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Yang Y, Zhao B, Wang Y, Lan H, Liu X, Hu Y, Cao P. Diabetic neuropathy: cutting-edge research and future directions. Signal Transduct Target Ther 2025; 10:132. [PMID: 40274830 PMCID: PMC12022100 DOI: 10.1038/s41392-025-02175-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 12/12/2024] [Accepted: 02/08/2025] [Indexed: 04/26/2025] Open
Abstract
Diabetic neuropathy (DN) is a prevalent and debilitating complication of diabetes mellitus, significantly impacting patient quality of life and contributing to morbidity and mortality. Affecting approximately 50% of patients with diabetes, DN is predominantly characterized by distal symmetric polyneuropathy, leading to sensory loss, pain, and motor dysfunction, often resulting in diabetic foot ulcers and lower-limb amputations. The pathogenesis of DN is multifaceted, involving hyperglycemia, dyslipidemia, oxidative stress, mitochondrial dysfunction, and inflammation, which collectively damage peripheral nerves. Despite extensive research, disease-modifying treatments remain elusive, with current management primarily focusing on symptom control. This review explores the complex mechanisms underlying DN and highlights recent advances in diagnostic and therapeutic strategies. Emerging insights into the molecular and cellular pathways have unveiled potential targets for intervention, including neuroprotective agents, gene and stem cell therapies, and innovative pharmacological approaches. Additionally, novel diagnostic tools, such as corneal confocal microscopy and biomarker-based tests, have improved early detection and intervention. Lifestyle modifications and multidisciplinary care strategies can enhance patient outcomes. While significant progress has been made, further research is required to develop therapies that can effectively halt or reverse disease progression, ultimately improving the lives of individuals with DN. This review provides a comprehensive overview of current understanding and future directions in DN research and management.
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Affiliation(s)
- Yang Yang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Bing Zhao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yuanzhe Wang
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Hongli Lan
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Xinyu Liu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yue Hu
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Cao
- State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial Medical Innovation Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
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Nowakowska A, Marchelek-Myśliwiec M, Skórka-Majewicz M, Żwierełło W, Grzeszczak K, Gutowska I. The Impact of Recreational Diving to a Depth of 40 m on Selected Intracellular DAMPs. Int J Mol Sci 2025; 26:3061. [PMID: 40243713 PMCID: PMC11989067 DOI: 10.3390/ijms26073061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/20/2025] [Accepted: 03/25/2025] [Indexed: 04/18/2025] Open
Abstract
Increasingly popular, recreational diving is a physical activity that takes place under extreme environmental conditions, which include hyperoxia, hyperbaria and exposure to cold water. The effects of these factors on the human body induce increased levels of reactive oxygen and nitrogen species in divers' bodies, which may modulate damage-associated molecular pattern (DAMPs), their receptors and the antioxidant response. This study involved 21 divers who descended to a depth of 40 metres. Determinations of selected intracellular DAMPs (high-mobility group box protein 1,HMGB1, S100 calcium-binding proteins A9 and A8, S100A8 and S100A9, heat shock protein family A member 1A, HSPA1A (Hsp70), heat shock protein family B, (small) member 1, HSPB1(Hsp27), thioredoxin, TXN), their receptors (Toll-like receptor 4, TLR4 and receptors for advanced glycation end products, RAGE), nuclear factor-κB (NF-κB) and antioxidant defence markers were performed before, after and 1 h after the dive. A significant transient reduction in HMGB1 expression was observed immediately after the dive at both the mRNA and protein levels. We noted an increase in S100A9 expression, which occurred 1 h post-dive compared to the post-dive time point, and a post-dive decrease in TLR4 expression only at the mRNA level. Diving also influenced the expression of genes encoding key enzymes associated with glutathione synthesis, (glutamate-cysteine ligase, catalytic subunit, GCLC and glutathione synthetase, GSS), and reduced plasma glutathione levels. However, no significant changes were observed in the expression of NF-κB, nitric oxide synthase 2 (NOS2) or circulating DAMP receptors (TLR4 and RAGE). The findings suggest an adaptive response to diving-induced oxidative stress, which appears to be a protective mechanism against an excessive inflammatory response. To our knowledge, this is the first study to analyse the role of intracellular DAMPs in recreational divers.
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Affiliation(s)
- Anna Nowakowska
- Institute of Biology, University of Szczecin, Wąska 13, 71-415 Szczecin, Poland
| | - Małgorzata Marchelek-Myśliwiec
- Clinical Department of Nephrology, Transplantology & Internal Medicine, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland;
| | - Marta Skórka-Majewicz
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.S.-M.); (W.Ż.)
| | - Wojciech Żwierełło
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.S.-M.); (W.Ż.)
| | - Konrad Grzeszczak
- Department of Laboratory Diagnostics, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.S.-M.); (W.Ż.)
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Pierre-Jerome C. The peripheral nervous system: peripheral neuropathies in the diabetic foot. MYOPATHIES AND TENDINOPATHIES OF THE DIABETIC FOOT 2025:451-482. [DOI: 10.1016/b978-0-443-13328-2.00022-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Evans AJ, Li YL. Remodeling of the Intracardiac Ganglia During the Development of Cardiovascular Autonomic Dysfunction in Type 2 Diabetes: Molecular Mechanisms and Therapeutics. Int J Mol Sci 2024; 25:12464. [PMID: 39596529 PMCID: PMC11594459 DOI: 10.3390/ijms252212464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 11/15/2024] [Accepted: 11/16/2024] [Indexed: 11/28/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most significant health issues worldwide, with associated healthcare costs estimated to surpass USD 1054 billion by 2045. The leading cause of death in T2DM patients is the development of cardiovascular disease (CVD). In the early stages of T2DM, patients develop cardiovascular autonomic dysfunction due to the withdrawal of cardiac parasympathetic activity. Diminished cardiac parasympathetic tone can lead to cardiac arrhythmia-related sudden cardiac death, which accounts for 50% of CVD-related deaths in T2DM patients. Regulation of cardiovascular parasympathetic activity is integrated by neural circuitry at multiple levels including afferent, central, and efferent components. Efferent control of cardiac parasympathetic autonomic tone is mediated through the activity of preganglionic parasympathetic neurons located in the cardiac extensions of the vagus nerve that signals to postganglionic parasympathetic neurons located in the intracardiac ganglia (ICG) on the heart. Postganglionic parasympathetic neurons exert local control on the heart, independent of higher brain centers, through the release of neurotransmitters, such as acetylcholine. Structural and functional alterations in cardiac parasympathetic postganglionic neurons contribute to the withdrawal of cardiac parasympathetic tone, resulting in arrhythmogenesis and sudden cardiac death. This review provides an overview of the remodeling of parasympathetic postganglionic neurons in the ICG, and potential mechanisms contributing to the withdrawal of cardiac parasympathetic tone, ventricular arrhythmogenesis, and sudden cardiac death in T2DM. Improving cardiac parasympathetic tone could be a therapeutic avenue to reduce malignant ventricular arrhythmia and sudden cardiac death, increasing both the lifespan and improving quality of life of T2DM patients.
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Affiliation(s)
- Anthony J. Evans
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Yu-Long Li
- Department of Emergency Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA;
- Department of Cellular & Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
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Geus TD, Franken G, Zuidema X, van Zundert J, Joosten EAJ. Structural changes in the nociceptive system induced by long-term conventional spinal cord stimulation in experimental painful diabetic polyneuropathy. Reg Anesth Pain Med 2024:rapm-2024-105919. [PMID: 39542640 DOI: 10.1136/rapm-2024-105919] [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: 07/31/2024] [Accepted: 10/28/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND Clinical studies suggest that long-term conventional spinal cord stimulation (LT-SCS) for painful diabetic peripheral neuropathy (PDPN) is initially effective but may decline in efficacy over time. Preclinical studies indicate that LT-SCS alleviates mechanical hypersensitivity and enhances hind paw blood flow in PDPN rats, suggesting nociceptive system plasticity. This study hypothesized that LT-SCS induces peripheral hind paw small-fiber sprouting and reduces central protein expression of glial and P2X4 brain-derived neurotrophic factor (BDNF) pathway markers. METHODS Diabetes was induced via Streptozotocin injection in 32 rats, with 16 developing PDPN and receiving a quadrupolar lead implant. LT-SCS was applied for 4 weeks, 12 hours per day. Pain behavior was assessed using the Von Frey test for mechanical hypersensitivity and the mechanical conflict avoidance system for motivational aspects of pain. Fiber sprouting was assessed via immunohistochemical analysis of nerve fibers in the hind paw skin. Protein expression in the spinal cord was assessed using western blotting. RESULTS LT-SCS increased the baseline threshold of mechanical hypersensitivity in PDPN animals, consistent with previous findings, but showed no effects on motivational aspects of pain. Hind paw tissue analysis revealed significantly increased intraepidermal nerve fiber density of PGP9.5 fibers in LT-SCS animals compared with Sham-SCS animals. Protein analysis showed significantly decreased pro-BDNF expression in LT-SCS animals compared with Sham-SCS animals. CONCLUSION LT-SCS induces structural changes in both peripheral and central components of the nociceptive system in PDPN animals. These changes may contribute to observed behavioral modifications, elucidating mechanisms underlying LT-SCS efficacy in PDPN management.
