEs have been characterized. Here, we identify the structure and physiological effects of an AGE derived from LA. We isolated a novel 3HP derivative, 2-acetamido-6-(3-hydroxy-5-methyl-pyridin-1-ium-1-yl)hexanoate, named as N-acetyl-LAPL (lactaldehyde-derived pyridinium-type lysine adduct), from a mixture of LA with Nα-acetyl-L-lysine. LAPL was also detected in the LA-modified protein. LAPL elicited toxicity in PC12 neuronal cells, but the effect was suppressed by the soluble form of RAGE as a decoy receptor. Moreover, surface plasmon resonance-based analysis revealed that LAPL specifically binds to recombinant RAGE. These results indicate that LA generates an AGE containing the 3HP moiety and contributes to RAGE-dependent cytotoxicity. Abbreviations: AGEs: advanced glycation end products; RAGE: receptor for advanced glycation end products; 3HP: 3-hydroxypyridinium; LA: lactaldehyde; LAPL: lactaldehyde-derived pyridinium-type lysine adduct; BSA: bovine serum albumin; GLAP: glyceraldehyde-derived pyridinium; MPO: myeloperoxidase; HFBA: heptafluorobutyric acid; TFA: trifluoroacetic acid; HPLC: high performance liquid chromatography; LC-ESI-QTOF-MS: liquid chromatography-electrospray ionization-quadrupole time-of-flight-mass spectrometry; NMR: nuclear magnetic resonance; LA-BSA: lactaldehyde-modified bovine serum albumin; PBS: phosphate buffered saline, GST, glutathione S-transferase; SPR: surface plasmon resonance; OP-lysine: 2-ammonio-6-(3-oxidopyridinium-1-yl)hexanoate; GLO1: glyoxalase 1; MG, methylglyoxal.
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Affiliation(s)
- Shiori Fujimoto
- a Department of Agriculture , Meiji University , Kawasaki , Japan
| | - Yoto Murakami
- a Department of Agriculture , Meiji University , Kawasaki , Japan
| | - Haruna Miyake
- a Department of Agriculture , Meiji University , Kawasaki , Japan
| | - Fumitaka Hayase
- a Department of Agriculture , Meiji University , Kawasaki , Japan
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Ghodsi R, Kheirouri S. Positive Association Between Plasma Levels of Advanced Glycation and Precursor of Lipoxidation end Products with Gastrointestinal Problems in Children with Autism. Curr Pediatr Rev 2019; 15:184-190. [PMID: 31264551 DOI: 10.2174/1573396315666190628141333] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/08/2019] [Accepted: 05/15/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Increased oxidative stress has been reported in autistic patients besides, evidence linking oxidative stress to enhancement of advanced glycation and lipoxidation end products (AGEs and ALEs) and their precursors. OBJECTIVE This study aimed to compare the plasma levels of the AGEs and precursors of ALEs in autistic and healthy children and to evaluate their relationship with autism comorbidities. METHODS In this descriptive study, 54 children, 36 autistic and 18 healthy participated. Plasma levels of AGEs and precursors of ALEs were measured by ELISA method. Severity of autism and Gastrointestinal (GI) disorders were measured by GARSII questionnaire and QPGS-ROME III questionnaire, respectively. RESULTS Plasma levels of AGEs and precursors of ALEs in autistic children were comparable with healthy children. Plasma levels of AGEs and precursor of ALEs were correlated with physical activity and GI disorders in autistic children. A strong association was also found between AGEs and precursors of ALEs. CONCLUSION The results indicate that AGEs and ALEs have a strong correlation together but the AGEs and precursor of ALEs in autistic children are not different from healthy children.
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Affiliation(s)
- Ramin Ghodsi
- Department of Nutrition, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sorayya Kheirouri
- Nutrition Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Fournet M, Bonté F, Desmoulière A. Glycation Damage: A Possible Hub for Major Pathophysiological Disorders and Aging. Aging Dis 2018; 9:880-900. [PMID: 30271665 PMCID: PMC6147582 DOI: 10.14336/ad.2017.1121] [Citation(s) in RCA: 168] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 11/21/2017] [Indexed: 12/25/2022] Open
Abstract
Glycation is both a physiological and pathological process which mainly affects proteins, nucleic acids and lipids. Exogenous and endogenous glycation produces deleterious reactions that take place principally in the extracellular matrix environment or within the cell cytosol and organelles. Advanced glycation end product (AGE) formation begins by the non-enzymatic glycation of free amino groups by sugars and aldehydes which leads to a succession of rearrangements of intermediate compounds and ultimately to irreversibly bound products known as AGEs. Epigenetic factors, oxidative stress, UV and nutrition are important causes of the accumulation of chemically and structurally different AGEs with various biological reactivities. Cross-linked proteins, deriving from the glycation process, present both an altered structure and function. Nucleotides and lipids are particularly vulnerable targets which can in turn favor DNA mutation or a decrease in cell membrane integrity and associated biological pathways respectively. In mitochondria, the consequences of glycation can alter bioenergy production. Under physiological conditions, anti-glycation defenses are sufficient, with proteasomes preventing accumulation of glycated proteins, while lipid turnover clears glycated products and nucleotide excision repair removes glycated nucleotides. If this does not occur, glycation damage accumulates, and pathologies may develop. Glycation-induced biological products are known to be mainly associated with aging, neurodegenerative disorders, diabetes and its complications, atherosclerosis, renal failure, immunological changes, retinopathy, skin photoaging, osteoporosis, and progression of some tumors.
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Affiliation(s)
- Maxime Fournet
- 1University of Limoges, Faculty of Pharmacy, Department of Physiology, EA 6309, F-87025 Limoges, France
| | | | - Alexis Desmoulière
- 3University of Limoges, Faculty of Pharmacy, Department of Physiology, EA 6309, F-87025 Limoges, France
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Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother 2018; 107:306-328. [PMID: 30098549 DOI: 10.1016/j.biopha.2018.07.157] [Citation(s) in RCA: 268] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 07/15/2018] [Accepted: 07/31/2018] [Indexed: 02/09/2023] Open
Abstract
Chronic exposure of glucose rich environment creates several physiological and pathophysiological changes. There are several pathways by which hyperglycemia exacerbate its toxic effect on cells, tissues and organ systems. Hyperglycemia can induce oxidative stress, upsurge polyol pathway, activate protein kinase C (PKC), enhance hexosamine biosynthetic pathway (HBP), promote the formation of advanced glycation end-products (AGEs) and finally alters gene expressions. Prolonged hyperglycemic condition leads to severe diabetic condition by damaging the pancreatic β-cell and inducing insulin resistance. Numerous complications have been associated with diabetes, thus it has become a major health issue in the 21st century and has received serious attention. Dysregulation in the cardiovascular and reproductive systems along with nephropathy, retinopathy, neuropathy, diabetic foot ulcer may arise in the advanced stages of diabetes. High glucose level also encourages proliferation of cancer cells, development of osteoarthritis and potentiates a suitable environment for infections. This review culminates how elevated glucose level carries out its toxicity in cells, metabolic distortion along with organ dysfunction and elucidates the complications associated with chronic hyperglycemia.
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Affiliation(s)
- Biplab Giri
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India; Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India.
| | - Sananda Dey
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India; Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Tanaya Das
- Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Mrinmoy Sarkar
- Experimental Medicine and Stem Cell Research Laboratory, Department of Physiology, West Bengal State University, Barasat, Kolkata 700126, India
| | - Jhimli Banerjee
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India
| | - Sandeep Kumar Dash
- Department of Physiology, University of Gour Banga, Mokdumpur, Malda 732103, India.
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Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018; 833:472-523. [DOI: 10.1016/j.ejphar.2018.06.034] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 06/15/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
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32
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Zhu L, Hao J, Cheng M, Zhang C, Huo C, Liu Y, Du W, Zhang X. Hyperglycemia-induced Bcl-2/Bax-mediated apoptosis of Schwann cells via mTORC1/S6K1 inhibition in diabetic peripheral neuropathy. Exp Cell Res 2018; 367:186-195. [PMID: 29621478 DOI: 10.1016/j.yexcr.2018.03.034] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 02/27/2018] [Accepted: 03/26/2018] [Indexed: 12/31/2022]
Abstract
Schwann cell apoptosis is one of the characteristics of diabetic peripheral neuropathy (DPN). The mammalian target of rapamycin (mTOR) is a multifunctional signaling pathway that regulates cell apoptosis in various types of tissues and cells. To investigate whether the mTOR pathway is involved in cell apoptosis in the Schwann cells of DPN, diabetic mice and rat Schwann cells (RSC96) were chosen to detect phospho-mTOR (Ser 2448), phospho-S6K1 (Thr 389), phospho-4EBP1 (Thr 37/46), Bcl-2, Bax and cleaved caspase-3 by diverse pathological and biological techniques. The results showed that phospho-mTOR (Ser 2448) was decreased in the sciatic nerves of diabetic mice, concomitant with decreased Bcl-2, increased Bax, cleaved caspase-3 and cell apoptosis. In addition, high glucose treatment for 72 h caused a 35.95% decrease in the phospho-mTOR (Ser 2448)/mTOR ratio, a 65.50% decrease in the phospho-S6K1 (Thr 389)/S6K1 ratio, a 3.67-fold increase in the Bax/Bcl-2 ratio and a 1.47-fold increase in the cleaved caspase-3/caspase-3 ratio. Furthermore, mTORC1 inhibition, rather than mTORC2 inhibition, resulted in mitochondrial controlled apoptosis in RSC96 cells by silencing RAPTOR or RICTOR. Again, suppression of the mTORC1 pathway by a chemical inhibitor led to mitochondrial controlled apoptosis in cultured RSC96 cells in vitro. By contrast, activation of the mTORC1 pathway with MHY1485 prevented decreased phospho-S6K1 (Thr 389) levels caused by high glucose and cell apoptosis. Additionally, constitutive activation of S6K1 avoided high glucose-induced cell apoptosis in RSC96 cells. In summary, our findings suggest that activating mTORC1/S6K1 signaling in Schwann cells may be a promising strategy for the prevention and treatment of DPN.
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Affiliation(s)
- Lin Zhu
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Department of Electromyogram, Third Hospital of Hebei Medical University, Shijiazhuang 050051, China
| | - Jun Hao
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Meijuan Cheng
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Cuihong Zhang
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Department of Radiation Oncology, Bethune International Peace Hospital, Shijiazhuang 050051, China
| | - Chunxiu Huo
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Yaping Liu
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Wei Du
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China
| | - Xianghong Zhang
- Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Lab of Pathology, Hebei Medical University, Shijiazhuang 050017, China.