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Affiliation(s)
- Thomas de Geus
- Department of Anesthesiology and Pain Management, MUMC+, Maastricht, The Netherlands
- Maastricht University School for Mental Health and Neuroscience, Maastricht, The Netherlands
| | - Glenn Franken
- Department of Anesthesiology and Pain Management, MUMC+, Maastricht, The Netherlands
- Maastricht University School for Mental Health and Neuroscience, Maastricht, The Netherlands
| | - Xander Zuidema
- Department of Anesthesiology and Pain Management, MUMC+, Maastricht, The Netherlands
- Department of Anesthesiology and Pain Management, Diakonessenhuis Utrecht Zeist Doorn, Utrecht, The Netherlands
| | - Jan van Zundert
- Department of Anesthesiology and Pain Management, MUMC+, Maastricht, The Netherlands
- Department of Anesthesiology, Intensive Care, Emergency Medicine and Multidisciplinary Pain Center, Ziekenhuis Oost-Limburg, Genk, Belgium
| | - Elbert A J Joosten
- Department of Anesthesiology and Pain Management, MUMC+, Maastricht, The Netherlands
- Maastricht University School for Mental Health and Neuroscience, Maastricht, The Netherlands
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Miceli G, Basso MG, Pennacchio AR, Cocciola E, Pintus C, Cuffaro M, Profita M, Rizzo G, Sferruzza M, Tuttolomondo A. The Potential Impact of SGLT2-I in Diabetic Foot Prevention: Promising Pathophysiologic Implications, State of the Art, and Future Perspectives-A Narrative Review. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1796. [PMID: 39596981 PMCID: PMC11596194 DOI: 10.3390/medicina60111796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 10/24/2024] [Accepted: 10/30/2024] [Indexed: 11/29/2024]
Abstract
The impact of diabetic foot (DF) on the healthcare system represents a major public health problem, leading to a considerable clinical and economic burden. The factors contributing to DF's development and progression are strongly interconnected, including metabolic causes, neuropathy, arteriopathy, and inflammatory changes. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i), novel oral hypoglycemic drugs used as an adjunct to standard treatment, have recently changed the pharmacological management of diabetes. Nevertheless, data about the risk of limb amputation, discordant and limited to canagliflozin, which is currently avoided in the case of peripheral artery disease, have potentially discouraged the design of specific studies targeting DF. There is good evidence for the single immunomodulatory, neuroprotective, and beneficial vascular effects of SGLT2-i. Still, there is no clinical evidence about the early use of SGLT2-i in diabetic foot due to the lack of longitudinal and prospective studies proving the effect of these drugs without confounders. This narrative review aims to discuss the main evidence about the impact of SGLT2-i on the three complications of diabetes implicated in the development of DF, the state of the art, and the potential future implications.
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Affiliation(s)
- Giuseppe Miceli
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Maria Grazia Basso
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Andrea Roberta Pennacchio
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Elena Cocciola
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Chiara Pintus
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Mariagiovanna Cuffaro
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Martina Profita
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Giuliana Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Mariachiara Sferruzza
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
| | - Antonino Tuttolomondo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (ProMISE), Università degli Studi di Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy; (M.G.B.); (A.R.P.); (E.C.); (C.P.); (M.C.); (M.P.); (G.R.); (M.S.); (A.T.)
- Internal Medicine and Stroke Care Ward, University Hospital, Policlinico “P. Giaccone”, 90127 Palermo, Italy
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Liao C, Zhang W. Nerve decompression for diabetic peripheral neuropathy with nerve entrapment: a narrative review. Ther Adv Neurol Disord 2024; 17:17562864241265287. [PMID: 39411723 PMCID: PMC11475385 DOI: 10.1177/17562864241265287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 06/12/2024] [Indexed: 10/19/2024] Open
Abstract
Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes which primarily affects the sensory nervous system. Pain is the most common complaint that prompts patients to seek medical advice. With various presentations and intricate pathological mechanisms, diabetic peripheral neuropathic pain is currently the most crucial and challenging aspect of managing diabetic complications. As a heterogeneous disorder, there is no medication or treatment modality that is effective for all types of DPN and its associated neuropathic pain. Peripheral nerve decompression provides a new option for treating patients with diabetic peripheral neuropathic pain in the lower extremities. However, the clinical applicability of nerve decompression has been debated since it was first proposed. This review discusses the theoretical basis of nerve decompression, the clinical indications, and the progress of basic research based on the pathological mechanisms and nerve impairment patterns of diabetic peripheral neuropathic pain. The heterogeneity of DPN patients is summarized in terms of three aspects: complex pathophysiological mechanisms, multilevel nervous system involvement, and various nerve impairment properties. Identifying the presence of nerve entrapment among complex pathophysiological mechanisms is the key to successful outcomes. Tinel signs, focal pain, mechanical allodynia, and two-point discrimination were reported to be prognostic factors for good surgical outcomes, and their predictive ability might stem from their association with the early stage of entrapment neuropathy.
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Affiliation(s)
- Chenlong Liao
- Department of Neurosurgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenchuan Zhang
- Department of Neurosurgery, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, No. 639 Shanghai Zhizaoju Road, Huangpu District, Shanghai 200011, China
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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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Gao N, Li M, Wang W, Liu Z, Guo Y. The dual role of TRPV1 in peripheral neuropathic pain: pain switches caused by its sensitization or desensitization. Front Mol Neurosci 2024; 17:1400118. [PMID: 39315294 PMCID: PMC11417043 DOI: 10.3389/fnmol.2024.1400118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 08/12/2024] [Indexed: 09/25/2024] Open
Abstract
The transient receptor potential vanilloid 1 (TRPV1) channel plays a dual role in peripheral neuropathic pain (NeuP) by acting as a "pain switch" through its sensitization and desensitization. Hyperalgesia, commonly resulting from tissue injury or inflammation, involves the sensitization of TRPV1 channels, which modulates sensory transmission from primary afferent nociceptors to spinal dorsal horn neurons. In chemotherapy-induced peripheral neuropathy (CIPN), TRPV1 is implicated in neuropathic pain mechanisms due to its interaction with ion channels, neurotransmitter signaling, and oxidative stress. Sensitization of TRPV1 in dorsal root ganglion neurons contributes to CIPN development, and inhibition of TRPV1 channels can reduce chemotherapy-induced mechanical hypersensitivity. In diabetic peripheral neuropathy (DPN), TRPV1 is involved in pain modulation through pathways including reactive oxygen species and cytokine production. TRPV1's interaction with TRPA1 channels further influences chronic pain onset and progression. Therapeutically, capsaicin, a TRPV1 agonist, can induce analgesia through receptor desensitization, while TRPV1 antagonists and siRNA targeting TRPV1 show promise in preclinical studies. Cannabinoid modulation of TRPV1 provides another potential pathway for alleviating neuropathic pain. This review summarizes recent preclinical research on TRPV1 in association with peripheral NeuP.
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Affiliation(s)
- Ning Gao
- Department of Acupuncture and Moxibustion, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Meng Li
- Department of Gastroenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Weiming Wang
- Department of Acupuncture and Moxibustion, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhen Liu
- Department of Gastroenterology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yufeng Guo
- Department of Acupuncture and Moxibustion, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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Wu L, Wang XJ, Luo X, Zhang J, Zhao X, Chen Q. Diabetic peripheral neuropathy based on Schwann cell injury: mechanisms of cell death regulation and therapeutic perspectives. Front Endocrinol (Lausanne) 2024; 15:1427679. [PMID: 39193373 PMCID: PMC11348392 DOI: 10.3389/fendo.2024.1427679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 07/24/2024] [Indexed: 08/29/2024] Open
Abstract
Diabetic peripheral neuropathy (DPN) is a complication of diabetes mellitus that lacks specific treatment, its high prevalence and disabling neuropathic pain greatly affects patients' physical and mental health. Schwann cells (SCs) are the major glial cells of the peripheral nervous system, which play an important role in various inflammatory and metabolic neuropathies by providing nutritional support, wrapping axons and promoting repair and regeneration. Increasingly, high glucose (HG) has been found to promote the progression of DPN pathogenesis by targeting SCs death regulation, thus revealing the specific molecular process of programmed cell death (PCD) in which SCs are disrupted is an important link to gain insight into the pathogenesis of DPN. This paper is the first to review the recent progress of HG studies on apoptosis, autophagy, pyroptosis, ferroptosis and necroptosis pathways in SCs, and points out the crosstalk between various PCDs and the related therapeutic perspectives, with the aim of providing new perspectives for a deeper understanding of the mechanisms of DPN and the exploration of effective therapeutic targets.