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Zhao M, Liao D, Zhao J. Diabetes-induced mechanophysiological changes in the small intestine and colon. World J Diabetes 2017; 8:249-269. [PMID: 28694926 PMCID: PMC5483424 DOI: 10.4239/wjd.v8.i6.249] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/05/2017] [Accepted: 05/05/2017] [Indexed: 02/05/2023] Open
Abstract
The disorders of gastrointestinal (GI) tract including intestine and colon are common in the patients with diabetes mellitus (DM). DM induced intestinal and colonic structural and biomechanical remodeling in animals and humans. The remodeling is closely related to motor-sensory abnormalities of the intestine and colon which are associated with the symptoms frequently encountered in patients with DM such as diarrhea and constipation. In this review, firstly we review DM-induced histomorphological and biomechanical remodeling of intestine and colon. Secondly we review motor-sensory dysfunction and how they relate to intestinal and colonic abnormalities. Finally the clinical consequences of DM-induced changes in the intestine and colon including diarrhea, constipation, gut microbiota change and colon cancer are discussed. The final goal is to increase the understanding of DM-induced changes in the gut and the subsequent clinical consequences in order to provide the clinicians with a better understanding of the GI disorders in diabetic patients and facilitates treatments tailored to these patients.
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Zhao J, Gregersen H. Diabetes-induced mechanophysiological changes in the esophagus. Ann N Y Acad Sci 2016; 1380:139-154. [PMID: 27495976 DOI: 10.1111/nyas.13180] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 06/17/2016] [Accepted: 06/20/2016] [Indexed: 12/13/2022]
Abstract
Esophageal disorders are common in diabetes mellitus (DM) patients. DM induces mechanostructural remodeling in the esophagus of humans and animal models. The remodeling is related to esophageal sensorimotor abnormalities and to symptoms frequently encountered by DM patients. For example, gastroesophageal reflux disease (GERD) is a common disorder associated with DM. This review addresses diabetic remodeling of esophageal properties and function in light of the Esophagiome, a scientifically based modeling effort to describe the physiological dynamics of the normal, intact esophagus built upon interdisciplinary approaches with applications for esophageal disease. Unraveling the structural, biomechanical, and sensory remodeling of the esophagus in DM must be based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The first focus of this review is DM-induced morphodynamic and biomechanical remodeling in the esophagus. Second, we review the sensorimotor dysfunction in DM and how it relates to esophageal remodeling. Finally, we discuss the clinical consequences of DM-induced esophageal remodeling, especially in relation to GERD. The ultimate aim is to increase the understanding of DM-induced remodeling of esophageal structure and sensorimotor function in order to assist clinicians to better understand the esophageal disorders induced by DM and to develop better treatments for those patients.
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Affiliation(s)
- Jingbo Zhao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Hans Gregersen
- GIOME, Department of Surgery, Prince of Wales Hospital and Chinese University of Hong Kong, Shatin, Hong Kong SAR.,GIOME, College of Bioengineering, Chongqing University, Chongqing, China
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35
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Use of engineered Schwann cells in peripheral neuropathy: Hopes and hazards. Brain Res 2016; 1638:97-104. [DOI: 10.1016/j.brainres.2015.10.040] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Accepted: 10/23/2015] [Indexed: 01/16/2023]
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Yagihashi S. Glucotoxic Mechanisms and Related Therapeutic Approaches. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2016; 127:121-49. [PMID: 27133148 DOI: 10.1016/bs.irn.2016.03.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Neuropathy is the earliest and commonest complication of diabetes. With increasing duration of diabetes, frequency and severity of neuropathy are worsened. Long-term hyperglycemia is therefore implicated in the development of this disorder. Nerve tissues require glucose energy to function and survive. Upon excessive glucose entry into the peripheral nerve, the glycolytic pathway and collateral glucose-utilizing pathways are overactivated and initiate adverse effects on nerve tissues. During hyperglycemia, flux through the polyol pathway, formation of advanced glycation end-products, production of free radicals, flux into the glucosamine pathway, and protein kinase C activity are all enhanced to negatively influence nerve function and structure. Suppression of these aberrant metabolic pathways has succeeded in prevention and inhibition of the development of neuropathy in animal models with diabetes. Satisfactory results were not attained, however, in patients with diabetes and further clinical trials are required. In this review, the author summarizes the hitherto proposed theories on the pathogenesis of diabetic neuropathy related to glucose metabolism and future prospects for the effective treatment of neuropathy.
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Affiliation(s)
- S Yagihashi
- Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
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Sato K, Tatsunami R, Yama K, Murao Y, Tampo Y. Glycolaldehyde induces endoplasmic reticulum stress and apoptosis in Schwann cells. Toxicol Rep 2015; 2:1454-1462. [PMID: 28962488 PMCID: PMC5598486 DOI: 10.1016/j.toxrep.2015.10.014] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 10/06/2015] [Accepted: 10/26/2015] [Indexed: 02/02/2023] Open
Abstract
Glycolaldehyde induces endoplasmic reticulum stress in Schwann cells. Glycolaldehyde causes apoptosis in Schwann cells. Nrf2 activated by glycolaldehyde plays a protective role in the cytotoxicity. Schwann cell injury is caused by diabetic neuropathy. The apoptosis of Schwann cells plays a pivotal role in diabetic nerve dysfunction. Glycolaldehyde is a precursor of advanced glycation end products that contribute to the pathogenesis of diabetic neuropathy. In this study, we examined whether glycolaldehyde induces endoplasmic reticulum (ER) stress and apoptosis in rat Schwann cells. Schwann cells treated with 500 μM glycolaldehyde showed morphological changes characteristic of apoptosis. Glycolaldehyde activated apoptotic signals, such as caspase-3 and caspase-8. Furthermore, it induced ER stress response involving RNA-dependent protein kinase-like ER kinase (PERK), inositol-requiring ER-to-nucleus signal kinase 1α (IRE1α), and eukaryotic initiation factor 2α (eIF2α). In addition, glycolaldehyde activated CCAAT/enhancer-binding homologous protein (CHOP), an ER stress response factor crucial to executing apoptosis. Knockdown of nuclear factor E2-related factor 2 (Nrf2), which is involved in the promotion of cell survival following ER stress, enhanced glycolaldehyde-induced cytotoxicity, indicating that Nrf2 plays a protective role in the cytotoxicity caused by glycolaldehyde. Taken together, these findings indicate that glycolaldehyde is capable of inducing apoptosis and ER stress in Schwann cells. The ER stress induced by glycolaldehyde may trigger the glycolaldehyde-induced apoptosis in Schwann cells. This study demonstrated for the first time that glycolaldehyde induced ER stress.
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Key Words
- AGEs, advanced glycation end products
- ATF6, activating transcription factor 6
- Apoptosis
- CHOP, CCAAT/enhancer-binding homologous protein
- ER, endoplasmic reticulum
- Endoplasmic reticulum stress
- GA, glycolaldehyde
- Glycolaldehyde
- HO-1, heme oxygenase-1
- IRE1, inositol-requiring ER-to-nucleus signal kinase 1
- MG, methylglyoxal
- Nrf2, nuclear factor E2-related factor 2
- Nuclear factor E2-related factor 2
- PERK, RNA-dependent protein kinase-like ER kinase
- Schwann cell
- eIF2, eukaryotic initiation factor 2
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Cashman CR, Höke A. Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett 2015; 596:33-50. [PMID: 25617478 PMCID: PMC4428955 DOI: 10.1016/j.neulet.2015.01.048] [Citation(s) in RCA: 145] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 01/16/2015] [Accepted: 01/19/2015] [Indexed: 02/08/2023]
Abstract
Peripheral neuropathy is a common complication of a variety of diseases and treatments, including diabetes, cancer chemotherapy, and infectious causes (HIV, hepatitis C, and Campylobacter jejuni). Despite the fundamental difference between these insults, peripheral neuropathy develops as a combination of just six primary mechanisms: altered metabolism, covalent modification, altered organelle function and reactive oxygen species formation, altered intracellular and inflammatory signaling, slowed axonal transport, and altered ion channel dynamics and expression. All of these pathways converge to lead to axon dysfunction and symptoms of neuropathy. The detailed mechanisms of axon degeneration itself have begun to be elucidated with studies of animal models with altered degeneration kinetics, including the slowed Wallerian degeneration (Wld(S)) and Sarm knockout animal models. These studies have shown axonal degeneration to occur through a programmed pathway of injury signaling and cytoskeletal degradation. Insights into the common disease insults that converge on the axonal degeneration pathway promise to facilitate the development of therapeutics that may be effective against other mechanisms of neurodegeneration.
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Affiliation(s)
- Christopher R Cashman
- Departments of Neuroscience and Neurology, USA; MSTP- MD/PhD Program, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Ahmet Höke
- Departments of Neuroscience and Neurology, USA.
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Tanaka KI, Yamaguchi T, Kanazawa I, Sugimoto T. Effects of high glucose and advanced glycation end products on the expressions of sclerostin and RANKL as well as apoptosis in osteocyte-like MLO-Y4-A2 cells. Biochem Biophys Res Commun 2015; 461:193-9. [PMID: 25721666 DOI: 10.1016/j.bbrc.2015.02.091] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Accepted: 02/13/2015] [Indexed: 12/19/2022]
Abstract
In diabetes mellitus (DM), high glucose (HG) and advanced glycation end products (AGEs) are involved in bone quality deterioration. Osteocytes produce sclerostin and receptor activator of nuclear factor-кB ligand (RANKL) and regulate osteoblast and osteoclast function. However, whether HG or AGEs directly affect osteocytes and regulate sclerostin and RANKL production is unknown. Here, we examined the effects of HG, AGE2, and AGE3 on the expression of sclerostin and RANKL and on apoptosis in osteocyte-like MLO-Y4-A2 cells. Treatment of the cells with 22 mM glucose, 100 μg/mL either AGE2 or AGE3 significantly increased the expression of sclerostin protein and mRNA; however, both AGEs, but not glucose, significantly decreased the expression of RANKL protein and mRNA. Moreover, treatment of the cells with HG, AGE2, or AGE3 for 72 h induced significant apoptosis. These detrimental effects of HG, AGE2, and AGE3 on sclerostin and RANKL expressions and on apoptosis were antagonized by pretreatment of the cells with 10(-8) M human parathyroid hormone (PTH)-(1-34). Thus, HG and AGEs likely suppress bone formation by increasing sclerostin expression in osteocytes, whereas AGEs suppress bone resorption by decreasing RANKL expression. Together, these processes may cause low bone turnover in DM. In addition, HG and AGEs may cause cortical bone deterioration by inducing osteocyte apoptosis. PTH may effectively treat these pathological processes and improve osteocyte function.