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Affiliation(s)
- Lijiao Wu
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiang Jin Wang
- School of Sports Medicine and Health, Chengdu Sports University, Chengdu, China
| | - Xi Luo
- Jiangsu Key Laboratory for Functional Substance of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Jingqi Zhang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyi Zhao
- College of lntegrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Hunan, China
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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11
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Vernì F. Vitamin B6 and diabetes and its role in counteracting advanced glycation end products. VITAMINS AND HORMONES 2024; 125:401-438. [PMID: 38997171 DOI: 10.1016/bs.vh.2024.02.005] [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: 07/14/2024]
Abstract
Naturally occurring forms of vitamin B6 include six interconvertible water-soluble compounds: pyridoxine (PN), pyridoxal (PL), pyridoxamine (PM), and their respective monophosphorylated derivatives (PNP, PLP, and PMP). PLP is the catalytically active form which works as a cofactor in approximately 200 reactions that regulate the metabolism of glucose, lipids, amino acids, DNA, and neurotransmitters. Most of vitamers can counteract the formation of reactive oxygen species and the advanced glycation end-products (AGEs) which are toxic compounds that accumulate in diabetic patients due to prolonged hyperglycemia. Vitamin B6 levels have been inversely associate with diabetes, while vitamin B6 supplementation reduces diabetes onset and its vascular complications. The mechanisms at the basis of the relation between vitamin B6 and diabetes onset are still not completely clarified. In contrast more evidence indicates that vitamin B6 can protect from diabetes complications through its role as scavenger of AGEs. It has been demonstrated that in diabetes AGEs can destroy the functionality of macromolecules such as protein, lipids, and DNA, thus producing tissue damage that result in vascular diseases. AGEs can be in part also responsible for the increased cancer risk associated with diabetes. In this chapter the relationship between vitamin B6, diabetes and AGEs will be discussed by showing the acquired knowledge and questions that are still open.
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Affiliation(s)
- F Vernì
- Department of Biology and Biotechnology "Charles Darwin" Sapienza University of Rome, Rome, Italy.
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12
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Blaibel D, Fernandez CJ, Pappachan JM. Non-pharmacological interventions for diabetic peripheral neuropathy: Are we winning the battle? World J Diabetes 2024; 15:579-585. [PMID: 38680695 PMCID: PMC11045424 DOI: 10.4239/wjd.v15.i4.579] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/18/2024] [Accepted: 03/04/2024] [Indexed: 04/11/2024] Open
Abstract
Despite the advent of relatively reliable modalities of diagnosing diabetic peripheral neuropathy (DPN), such as nerve conduction studies, there is still a knowledge gap about the pathophysiology, and thus limited available interventions for symptom control and curtailing disease progression. The pharmacologic aspect of management is mainly centred on pain control, however, there are several important aspects of DPN such as loss of vibration sense, pressure sense, and proprioception which are associated with risks to lower limb health, which pharmacotherapy does not address. Furthermore, published evidence suggests non-pharmacologic interventions such as glycaemic control through dietary modification and exercise need to be combined with other measures such as psychotherapy, to reach a desired, however modest effect. Acupuncture is emerging as an important treatment modality for several chronic medical conditions including neuropathic and other pain syndromes. In their study published in the World Journal of Diabetes on the potential of acupuncture to reduce DPN symptoms and enhance nerve conduction parameters, Hoerder et al have been able to demonstrate that acupuncture improves sensory function and that this effect is likely sustained two months after treatment cessation. Although previous studies also support these findings, larger multi-center randomized control trials including a sham-controlled arm accounting for a placebo effect are required. Overall, given the satisfactory safety profile and the positive results found in these studies, it is likely that acupuncture may become an important aspect of the repertoire of effective DPN management.
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Affiliation(s)
- Dania Blaibel
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
| | - Cornelius James Fernandez
- Department of Endocrinology & Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, United Kingdom
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine & Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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13
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Araldi D, Khomula EV, Bonet IJM, Bogen O, Green PG, Levine JD. Role of pattern recognition receptors in chemotherapy-induced neuropathic pain. Brain 2024; 147:1025-1042. [PMID: 37787114 PMCID: PMC10907096 DOI: 10.1093/brain/awad339] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 07/25/2023] [Accepted: 09/12/2023] [Indexed: 10/04/2023] Open
Abstract
Progress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment. CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in response to cellular stress and injury, including by chemotherapy drugs. DAMPs, in turn, are ligands for pattern recognition receptors (PRRs), several of which are found on sensory neurons, as well as satellite cells, and cells of the immune system. In the present experiments, we evaluated the role of two PRRs, TLR4 and RAGE, present in dorsal root ganglion (DRG), in CIPN. Antisense (AS)-oligodeoxynucleotides (ODN) against TLR4 and RAGE mRNA were administered intrathecally before ('prevention protocol') or 3 days after ('reversal protocol') the last administration of each of three chemotherapy drugs that treat cancer by different mechanisms (oxaliplatin, paclitaxel and bortezomib). TLR4 and RAGE AS-ODN prevented the development of CIPN induced by all three chemotherapy drugs. In the reversal protocol, however, while TLR4 AS-ODN completely reversed oxaliplatin- and paclitaxel-induced CIPN, in rats with bortezomib-induced CIPN it only produced a temporary attenuation. RAGE AS-ODN, in contrast, reversed CIPN induced by all three chemotherapy drugs. When a TLR4 antagonist was administered intradermally to the peripheral nociceptor terminal, it did not affect CIPN induced by any of the chemotherapy drugs. However, when administered intrathecally, to the central terminal, it attenuated hyperalgesia induced by all three chemotherapy drugs, compatible with a role of TLR4 in neurotransmission at the central terminal but not sensory transduction at the peripheral terminal. Finally, since it has been established that cultured DRG neurons can be used to study direct effects of chemotherapy on nociceptors, we also evaluated the role of TLR4 in CIPN at the cellular level, using patch-clamp electrophysiology in DRG neurons cultured from control and chemotherapy-treated rats. We found that increased excitability of small-diameter DRG neurons induced by in vivo and in vitro exposure to oxaliplatin is TLR4-dependent. Our findings suggest that in addition to the established contribution of PRR-dependent neuroimmune mechanisms, PRRs in DRG cells also have an important role in CIPN.
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Affiliation(s)
- Dionéia Araldi
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Eugen V Khomula
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Ivan J M Bonet
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Oliver Bogen
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Paul G Green
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
- Department of Preventative and Restorative Dental Sciences, Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Jon D Levine
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
- Department of Medicine, Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA
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14
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Yang LY, Tang SC, Lee JE, Chen YR, Chen YT, Chen KW, Hsieh ST, Wang KC. Recombinant soluble form of receptor for advanced glycation end products ameliorates microcirculation impairment and neuroinflammation after subarachnoid hemorrhage. Neurotherapeutics 2024; 21:e00312. [PMID: 38177024 DOI: 10.1016/j.neurot.2023.e00312] [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: 11/30/2023] [Revised: 12/12/2023] [Accepted: 12/15/2023] [Indexed: 01/06/2024] Open
Abstract
Impaired cerebral microcirculation after subarachnoid hemorrhage (SAH) has been shown to be related to delayed ischemic neurological deficits (DIND). We previously demonstrated the involvement of the receptor for advanced glycation end products (RAGE) in the pathogenesis of SAH related neuronal death. In the present study, we aimed to investigate the therapeutic effects of a recombinant soluble form of RAGE (sRAGE) on microcirculation impairment following SAH. Intrathecal injection of autologous blood in rats, mixed primary astrocyte and microglia cultures exposed to hemolysates and endothelial cells (ECs) from human brain microvascular exposed to glia-conditioned medium or SAH patient's CSF were used as experimental SAH models in vivo and in vitro. The results indicated that intrathecal administration of recombinant sRAGE significantly ameliorated the vasoconstriction of cortical arterioles and associated perfusion impairment, brain edema, reduced cell death, endothelial dysfunction, and improved motor performance at 24 and 48 h after SAH induction in rats. The in vitro results further showed that recombinant sRAGE significantly reduced astrocyte swelling and microglia activation, in parallel with decreased mRNA expression levels of pro-inflammatory cytokines including interleukin-6 (IL-6) and interleukin-1β (IL-1β) in vitro. Moreover, the in vitro model of SAH-induced p-eNOS and eNOS suppression, along with stress fiber formation in brain microvascular ECs, was effectively reversed by sRAGE treatment and led to a decrease in cleaved-caspase 3 expression. In summary, recombinant sRAGE effectively lessened microcirculation impairment and vascular injury after SAH via the mechanism of anti-inflammation, which may provide a potential therapeutic strategy for SAH.
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Affiliation(s)
- Ling-Yu Yang
- Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sung-Chun Tang
- Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Jing-Er Lee
- Department of Neurology, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan
| | - Yong-Ren Chen
- Non-invasive Cancer Therapy Research Institute, Taipei, Taiwan; Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital Jin-Shan Branch, New Taipei City, Taiwan
| | - Yi-Tzu Chen
- Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuo-Wei Chen
- Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sung-Tsang Hsieh
- Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan; Department of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Kuo-Chuan Wang
- Division of Neurosurgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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15
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Liu C, Wu T, Ren N. Glucagon-like peptide-1 receptor agonists for the management of diabetic peripheral neuropathy. Front Endocrinol (Lausanne) 2024; 14:1268619. [PMID: 38313844 PMCID: PMC10836428 DOI: 10.3389/fendo.2023.1268619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 12/27/2023] [Indexed: 02/06/2024] Open
Abstract
Diabetes mellitus is a prevalent chronic disease characterized by hyperglycemia. Diabetic peripheral neuropathy (DPN) is one of the complications of diabetes mellitus and is caused by neuron injury induced by hyperglycemic circumstances. The incidence of DPN varies among different countries and regions, ranging from nearly 20% to over 70%. Patients with DPN may encounter symmetric pain or discomfort of the extremes, leading to reduced quality of life and even amputation. The pharmacological management for painful DPN mainly includes antidepressants due to their analgesic effects. Nevertheless, effective therapies to impact the pathogenesis and progression of DPN are lacking. Glucagon-like peptide-1 receptor (GLP-1R) agonists show efficacy in controlling blood glucose and serve as a treatment modality for diabetes mellitus. In recent years, evidence has been proposed that GLP-1R agonists exert neuroprotective effects through modulating inflammation, oxidative stress, and mitochondrial dysfunction. On the other hand, clinical evidence on the potential of GLP-1R agonists for treating DPN is still controversial and limited. This narrative review summarizes the preclinical and clinical studies investigating the capacity of GLP-1R agonists as therapeutic agents for DPN.
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Affiliation(s)
- Chunyan Liu
- Department of Endocrinology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Tianqiang Wu
- Department of Integrated Traditional Chinese and Western Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Na Ren
- Department of Endocrinology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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16
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Singh P, Sharma S, Sharma PK, Alam A. Topical Anti-ulcerogenic Effect of the Beta-adrenergic Blockers on Diabetic Foot Ulcers: Recent Advances and Future Prospectives. Curr Diabetes Rev 2024; 20:23-37. [PMID: 37867269 DOI: 10.2174/0115733998249061231009093006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/01/2023] [Accepted: 08/25/2023] [Indexed: 10/24/2023]
Abstract
BACKGROUND Patients with diabetes suffer from major complications like Diabetic Retinopathy, Diabetic Coronary Artery Disease, and Diabetic Foot ulcers (DFUs). Diabetes complications are a group of ailments whose recovery time is especially delayed, irrespective of the underlying reason. The longer duration of wound healing enhances the probability of problems like sepsis and amputation. The delayed healing makes it more critical for research focus. By understanding the molecular pathogenesis of diabetic wounds, it is quite easy to target the molecules involved in the healing of wounds. Recent research on beta-adrenergic blocking drugs has revealed that these classes of drugs possess therapeutic potential in the healing of DFUs. However, because the order of events in defective healing is adequately defined, it is possible to recognize moieties that are currently in the market that are recognized to aim at one or several identified molecular processes. OBJECTIVE The aim of this study was to explore some molecules with different therapeutic categories that have demonstrated favorable effects in improving diabetic wound healing, also called the repurposing of drugs. METHOD Various databases like PubMed/Medline, Google Scholar and Web of Science (WoS) of all English language articles were searched, and relevant information was collected regarding the role of beta-adrenergic blockers in diabetic wounds or diabetic foot ulcers (DFUs) using the relevant keywords for the literature review. RESULT The potential beta-blocking agents and their mechanism of action in diabetic foot ulcers were studied, and it was found that these drugs have a profound effect on diabetic foot ulcer healing as per reported literatures. CONCLUSION There is a need to move forward from preclinical studies to clinical studies to analyze clinical findings to determine the effectiveness and safety of some beta-antagonists in diabetic foot ulcer treatment.
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Affiliation(s)
- Prateek Singh
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Shweta Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Aftab Alam
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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17
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Singh L, Kaur H, Chandra Arya G, Bhatti R. Neuroprotective potential of formononetin, a naturally occurring isoflavone phytoestrogen. Chem Biol Drug Des 2024; 103:e14353. [PMID: 37722967 DOI: 10.1111/cbdd.14353] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/17/2023] [Accepted: 09/04/2023] [Indexed: 09/20/2023]
Abstract
The increased prevalence of neurological illnesses is a burgeoning challenge to the public healthcare system and presents greater financial pressure. Formononetin, an O-methylated isoflavone, has gained a lot of attention due to its neuroprotective potential explored in several investigations. Formononetin is widely found in legumes and several types of clovers including Trifolium pratense L., Astragalus membranaceus, Sophora tomentosa, etc. Formononetin modulates various endogenous mediators to confer neuroprotection. It prevents RAGE activation that results in the inhibition of neuronal damage via downregulating the level of ROS and proinflammatory cytokines. Furthermore, formononetin also increases the expression of ADAM-10, which affects the pathology of neurodegenerative disease by lowering tau phosphorylation, maintaining synaptic plasticity, and boosting hippocampus neurogenesis. Besides these, formononetin also increases the expression of antioxidants, Nrf-2, PI3K, ApoJ, and LRP1. Whereas, reduces the expression of p65-NF-κB and proinflammatory cytokines. It also inhibits the deposition of Aβ and MAO-B activity. An inhibition of Aβ/RAGE-induced activation of MAPK and NOX governs the protection elicited by formononetin against inflammatory and oxidative stress-induced neuronal damage. Besides this, PI3K/Akt and ER-α-mediated activation of ADAM10, ApoJ/LRP1-mediated clearance of Aβ, and MAO-B inhibition-mediated preservation of dopaminergic neurons integrity are the major modulations produced by formononetin. This review covers the biosynthesis of formononetin and key molecular pathways modulated by formononetin to confer neuroprotection.
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Affiliation(s)
- Lovedeep Singh
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
- University Institute of Pharma Sciences, Chandigarh University, Mohali, India
| | - Harpreet Kaur
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | - Girish Chandra Arya
- University Institute of Pharma Sciences, Chandigarh University, Mohali, India
| | - Rajbir Bhatti
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
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18
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Jiang S, Xia N, Buonfiglio F, Böhm EW, Tang Q, Pfeiffer N, Olinger D, Li H, Gericke A. High-fat diet causes endothelial dysfunction in the mouse ophthalmic artery. Exp Eye Res 2024; 238:109727. [PMID: 37972749 DOI: 10.1016/j.exer.2023.109727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/27/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
Obesity is a significant health concern that leads to impaired vascular function and subsequent abnormalities in various organs. The impact of obesity on ocular blood vessels, however, remains largely unclear. In this study, we examined the hypothesis that obesity induced by high-fat diet produces vascular endothelial dysfunction in the ophthalmic artery. Mice were subjected to a high-fat diet for 20 weeks, while age-matched controls were maintained on a standard diet. Reactivity of isolated ophthalmic artery segments was assessed in vitro. Reactive oxygen species (ROS) were quantified in cryosections by dihydroethidium (DHE) staining. Redox gene expression was determined in ophthalmic artery explants by real-time PCR. Furthermore, the expression of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), the receptor for advanced glycation end products (RAGE), and of the lectin-like oxidized low-density-lipoprotein receptor-1 (LOX-1) was determined in cryosections using immunofluorescence microscopy. Ophthalmic artery segments from mice on a high-fat diet exhibited impaired vasodilation responses to the endothelium-dependent vasodilator acetylcholine, while endothelium-independent responses to nitroprusside remained preserved. DHE staining intensity in the vascular wall was notably stronger in mice on a high-fat diet. Messenger RNA expression for NOX2 was elevated in the ophthalmic artery of mice subjected to high fat diet. Likewise, immunostainings revealed increased expression of NOX2 and of RAGE, but not of LOX-1. These findings suggest that a high-fat diet triggers endothelial dysfunction by inducing oxidative stress in the ophthalmic artery via involvement of RAGE and NOX2.
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Affiliation(s)
- Subao Jiang
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Ning Xia
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Elsa W Böhm
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Qi Tang
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Norbert Pfeiffer
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Dominik Olinger
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Huige Li
- Department of Pharmacology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131, Mainz, Germany.