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Affiliation(s)
- Ken-ichiro Tanaka
- Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan.
| | - Toru Yamaguchi
- Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan.
| | - Ippei Kanazawa
- Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan.
| | - Toshitsugu Sugimoto
- Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan.
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Abstract
Neuropathy is the most common complication of diabetes. As a consequence of longstanding hyperglycemia, a downstream metabolic cascade leads to peripheral nerve injury through an increased flux of the polyol pathway, enhanced advanced glycation end‐products formation, excessive release of cytokines, activation of protein kinase C and exaggerated oxidative stress, as well as other confounding factors. Although these metabolic aberrations are deemed as the main stream for the pathogenesis of diabetic microvascular complications, organ‐specific histological and biochemical characteristics constitute distinct mechanistic processes of neuropathy different from retinopathy or nephropathy. Extremely long axons originating in the small neuronal body are vulnerable on the most distal side as a result of malnutritional axonal support or environmental insults. Sparse vascular supply with impaired autoregulation is likely to cause hypoxic damage in the nerve. Such dual influences exerted by long‐term hyperglycemia are critical for peripheral nerve damage, resulting in distal‐predominant nerve fiber degeneration. More recently, cellular factors derived from the bone marrow also appear to have a strong impact on the development of peripheral nerve pathology. As evident from such complicated processes, inhibition of single metabolic factors might not be sufficient for the treatment of neuropathy, but a combination of several inhibitors might be a promising approach to overcome this serious disorder. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00070.x, 2010)
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Affiliation(s)
| | | | - Kazuhiro Sugimoto
- Laboratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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Nishizawa Y, Wada RI, Baba M, Takeuchi M, Hanyu-Itabashi C, Yagihashi S. Neuropathy induced by exogenously administered advanced glycation end-products in rats. J Diabetes Investig 2014; 1:40-9. [PMID: 24843407 PMCID: PMC4020676 DOI: 10.1111/j.2040-1124.2009.00002.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Aims/Introduction: Advanced glycation end‐products (AGE) have been implicated in the development of diabetic neuropathy. It still remains unknown, however, how AGE cause functional and structural changes of the peripheral nerve in diabetes. To explore the role of AGE in diabetic neuropathy, we examined the peripheral nerve by injecting AGE into normal Wistar rats. Materials and Methods: Young, normal male Wistar rats were injected intraperitoneally (i.p.) daily for 12 weeks with purified AGE prepared by incubating D‐glucose with bovine serum albumin (BSA). A control group received BSA alone. A group of rats given AGE were co‐treated with aminoguanidine (50 mg/kg/day, i.p.). Peripheral nerve function and structure, as well as nerve Na+,K+‐ATPase activity, were examined in these rats. Immunohistochemical expressions of 8‐hydroxy‐2′‐deoxyguanosine (8OHdG) and nuclear factor‐κB (NF‐κB)p65 were also examined. Results: Serum AGE levels were increased two to threefold in the AGE‐treated group compared with those in the BSA‐treated control group. AGE‐treated rats showed a marked slowing of motor nerve conduction velocity (MNCV) and decreased nerve Na+,K+‐ATPase activity compared with those in the BSA‐treated group. These changes were accompanied by intensified expressions of 8OHdG and NF‐κBp65 in endothelial cells and Schwann cells. Aminoguanidine treatment corrected MNCV delay, Na+,K+‐ATPase activity, and suppressed the expression of 8OHdG and NF‐κB, despite there being no influence on serum AGE levels. Conclusions: The results suggest that an elevated concentration of blood AGE might be one of the contributing factors to the development of neuropathic changes in diabetes.
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Affiliation(s)
- Yusuke Nishizawa
- Department of Pathology and Molecular Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki
| | - Ryu-Ichi Wada
- Department of Pathology and Molecular Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki
| | - Masayuki Baba
- Division of Neurology, Aomori Prefectural Hospital, Aomori
| | - Masayoshi Takeuchi
- Department of Pathophysiological Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan
| | - Chieko Hanyu-Itabashi
- Department of Pathology and Molecular Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki
| | - Soroku Yagihashi
- Department of Pathology and Molecular Medicine, Graduate School of Medicine, Hirosaki University, Hirosaki
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Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014; 18:1-14. [PMID: 24634591 PMCID: PMC3951818 DOI: 10.4196/kjpp.2014.18.1.1] [Citation(s) in RCA: 937] [Impact Index Per Article: 85.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2013] [Revised: 10/11/2013] [Accepted: 12/10/2013] [Indexed: 02/06/2023]
Abstract
During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.