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19
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Cheng W, Cai C, Xu Y, Xiao X, Shi T, Liao Y, Wang X, Chen S, Zhou M, Liao Z. The TRIM21-FOXD1-BCL-2 axis underlies hyperglycaemic cell death and diabetic tissue damage. Cell Death Dis 2023; 14:825. [PMID: 38092733 PMCID: PMC10719266 DOI: 10.1038/s41419-023-06355-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 11/26/2023] [Accepted: 11/30/2023] [Indexed: 12/17/2023]
Abstract
Chronic hyperglycaemia is a devastating factor that causes diabetes-induced damage to the retina and kidney. However, the precise mechanism by which hyperglycaemia drives apoptotic cell death is incompletely known. Herein, we found that FOXD1, a FOX family transcription factor specifically expressed in the retina and kidney, regulated the transcription of BCL-2, a master regulator of cell survival. Intriguingly, the protein level of FOXD1, which responded negatively to hyperglycaemic conditions, was controlled by the TRIM21-mediated K48-linked polyubiquitination and subsequent proteasomal degradation. The TRIM21-FOXD1-BCL-2 signalling axis was notably active during diabetes-induced damage to murine retinal and renal tissues. Furthermore, we found that tartary buckwheat flavonoids effectively reversed the downregulation of FOXD1 protein expression and thus restored BCL-2 expression and facilitated the survival of retinal and renal tissues. In summary, we identified a transcription factor responsible for BCL-2 expression, a signalling axis (TRM21-FOXD1-BCL-2) underlying hyperglycaemia-triggered apoptosis, and a potential treatment for deleterious diabetic complications.
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Affiliation(s)
- Wenwen Cheng
- College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Cifeng Cai
- College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Yifan Xu
- College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Xueqi Xiao
- College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Tiantian Shi
- College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Yueling Liao
- College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China
| | - Xiaoyi Wang
- First Affiliated Hospital of Huzhou University, Huzhou, 313000, China
| | - Shasha Chen
- College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China.
| | - Meiliang Zhou
- Institute of Crop Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.
| | - Zhiyong Liao
- College of Life and Environmental Science, Wenzhou University, Wenzhou, 325035, China.
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20
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Horvat A, Vlašić I, Štefulj J, Oršolić N, Jazvinšćak Jembrek M. Flavonols as a Potential Pharmacological Intervention for Alleviating Cognitive Decline in Diabetes: Evidence from Preclinical Studies. Life (Basel) 2023; 13:2291. [PMID: 38137892 PMCID: PMC10744738 DOI: 10.3390/life13122291] [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: 09/30/2023] [Revised: 11/15/2023] [Accepted: 11/24/2023] [Indexed: 12/24/2023] Open
Abstract
Diabetes mellitus is a complex metabolic disease associated with reduced synaptic plasticity, atrophy of the hippocampus, and cognitive decline. Cognitive impairment results from several pathological mechanisms, including increased levels of advanced glycation end products (AGEs) and their receptors, prolonged oxidative stress and impaired activity of endogenous mechanisms of antioxidant defense, neuroinflammation driven by the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), decreased expression of brain-derived neurotrophic factor (BDNF), and disturbance of signaling pathways involved in neuronal survival and cognitive functioning. There is increasing evidence that dietary interventions can reduce the risk of various diabetic complications. In this context, flavonols, a highly abundant class of flavonoids in the human diet, are appreciated as a potential pharmacological intervention against cognitive decline in diabetes. In preclinical studies, flavonols have shown neuroprotective, antioxidative, anti-inflammatory, and memory-enhancing properties based on their ability to regulate glucose levels, attenuate oxidative stress and inflammation, promote the expression of neurotrophic factors, and regulate signaling pathways. The present review gives an overview of the molecular mechanisms involved in diabetes-induced cognitive dysfunctions and the results of preclinical studies showing that flavonols have the ability to alleviate cognitive impairment. Although the results from animal studies are promising, clinical and epidemiological studies are still needed to advance our knowledge on the potential of flavonols to improve cognitive decline in diabetic patients.
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Affiliation(s)
- Anđela Horvat
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
| | - Ignacija Vlašić
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
| | - Jasminka Štefulj
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
- Department of Psychology, Catholic University of Croatia, Ilica 242, 10000 Zagreb, Croatia
| | - Nada Oršolić
- Division of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10000 Zagreb, Croatia
| | - Maja Jazvinšćak Jembrek
- Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
- Department of Psychology, Catholic University of Croatia, Ilica 242, 10000 Zagreb, Croatia
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21
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Ghaderpour S, Keyhanmanesh R, Hamidian G, Heydari H, Ghiasi F. The effects of voluntary exercise on histological and stereological changes of sciatic nerve, nitric oxide levels, and peripheral neuropathy caused by high-fat diet-induced type 2 diabetes in male rats. Behav Brain Res 2023; 451:114507. [PMID: 37236269 DOI: 10.1016/j.bbr.2023.114507] [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: 11/03/2022] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 05/28/2023]
Abstract
This research was conducted to investigate the possible beneficial impacts of voluntary exercise on sciatic tissue, nitric oxide levels, stereological changes, and peripheral neuropathy caused by "high-fat-diet (HFD)"-induced "type 2 diabetes mellitus (T2DM)" in male rats. Rats were put into four experimental groups at random: "healthy control (C), voluntary exercise (VE), diabetic (D), and diabetic rats treated by voluntary exercise (VED)"; each group contain eight animals. Animals in VE and VED groups performed "voluntary exercise (VE)" for ten weeks. Animals in D and VED groups became diabetic after receiving a HFD for four weeks and an intraperitoneal injection (IP) of "streptozotocin (STZ)" (35 mg/kg). In order to evaluate mechanical and thermal algesia, hot plate, tail withdrawal, and von Frey tests were carried out. At the end of this study, serum NOx levels were assessed, and histological and stereological analyses were conducted. Mechanical nociceptive thresholds indicated considerable reduction (p < 0.001) which was followed by a remarkable enhance (p < 0.001) in thermal nociceptive threshold of D group. Tissue changes were also seen in sciatic nerve of D group. Voluntary exercise modified thermal and mechanical sensitivity in diabetic rats. It also improved the damaged sciatic nerve in diabetic animals.
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Affiliation(s)
- Saber Ghaderpour
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rana Keyhanmanesh
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gholamreza Hamidian
- Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Hamed Heydari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fariba Ghiasi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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22
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Urbano F, Farella I, Brunetti G, Faienza MF. Pediatric Type 1 Diabetes: Mechanisms and Impact of Technologies on Comorbidities and Life Expectancy. Int J Mol Sci 2023; 24:11980. [PMID: 37569354 PMCID: PMC10418611 DOI: 10.3390/ijms241511980] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases in childhood, with a progressively increasing incidence. T1D management requires lifelong insulin treatment and ongoing health care support. The main goal of treatment is to maintain blood glucose levels as close to the physiological range as possible, particularly to avoid blood glucose fluctuations, which have been linked to morbidity and mortality in patients with T1D. Indeed, the guidelines of the International Society for Pediatric and Adolescent Diabetes (ISPAD) recommend a glycated hemoglobin (HbA1c) level < 53 mmol/mol (<7.0%) for young people with T1D to avoid comorbidities. Moreover, diabetic disease strongly influences the quality of life of young patients who must undergo continuous monitoring of glycemic values and the administration of subcutaneous insulin. In recent decades, the development of automated insulin delivery (AID) systems improved the metabolic control and the quality of life of T1D patients. Continuous subcutaneous insulin infusion (CSII) combined with continuous glucose monitoring (CGM) devices connected to smartphones represent a good therapeutic option, especially in young children. In this literature review, we revised the mechanisms of the currently available technologies for T1D in pediatric age and explored their effect on short- and long-term diabetes-related comorbidities, quality of life, and life expectation.
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Affiliation(s)
- Flavia Urbano
- Giovanni XXIII Pediatric Hospital, 70126 Bari, Italy;
| | - Ilaria Farella
- Clinica Medica “A. Murri”, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies, and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy
| | - Maria Felicia Faienza
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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23
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Bowen DR, Pathak S, Nadar RM, Parise RD, Ramesh S, Govindarajulu M, Moore A, Ren J, Moore T, Dhanasekaran M. Oxidative stress and COVID-19-associated neuronal dysfunction: mechanisms and therapeutic implications. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1153-1167. [PMID: 37357527 PMCID: PMC10465323 DOI: 10.3724/abbs.2023085] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 02/09/2023] [Indexed: 06/27/2023] Open
Abstract
Severe acute respiratory syndrome (SARS)-CoV-2 virus causes novel coronavirus disease 2019 (COVID-19), and there is a possible role for oxidative stress in the pathophysiology of neurological diseases associated with COVID-19. Excessive oxidative stress could be responsible for the thrombosis and other neuronal dysfunctions observed in COVID-19. This review discusses the role of oxidative stress associated with SARS-CoV-2 and the mechanisms involved. Furthermore, the various therapeutics implicated in treating COVID-19 and the oxidative stress that contributes to the etiology and pathogenesis of COVID-19-induced neuronal dysfunction are discussed. Further mechanistic and clinical research to combat COVID-19 is warranted to understand the exact mechanisms, and its true clinical effects need to be investigated to minimize neurological complications from COVID-19.
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Affiliation(s)
- Dylan R. Bowen
- Department of Drug Discovery and DevelopmentHarrison College of PharmacyAuburn UniversityAuburn-AL36849USA
| | - Suhrud Pathak
- Department of Drug Discovery and DevelopmentHarrison College of PharmacyAuburn UniversityAuburn-AL36849USA
| | - Rishi M. Nadar
- Department of Drug Discovery and DevelopmentHarrison College of PharmacyAuburn UniversityAuburn-AL36849USA
| | - Rachel D. Parise
- Department of Drug Discovery and DevelopmentHarrison College of PharmacyAuburn UniversityAuburn-AL36849USA
| | - Sindhu Ramesh
- Department of Drug Discovery and DevelopmentHarrison College of PharmacyAuburn UniversityAuburn-AL36849USA
| | - Manoj Govindarajulu
- Department of Drug Discovery and DevelopmentHarrison College of PharmacyAuburn UniversityAuburn-AL36849USA
| | - Austin Moore
- Department of Drug Discovery and DevelopmentHarrison College of PharmacyAuburn UniversityAuburn-AL36849USA
| | - Jun Ren
- Department of CardiologyZhongshan Hospital Fudan UniversityShanghai200032China
- Department of Laboratory Medicine and PathologyUniversity of WashingtonSeattleWA98195USA
| | - Timothy Moore
- Department of Drug Discovery and DevelopmentHarrison College of PharmacyAuburn UniversityAuburn-AL36849USA
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24
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Galiero R, Caturano A, Vetrano E, Beccia D, Brin C, Alfano M, Di Salvo J, Epifani R, Piacevole A, Tagliaferri G, Rocco M, Iadicicco I, Docimo G, Rinaldi L, Sardu C, Salvatore T, Marfella R, Sasso FC. Peripheral Neuropathy in Diabetes Mellitus: Pathogenetic Mechanisms and Diagnostic Options. Int J Mol Sci 2023; 24:ijms24043554. [PMID: 36834971 PMCID: PMC9967934 DOI: 10.3390/ijms24043554] [Citation(s) in RCA: 63] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/01/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Diabetic neuropathy (DN) is one of the main microvascular complications of both type 1 and type 2 diabetes mellitus. Sometimes, this could already be present at the time of diagnosis for type 2 diabetes mellitus (T2DM), while it appears in subjects with type 1 diabetes mellitus (T1DM) almost 10 years after the onset of the disease. The impairment can involve both somatic fibers of the peripheral nervous system, with sensory-motor manifestations, as well as the autonomic system, with neurovegetative multiorgan manifestations through an impairment of sympathetic/parasympathetic conduction. It seems that, both indirectly and directly, the hyperglycemic state and oxygen delivery reduction through the vasa nervorum can determine inflammatory damage, which in turn is responsible for the alteration of the activity of the nerves. The symptoms and signs are therefore various, although symmetrical painful somatic neuropathy at the level of the lower limbs seems the most frequent manifestation. The pathophysiological aspects underlying the onset and progression of DN are not entirely clear. The purpose of this review is to shed light on the most recent discoveries in the pathophysiological and diagnostic fields concerning this complex and frequent complication of diabetes mellitus.
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Affiliation(s)
- Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Erica Vetrano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Domenico Beccia
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Chiara Brin
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Maria Alfano
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Jessica Di Salvo
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Raffaella Epifani
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Alessia Piacevole
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Giuseppina Tagliaferri
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Maria Rocco
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Ilaria Iadicicco
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Giovanni Docimo
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Teresa Salvatore
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, I-80138 Naples, Italy
- Correspondence: ; Tel.: +39-08-1566-5010
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25
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Balkrishna A, Pathak R, Bhatt S, Arya V. Molecular Insights of Plant Phytochemicals Against Diabetic Neuropathy. Curr Diabetes Rev 2023; 19:e250822207994. [PMID: 36028963 DOI: 10.2174/1573399819666220825124510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/23/2022] [Accepted: 04/26/2022] [Indexed: 11/22/2022]
Abstract
Diabetes and its associated complications including diabetic neuropathy have become a menacing headache for health workers and scientists all over the world. The number of diabetic individuals has been growing exponentially every day while the entire medical fraternity feels crippled and unable to handle such an enormous and anarchical scenario. The disease also demonstrates itself in the patients in numerous ways ranging from a little discomfort to death. Diabetic neuropathy has a poor prognosis since it might go unnoticed for years after the onset of diabetes. The etiology of the disease has been linked to oxidative stress caused by increased free radical production. Hyperglycemia causes multiple metabolic pathways to be activated, as well as significant oxidative stress, which becomes the major cause of cell death, culminating in Diabetic Neuropathy. So, it is the need of the hour to find out permanent treatment for this life-threatening disease. The primary goal of this study is to emphasize the potential importance of numerous processes and pathways in the development of diabetic neuropathy as well as the possible role of plant metabolites to control the disease at a molecular level. A possible mechanism was also summarized in the study about scavenging the reactive oxygen species by a flavonoid component. The study also covered the in vivo data of various plants and some of the flavonoid compounds actively studied against Diabetic Neuropathy by inhibiting or reducing the contributing factors such as proinflammatory cytokines, ROS, RNS inhibition, and upregulating the various cellular antioxidants such as GSH, SOD, and CAT.
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Affiliation(s)
- Acharya Balkrishna
- Department of Patanjali Herbal Research, Patanjali Research Institute, Haridwar-249405, Uttarakhand, India
| | - Rakshit Pathak
- Department of Patanjali Herbal Research, Patanjali Research Institute, Haridwar-249405, Uttarakhand, India
| | - Shalini Bhatt
- Department of Patanjali Herbal Research, Patanjali Research Institute, Haridwar-249405, Uttarakhand, India
| | - Vedpriya Arya
- Department of Patanjali Herbal Research, Patanjali Research Institute, Haridwar-249405, Uttarakhand, India
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26
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Dai Y, Lin J, Ren J, Zhu B, Wu C, Yu L. NAD + metabolism in peripheral neuropathic pain. Neurochem Int 2022; 161:105435. [PMID: 36273706 DOI: 10.1016/j.neuint.2022.105435] [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: 04/17/2022] [Revised: 10/04/2022] [Accepted: 10/16/2022] [Indexed: 11/07/2022]
Abstract
Nicotinamide adenine dinucleotide (NAD+) is an omnipresent metabolite that participates in redox reactions. Multiple NAD+-consuming enzymes are implicated in numerous biological processes, including transcription, signaling, and cell survival. Multiple pieces of evidence have demonstrated that NAD+-consuming enzymes, including poly(ADP-ribose) polymerases (PARPs), sirtuins (SIRTs), and sterile alpha and TIR motif-containing 1 (SARM1), play major roles in peripheral neuropathic pain of various etiologies. These NAD+ consumers primarily participate in peripheral neuropathic pain via mechanisms such as mitochondrial dysfunction, oxidative stress, and inflammation. Furthermore, NAD+ synthase and nicotinamide phosphoribosyltransferase (NAMPT) have recently been found to contribute to the regulation of pain. Here, we review the evidence indicating the involvement of NAD+ metabolism in the pathological mechanisms of peripheral neuropathic pain. Advanced understanding of the molecular and cellular mechanisms associated with NAD+ in peripheral neuropathic pain will facilitate the development of novel treatment options for diverse types of peripheral neuropathic pain.
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Affiliation(s)
- Yi Dai
- Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, PR China
| | - Jiaqi Lin
- Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, PR China
| | - Jinxuan Ren
- Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, PR China
| | - Bin Zhu
- Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, PR China
| | - Chengwei Wu
- Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, PR China
| | - Lina Yu
- Department of Anesthesiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310009, PR China.