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Affiliation(s)
- Varun Parkash Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Anjana Bali
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
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Singh VP, Bali A, Singh N, Jaggi AS. Advanced glycation end products and diabetic complications. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2014. [PMID: 24634591 DOI: 10.4196/kjpp] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
During long standing hyperglycaemic state in diabetes mellitus, glucose forms covalent adducts with the plasma proteins through a non-enzymatic process known as glycation. Protein glycation and formation of advanced glycation end products (AGEs) play an important role in the pathogenesis of diabetic complications like retinopathy, nephropathy, neuropathy, cardiomyopathy along with some other diseases such as rheumatoid arthritis, osteoporosis and aging. Glycation of proteins interferes with their normal functions by disrupting molecular conformation, altering enzymatic activity, and interfering with receptor functioning. AGEs form intra- and extracellular cross linking not only with proteins, but with some other endogenous key molecules including lipids and nucleic acids to contribute in the development of diabetic complications. Recent studies suggest that AGEs interact with plasma membrane localized receptors for AGEs (RAGE) to alter intracellular signaling, gene expression, release of pro-inflammatory molecules and free radicals. The present review discusses the glycation of plasma proteins such as albumin, fibrinogen, globulins and collagen to form different types of AGEs. Furthermore, the role of AGEs in the pathogenesis of diabetic complications including retinopathy, cataract, neuropathy, nephropathy and cardiomyopathy is also discussed.
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Affiliation(s)
- Varun Parkash Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Anjana Bali
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Nirmal Singh
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
| | - Amteshwar Singh Jaggi
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala-147002, India
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Han J, Tan P, Li Z, Wu Y, Li C, Wang Y, Wang B, Zhao S, Liu Y. Fuzi attenuates diabetic neuropathy in rats and protects schwann cells from apoptosis induced by high glucose. PLoS One 2014; 9:e86539. [PMID: 24466139 PMCID: PMC3900563 DOI: 10.1371/journal.pone.0086539] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 12/15/2013] [Indexed: 02/04/2023] Open
Abstract
Radix aconite lateralis preparata (Fuzi), a folk medicine, has long been used for the treatment of diabetes and paralysis in China. We examined the effect of Fuzi alone on diabetic rats and Schwann cells in high glucose and the components responsible for its activity. The major constituents of FZE were identified by HPLC-MS/MS data. Male Sprague Dawley rats (n = 36) were randomly divided into control, diabetic, FZE 1.75 g/kg, FZE 3.50 g/kg, FZE 7.00 g/kg, and methylcobalamin groups. After two weeks treatment, nerve conduction velocity and paw withdrawal latency were measured. In vitro, the Schwann cells were grouped according to exposure: normal glucose (NG), normal glucose plus mannitol (NG+M), high glucose (HG), and HG plus different concentrations of FZE (0.1 µg/ml, 1.0 µg/ml, and 10.0 µg/ml). Oxygen free radicals and apoptosis were evaluated through DCFH2DA, DHE and annexin-PE/7-AAD assay, respectively. Apoptosis factors (Bax, Bcl-2, CytoC, caspase-3, and caspase-9) were analyzed using immunofluorescence. Nine alkaloids were identified. The results from animal model showed that FZE was effective in accelerating nerve conduction velocity and shortening paw withdrawal latency in diabetic rats. And in vitro, FZE was also found to protect Schwann cells against high glucose injury. FZE could significantly decrease the apoptotic ratio, superoxide anion and peroxide level. Furthermore, the apoptosis factors, including Bax, Bcl-2, CytoC, caspase-3, and caspase-9 were ameliorated in FZE treated groups. The HPLC-MSn method is simple and suitable for the identification of alkaloids in Fuzi. FZE has a protective effect in diabetic neuropathic rats, which is probably achieved by the antiapoptotic effect of FZE on Schwann cells. Apoptosis factor data imply that FZE protected Schwann cells through the mitochondria pathway. Alkaloids are major components contributing to the protective effect.
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Affiliation(s)
- Jing Han
- Beijing University of Chinese Medicine, Beijing, China
| | - Peng Tan
- Beijing University of Chinese Medicine, Beijing, China
| | - Zhiyong Li
- Minzu University of China, Beijing, China
| | - Yan Wu
- Beijing University of Chinese Medicine, Beijing, China
| | - Chun Li
- Beijing University of Chinese Medicine, Beijing, China
| | - Yong Wang
- Beijing University of Chinese Medicine, Beijing, China
| | - Beibei Wang
- Beijing University of Chinese Medicine, Beijing, China
| | - Shuang Zhao
- Beijing University of Chinese Medicine, Beijing, China
| | - Yonggang Liu
- Beijing University of Chinese Medicine, Beijing, China
- * E-mail:
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Chilelli NC, Burlina S, Lapolla A. AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: a "glycoxidation-centric" point of view. Nutr Metab Cardiovasc Dis 2013; 23:913-919. [PMID: 23786818 DOI: 10.1016/j.numecd.2013.04.004] [Citation(s) in RCA: 152] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Revised: 03/18/2013] [Accepted: 04/12/2013] [Indexed: 12/30/2022]
Abstract
AIMS Advanced glycation end products (AGE) excess is one of the most important mechanisms involved in the pathophysiology of chronic diabetic complications. This review first summarizes the role of these compounds in microvascular pathogenesis, particularly in the light of recently proposed biochemical mechanisms for diabetic retinopathy, nephropathy and neuropathy. Then we focus on the relationship between AGE and metabolic memory, trying to clarify the former's role in the missing link between micro- and macrovascular complications. DATA SYNTHESIS An excessive AGE formation has been demonstrated in the newly disclosed biochemical pathways involved in the microvascular pathobiology of type 2 diabetes, confirming the central role of AGE in the progression of diabetic neuropathy, retinopathy and nephropathy. As shown by recent studies, AGE seem to be not "actors", but "directors" of processes conducting to these complications, for at least two main reasons: first, AGE have several intra- and extracellular targets, so they can be seen as a "bridge" between intracellular and extracellular damage; secondly, whatever the level of hyperglycemia, AGE-related intracellular glycation of the mitochondrial respiratory chain proteins has been found to produce more reactive oxygen species, triggering a vicious cycle that amplifies AGE formation. This may help to explain the clinical link between micro- and macrovascular disease in diabetes, contributing to clarify the mechanisms behind metabolic memory. CONCLUSIONS The pathophysiological cascades triggered by AGE have a dominant, hyperglycemia-independent role in the onset of the microvascular complications of diabetes. An effective approach to prevention and treatment must therefore focus not only on early glycemic control, but also on reducing factors related to oxidative stress, and the dietary intake of exogenous AGE in particular.