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27
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Martens GA, Geßner C, Osterhof C, Hankeln T, Burmester T. Transcriptomes of Clusterin- and S100B-transfected neuronal cells elucidate protective mechanisms against hypoxia and oxidative stress in the hooded seal (Cystophora cristata) brain. BMC Neurosci 2022; 23:59. [PMID: 36243678 PMCID: PMC9571494 DOI: 10.1186/s12868-022-00744-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 10/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The hooded seal (Cystophora cristata) exhibits impressive diving skills and can tolerate extended durations of asphyxia, hypoxia and oxidative stress, without suffering from irreversible neuronal damage. Thus, when exposed to hypoxia in vitro, neurons of fresh cortical and hippocampal tissue from hooded seals maintained their membrane potential 4-5 times longer than neurons of mice. We aimed to identify the molecular mechanisms underlying the intrinsic neuronal hypoxia tolerance. Previous comparative transcriptomics of the visual cortex have revealed that S100B and clusterin (apolipoprotein J), two stress proteins that are involved in neurological disorders characterized by hypoxic conditions, have a remarkably high expression in hooded seals compared to ferrets. When overexpressed in murine neuronal cells (HN33), S100B and clusterin had neuroprotective effects when cells were exposed to hypoxia. However, their specific roles in hypoxia have remained largely unknown. METHODS In order to shed light on potential molecular pathways or interaction partners, we exposed HN33 cells transfected with either S100B, soluble clusterin (sCLU) or nuclear clusterin (nCLU) to normoxia, hypoxia and oxidative stress for 24 h. We then determined cell viability and compared the transcriptomes of transfected cells to control cells. Potential pathways and upstream regulators were identified via Gene Ontology (GO) and Ingenuity Pathway Analysis (IPA). RESULTS HN33 cells transfected with sCLU and S100B demonstrated improved glycolytic capacity and reduced aerobic respiration at normoxic conditions. Additionally, sCLU appeared to enhance pathways for cellular homeostasis to counteract stress-induced aggregation of proteins. S100B-transfected cells sustained lowered energy-intensive synaptic signaling. In response to hypoxia, hypoxia-inducible factor (HIF) pathways were considerably elevated in nCLU- and sCLU-transfected cells. In a previous study, S100B and sCLU decreased the amount of reactive oxygen species and lipid peroxidation in HN33 cells in response to oxidative stress, but in the present study, these functional effects were not mirrored in gene expression changes. CONCLUSIONS sCLU and S100B overexpression increased neuronal survival by decreasing aerobic metabolism and synaptic signaling in advance to hypoxia and oxidative stress conditions, possibly to reduce energy expenditure and the build-up of deleterious reactive oxygen species (ROS). Thus, a high expression of CLU isoforms and S100B is likely beneficial during hypoxic conditions.
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Affiliation(s)
- Gerrit A Martens
- Institute of Animal Cell and Systems Biology, Biocenter Grindel, University of Hamburg, 20146, Hamburg, Germany.
| | - Cornelia Geßner
- Institute of Animal Cell and Systems Biology, Biocenter Grindel, University of Hamburg, 20146, Hamburg, Germany
| | - Carina Osterhof
- Institute of Organismic and Molecular Evolution, Molecular Genetics & Genome Analysis, Johannes Gutenberg University Mainz, 55128, Mainz, Germany
| | - Thomas Hankeln
- Institute of Organismic and Molecular Evolution, Molecular Genetics & Genome Analysis, Johannes Gutenberg University Mainz, 55128, Mainz, Germany
| | - Thorsten Burmester
- Institute of Animal Cell and Systems Biology, Biocenter Grindel, University of Hamburg, 20146, Hamburg, Germany
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28
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Luo J, Zhu HQ, Gou B, Zheng YL. Mechanisms of exercise for diabetic neuropathic pain. Front Aging Neurosci 2022; 14:975453. [PMID: 36313015 PMCID: PMC9605799 DOI: 10.3389/fnagi.2022.975453] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/08/2022] [Indexed: 11/25/2022] Open
Abstract
Diabetic neuropathic pain (DNP) is a common disease that affects the daily lives of diabetic patients, and its incidence rate is very high worldwide. At present, drug and exercise therapies are common treatments for DNP. Drug therapy has various side effects. In recent years, exercise therapy has received frequent research and increasing attention by many researchers. Currently, the treatment of DNP is generally symptomatic. We can better select the appropriate exercise prescription for DNP only by clarifying the exercise mechanism for its therapy. The unique pathological mechanism of DNP is still unclear and may be related to the pathological mechanism of diabetic neuropathy. In this study, the mechanisms of exercise therapy for DNP were reviewed to understand better the role of exercise therapy in treating DNP.
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Affiliation(s)
- Jing Luo
- Department of Sport Rehabilitation, Xian Physical Education University, Xian, China
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
| | - Hui-Qi Zhu
- College of Kinesiology, Shenyang Sport University, Shenyang, China
| | - Bo Gou
- Department of Sport Rehabilitation, Xian Physical Education University, Xian, China
- *Correspondence: Bo Gou,
| | - Yi-Li Zheng
- Department of Sport Rehabilitation, Shanghai University of Sport, Shanghai, China
- *Correspondence: Bo Gou,
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29
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Haddad M, Eid S, Harb F, Massry MEL, Azar S, Sauleau EA, Eid AA. Activation of 20-HETE Synthase Triggers Oxidative Injury and Peripheral Nerve Damage in Type 2 Diabetic Mice. THE JOURNAL OF PAIN 2022; 23:1371-1388. [PMID: 35339661 DOI: 10.1016/j.jpain.2022.02.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 01/26/2022] [Accepted: 02/24/2022] [Indexed: 12/13/2022]
Abstract
Diabetic Peripheral Neuropathy (DPN), highly prevalent among patients with diabetes, is characterized by peripheral nerve dysfunction. Reactive Oxygen Species (ROS) overproduction has been suggested to orchestrate diabetic complications including DPN. Untargeted antioxidant therapy has exhibited limited efficacy, highlighting a critical need to explore ROS sources altered in a cell-specific manner in DPN. Cytochromes P450 (CYP) enzymes are prominent sources of ROS. Particularly, the 20-HETE synthase, CYP4A, is reported to mediate diabetes-induced renal, retinal, and cardiovascular injuries. This work investigates the role of CYP4A/20-HETE in DPN and their mechanisms of action. Non-obese type 2 Diabetic mice (MKR) were used and treated with a CYP4A-inhibitor (HET0016) or AMPK-activator (Metformin). Peripheral nerves of MKR mice reflect increased CYP4A and 20-HETE levels, concurrent with altered myelin proteins and sensorimotor deficits. This was associated with increased ROS production and altered Beclin-1 and LC3 protein levels, indicative of disrupted autophagic responses in tandem with AMPK inactivation. AMPK activation via Metformin restored nerve integrity, reduced ROS production, and regulated autophagy. Interestingly, similar outcomes were revealed upon HET0016 treatment whereby ROS production, autophagic responses, and AMPK signaling were normalized in diabetic mice. Altogether, the results highlight hyperglycemia-mediated oxidative injury in DPN through a novel CYP4A/20-HETE/AMPK pathological axis. PERSPECTIVE: To our knowledge, this is the first study to highlight the role of CYPs/20-HETE-induced oxidative injury in the pathogenesis of diabetic peripheral neuropathy. Targeting the identified pathological axis CYP4A/20-HETE/AMPK may be of clinical potential in predicting and alleviating peripheral nerve injury in patients with Type 2 Diabetes Mellitus.
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Affiliation(s)
- Mary Haddad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; Department of Biostatistics, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7357 ICube, University of Strasbourg, Strasbourg, France
| | - Stéphanie Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Frederic Harb
- Department of Life and Earth Sciences, Faculty of Sciences, Lebanese University, Fanar, Lebanon
| | - Mohamed E L Massry
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon
| | - Sami Azar
- Department of Internal Medicine, Division of Diabetes and Endocrinology, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; AUB Diabetes, American University of Beirut, Beirut, Lebanon
| | - Erik-Andre Sauleau
- Department of Biostatistics, Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 7357 ICube, University of Strasbourg, Strasbourg, France
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon; AUB Diabetes, American University of Beirut, Beirut, Lebanon.
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30
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Pathak R, Sachan N, Chandra P. Mechanistic approach towards diabetic neuropathy screening techniques and future challenges: A review. Biomed Pharmacother 2022; 150:113025. [PMID: 35658222 DOI: 10.1016/j.biopha.2022.113025] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/16/2022] [Accepted: 04/20/2022] [Indexed: 11/24/2022] Open
Abstract
Diabetic neuropathy, also called peripheral diabetic neuropathy (PDN), is among the most significant diabetes health consequences, alongside diabetic nephropathy, diabetic cardiomyopathy and diabetic retinopathy. Diabetic neuropathy is the existence of signs and indications of peripheral nerve damage in patients with diabetes after other causes have been governed out. Diabetic neuropathy is a painful and severe complication of diabetes that affects roughly 20% of people. The development of diabetic neuropathy is regulated by blood arteries that nourish the peripheral nerves and metabolic problems such as increased stimulation of polyol pathway, loss of myo-inositol and enhanced non-enzymatic glycation. It's divided into four types based on where neurons are most affected: autonomic, peripheral, proximal, and focal, with each kind presenting different symptoms like numbing, gastrointestinal disorders, and heart concerns. Pharmacotherapy for neuropathic pain is complex and for many patients, effective treatment is lacking; as a result, scientific proof recommendations are crucial. As a result, the current demand is to give the most vital medications or combinations of drugs that work directly on the nerves to help diabetic neuropathy patients feel less pain without causing any adverse effects. In diabetic neuropathy research, animal models are ubiquitous, with rats and mice being the most typically chosen for various reasons. This review covers the epidemiology, clinical features, pathology, clinical symptom, mechanism of diabetic neuropathy development, diagnosis, screening models of animals, diabetic neuropathy pharmacotherapy.