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Affiliation(s)
- N C Chilelli
- Department of Medicine, Division of Metabolic Diseases, University of Padova, Via Giustiniani n 2, 35128 Padova, Italy
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Morita M, Yano S, Yamaguchi T, Sugimoto T. Advanced glycation end products-induced reactive oxygen species generation is partly through NF-kappa B activation in human aortic endothelial cells. J Diabetes Complications 2013; 27:11-5. [PMID: 22944044 DOI: 10.1016/j.jdiacomp.2012.07.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Revised: 07/29/2012] [Accepted: 07/29/2012] [Indexed: 10/27/2022]
Abstract
Tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) are involved in the endothelial dysfunction and the progression of atherosclerosis. In the pathogenesis of diabetic micro- and macro-vascular complications, advanced glycation end products (AGEs) and their receptor signaling are thought to play pivotal roles. We have studied the interaction among AGEs, TNF-α and ROS production using human aortic endothelial cells (HAoEC), and elucidated the significance of transcription factor NF-κB in that interaction. Concentration of TNF-α as well as 8-hydroxy-2'-deoxyguanosine (8-OHdG), an indicator of ROS generation, in the culture medium was significantly elevated 24 h after treatment with glycolaldehyde-derived AGE3. Antioxidant TEMPOL almost completely inhibited AGE3-induced TNF-α secretion, whereas NF-κB inhibitor PDTC partly suppressed AGE3-induced 8-OHdG production. Since NF-κB, which induces TNF-α expression is activated by ROS and TNF-α itself, AGE3-induced ROS generation is partly through NF-κB activation and subsequent TNF-α production in these cells. Our findings suggest that sustained activation of NF-κB might be crucial for endothelial dysfunction in diabetes, and that inhibition of local NF-κB and/or TNF-α action could be one of therapeutic strategies for vascular complications.
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Affiliation(s)
- Miwa Morita
- Department of Internal Medicine 1, Shimane University Faculty of Medicine, Shimane, Japan
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Farmer KL, Li C, Dobrowsky RT. Diabetic peripheral neuropathy: should a chaperone accompany our therapeutic approach? Pharmacol Rev 2012; 64:880-900. [PMID: 22885705 PMCID: PMC3462992 DOI: 10.1124/pr.111.005314] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes that is associated with axonal atrophy, demyelination, blunted regenerative potential, and loss of peripheral nerve fibers. The development and progression of DPN is due in large part to hyperglycemia but is also affected by insulin deficiency and dyslipidemia. Although numerous biochemical mechanisms contribute to DPN, increased oxidative/nitrosative stress and mitochondrial dysfunction seem intimately associated with nerve dysfunction and diminished regenerative capacity. Despite advances in understanding the etiology of DPN, few approved therapies exist for the pharmacological management of painful or insensate DPN. Therefore, identifying novel therapeutic strategies remains paramount. Because DPN does not develop with either temporal or biochemical uniformity, its therapeutic management may benefit from a multifaceted approach that inhibits pathogenic mechanisms, manages inflammation, and increases cytoprotective responses. Finally, exercise has long been recognized as a part of the therapeutic management of diabetes, and exercise can delay and/or prevent the development of painful DPN. This review presents an overview of existing therapies that target both causal and symptomatic features of DPN and discusses the role of up-regulating cytoprotective pathways via modulating molecular chaperones. Overall, it may be unrealistic to expect that a single pharmacologic entity will suffice to ameliorate the multiple symptoms of human DPN. Thus, combinatorial therapies that target causal mechanisms and enhance endogenous reparative capacity may enhance nerve function and improve regeneration in DPN if they converge to decrease oxidative stress, improve mitochondrial bioenergetics, and increase response to trophic factors.
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Affiliation(s)
- Kevin L Farmer
- Department of Pharmacology and Toxicology, The University of Kansas, Lawrence, KS 66045, USA
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Okazaki K, Yamaguchi T, Tanaka KI, Notsu M, Ogawa N, Yano S, Sugimoto T. Advanced glycation end products (AGEs), but not high glucose, inhibit the osteoblastic differentiation of mouse stromal ST2 cells through the suppression of osterix expression, and inhibit cell growth and increasing cell apoptosis. Calcif Tissue Int 2012; 91:286-96. [PMID: 22903508 DOI: 10.1007/s00223-012-9641-2] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2012] [Accepted: 07/21/2012] [Indexed: 11/30/2022]
Abstract
Diabetes mellitus is known to be associated with osteoporotic fractures through a decrease in osteoblastic bone formation rather than an increase in osteoclastic bone resorption. However, its precise mechanism is unknown, and we examined whether or not high glucose or advanced glycation end products (AGEs), which play key roles in the pathogenesis and complications of diabetes, would affect the osteoblastic differentiation, growth, and apoptosis of mouse stromal ST2 cells. Ten to 200 μg/mL AGE2 or AGE3 alone dose-dependently inhibited the mineralization. AGE2 or AGE3 alone (200 μg/mL) significantly inhibited alkaline phosphatase (ALP) activities as well as the mineralization of the cells (p < 0.01). In contrast, 22 mM glucose alone or in combination with 200 μg/mL AGE2 or AGE3 did not affect these cellular phenotypes. Real-time PCR showed that AGE2 or AGE3 alone (200 μg/mL) significantly decreased mRNA expressions of osteocalcin as well as osterix on day 14 (p < 0.01). Western blot analysis showed that AGE2 or AGE3 alone (200 μg/mL) also decreased the levels of Runx2 and osterix protein expressions on days 7 and 14. AGE2 or AGE3 significantly suppressed cell growth and increased apoptotic cell death in time- and dose-dependent manners (p < 0.01). Moreover, AGE3 alone (200 μg/mL) significantly increased mRNA expression of the receptor for AGEs (RAGE) on days 2 and 3 (p < 0.01). These results suggest that AGE2 and AGE3, but not high glucose, may inhibit the osteoblastic differentiation of stromal cells by decreasing osterix expression and partly by increasing RAGE expression, as well as inhibiting cell growth and increasing cell apoptosis.
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Affiliation(s)
- Kyoko Okazaki
- Department of Internal Medicine, Shimane University, Enya-cho, Izumo, Shimane, Japan
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Immortalized adult rodent Schwann cells as in vitro models to study diabetic neuropathy. EXPERIMENTAL DIABETES RESEARCH 2011; 2011:374943. [PMID: 21747827 PMCID: PMC3124069 DOI: 10.1155/2011/374943] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2010] [Revised: 04/03/2011] [Accepted: 04/14/2011] [Indexed: 12/22/2022]
Abstract
We have established spontaneously immortalized Schwann cell lines from normal adult mice and rats and murine disease models. One of the normal mouse cell lines, IMS32, possesses some biological properties of mature Schwann cells and high proliferative activities. The IMS32 cells under hyperglycemic and/or hyperlipidemic conditions have been utilized to investigate the pathogenesis of diabetic neuropathy, especially the polyol pathway hyperactivity, glycation, increased oxidative stress, and reduced synthesis of neurotrophic factors. In addition to the mouse cell lines, our current study focuses on the characterization of a normal rat cell line, IFRS1, under normal and high glucose conditions. These Schwann cell lines can be valuable tools for exploring the detailed mechanisms leading to diabetic neuropathy and novel therapeutic approaches against that condition.
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50
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Patel KP, Mayhan WG, Bidasee KR, Zheng H. Enhanced angiotensin II-mediated central sympathoexcitation in streptozotocin-induced diabetes: role of superoxide anion. Am J Physiol Regul Integr Comp Physiol 2010; 300:R311-20. [PMID: 21084672 DOI: 10.1152/ajpregu.00246.2010] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Studies have shown that the superoxide mechanism is involved in angiotensin II (ANG II) signaling in the central nervous system. We hypothesized that ANG II activates sympathetic outflow by stimulation of superoxide anion in the paraventricular nucleus (PVN) of streptozotocin (STZ)-induced diabetic rats. In α-chloralose- and urethane-anesthetized rats, microinjection of ANG II into the PVN (50, 100, and 200 pmol) produced dose-dependent increases in renal sympathetic nerve activity (RSNA), arterial pressure (AP), and heart rate (HR) in control and STZ-induced diabetic rats. There was a potentiation of the increase in RSNA (35.0 ± 5.0 vs. 23.0 ± 4.3%, P < 0.05), AP, and HR due to ANG II type I (AT(1)) receptor activation in diabetic rats compared with control rats. Blocking endogenous AT(1) receptors within the PVN with AT(1) receptor antagonist losartan produced significantly greater decreases in RSNA, AP, and HR in diabetic rats compared with control rats. Concomitantly, there were significant increases in mRNA and protein expression of AT(1) receptor with increased superoxide levels and expression of NAD(P)H oxidase subunits p22(phox), p47(phox), and p67(phox) in the PVN of rats with diabetes. Pretreatment with losartan (10 mg·kg(-1)·day(-1) in drinking water for 3 wk) significantly reduced protein expression of NAD(P)H oxidase subunits (p22(phox) and p47(phox)) in the PVN of diabetic rats. Pretreatment with adenoviral vector-mediated overexpression of human cytoplasmic superoxide dismutase (AdCuZnSOD) within the PVN attenuated the increased central responses to ANG II in diabetes (RSNA: 20.4 ± 0.7 vs. 27.7 ± 2.1%, n = 6, P < 0.05). These data support the concept that superoxide anion contributes to an enhanced ANG II-mediated signaling in the PVN involved with the exaggerated sympathoexcitation in diabetes.
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Affiliation(s)
- Kaushik P Patel
- Dept. of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198-5850, USA
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