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Affiliation(s)
- Rashmi Pathak
- School of Pharmaceutical Sciences, IFTM University, Lodhipur Rajput Delhi Road (NH-24), Moradabad, UP 244102, India
| | - Neetu Sachan
- School of Pharmaceutical Sciences, IFTM University, Lodhipur Rajput Delhi Road (NH-24), Moradabad, UP 244102, India
| | - Phool Chandra
- School of Pharmaceutical Sciences, IFTM University, Lodhipur Rajput Delhi Road (NH-24), Moradabad, UP 244102, India.
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31
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Zhang Y, Li F, Chen C, Li Y, Xie W, Huang D, Zhai X, Yu W, Wan J, Li P. RAGE-mediated T cell metabolic reprogramming shapes T cell inflammatory response after stroke. J Cereb Blood Flow Metab 2022; 42:952-965. [PMID: 34910890 PMCID: PMC9125488 DOI: 10.1177/0271678x211067133] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 10/26/2021] [Accepted: 11/26/2021] [Indexed: 11/16/2022]
Abstract
The metabolic reprogramming of peripheral CD4+ T cells that occurs after stroke can lead to imbalanced differentiation of CD4+ T cells, including regulation of T cells, and presents a promising target for poststroke immunotherapy. However, the regulatory mechanism underlying the metabolic reprogramming of peripheral CD4+ T cell remains unknown. In this study, using combined transcription and metabolomics analyses, flow cytometry, and conditional knockout mice, we demonstrate that the receptor for advanced glycation end products (RAGE) can relay the ischemic signal to CD4+ T cells, which underwent acetyl coenzyme A carboxylase 1(ACC1)-dependent metabolic reprogramming after stroke. Furthermore, by administering soluble RAGE (sRAGE) after stroke, we demonstrate that neutralization of RAGE reversed the enhanced fatty acid synthesis of CD4+ T cells and the post-stroke imbalance of Treg/Th17. Finally, we found that post-stroke sRAGE treatment protected against infarct volume and ameliorated functional recovery. In conclusion, sRAGE can serve as a novel immunometabolic modulator that ameliorates ischemic stroke recovery by inhibiting fatty acid synthesis and thus favoring CD4+ T cells polarization toward Treg after cerebral ischemia injury. The above findings provide new insights for the treatment of neuroinflammatory responses after ischemia stroke.
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Affiliation(s)
- Yueman Zhang
- Department of Anesthesiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fengshi Li
- Department of Neurological Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen Chen
- Department of Anesthesiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Li
- Department of Anesthesiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wanqing Xie
- Department of Anesthesiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Dan Huang
- Department of Anesthesiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaozhu Zhai
- Department of Anesthesiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weifeng Yu
- Department of Anesthesiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jieqing Wan
- Department of Neurological Surgery, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peiying Li
- Department of Anesthesiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Sbai O, Djelloul M, Auletta A, Ieraci A, Vascotto C, Perrone L. AGE-TXNIP axis drives inflammation in Alzheimer's by targeting Aβ to mitochondria in microglia. Cell Death Dis 2022; 13:302. [PMID: 35379773 PMCID: PMC8980056 DOI: 10.1038/s41419-022-04758-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 03/01/2022] [Accepted: 03/16/2022] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) is the most common form of dementia characterized by progressive memory loss and cognitive decline. Although neuroinflammation and oxidative stress are well-recognized features of AD, their correlations with the early molecular events characterizing the pathology are not yet well clarified. Here, we characterize the role of RAGE-TXNIP axis in neuroinflammation in relation to amyloid-beta (Aβ) burden in both in vivo and in vitro models. In the hippocampus of 5xFAD mice microglial activation, cytokine secretion, and glial fibrillary acidic protein-enhanced expression are paralleled with increased TXNIP expression. TXNIP silencing or its pharmacological inhibition prevents neuroinflammation in those mice. TXNIP is also associated with RAGE and Aβ. In particular, RAGE-TXNIP axis is required for targeting Aβ in mitochondria, leading to mitochondrial dysfunction and oxidative stress. Silencing of TXNIP or inhibition of RAGE activation reduces Aβ transport from the cellular surface to mitochondria, restores mitochondrial functionality, and mitigates Aβ toxicity. Furthermore, Aβ shuttling into mitochondria promotes Drp1 activation and exacerbates mitochondrial dysfunction, which induces NLRP3 inflammasome activation, leading to secretion of IL-1β and activation of the pyroptosis-associated protein Gasdermin D (GSDMD). Downregulation of RAGE-TXNIP axis inhibits Aβ-induced mitochondria dysfunction, inflammation, and induction of GSDMD. Herein we unveil a new pathway driven by TXNIP that links the mitochondrial transport of Aβ to the activation of Drp1 and the NLRP3 inflammasome, promoting the secretion of IL-1β and the pyroptosis pathway associated with GSDMD cleavage. Altogether these data shed new light on a novel mechanism of action of RAGE-TXNIP axis in microglia, which is intertwined with Aβ and ultimately causes mitochondria dysfunction and NLRP3 inflammasome cascade activation, suggesting TXNIP as a druggable target to be better deepened for AD.
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Affiliation(s)
- Oualid Sbai
- Caminnov sas, Montpellier, France
- University Aix-Marseille, Marseille, France
| | | | - Antonia Auletta
- Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and InterUniversity Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Alessandro Ieraci
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | - Carlo Vascotto
- Department of Medicine, University of Udine, Udine, Italy.
| | - L Perrone
- Department of Advanced Medical and Surgical Sciences, 2nd Division of Neurology, Center for Rare Diseases and InterUniversity Center for Research in Neurosciences, University of Campania Luigi Vanvitelli, Naples, Italy.
- DKFZ, Department of Functional and Structural Genomics, Heidelberg, Germany.
- University of Poitiers, Poitiers, France.
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Oxidative stress and inflammatory markers in patients with COVID-19: Potential role of RAGE, HMGB1, GFAP and COX-2 in disease severity. Int Immunopharmacol 2022; 104:108502. [PMID: 35063743 PMCID: PMC8730710 DOI: 10.1016/j.intimp.2021.108502] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/11/2021] [Accepted: 12/23/2021] [Indexed: 02/07/2023]
Abstract
Background SARS-CoV-2 infection can lead to the abnormal induction of cytokines and a dysregulated hyperinflammatory state that is implicated in disease severity and risk of death. There are several molecules present in blood associated with immune cellular response, inflammation, and oxidative stress that could be used as severity markers in respiratory viral infections such as COVID-19. However, there is a lack of clinical studies evaluating the role of oxidative stress-related molecules including glial fibrillary acidic protein (GFAP), the receptor for advanced glycation end products (RAGE), high mobility group box-1 protein (HMGB1) and cyclo-oxygenase-2 (COX-2) in COVID-19 pathogenesis. Aim To evaluate the role of oxidative stress-related molecules in COVID-19. Method An observational study with 93 Brazilian participants from September 2020 to April 2021, comprising 23 patients with COVID-19 admitted to intensive care unit (ICU), 19 outpatients with COVID-19 with mild to moderate symptoms, 17 individuals reporting a COVID-19 history, and 34 healthy controls. Blood samples were taken from all participants and western blot assay was used to determine the RAGE, HMGB1, GFAP, and COX-2 immunocontent. Results We found that GFAP levels were higher in patients with severe or critical COVID-19 compared to outpatients (p = 0.030) and controls (p < 0.001). A significant increase in immunocontents of RAGE (p < 0.001) and HMGB1 (p < 0.001) were also found among patients admitted to the ICU compared to healthy controls, as well as an overexpression of the inducible COX-2 (p < 0.001). In addition, we found a moderate to strong correlation between RAGE, GFAP and HMGB1 proteins. Conclusion SARS-CoV-2 infection induces the upregulation of GFAP, RAGE, HMGB1, and COX-2 in patients with the most severe forms of COVID-19.
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A Study of the Protective Effect of Bushen Huoxue Prescription on Cerebral Microvascular Endothelia Based on Proteomics and Bioinformatics. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:2545074. [PMID: 35035499 PMCID: PMC8758271 DOI: 10.1155/2022/2545074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 11/27/2021] [Accepted: 12/17/2021] [Indexed: 11/17/2022]
Abstract
Diabetic cognitive dysfunction is a serious complication of type 2 diabetes mellitus (T2DM), which can cause neurological and microvascular damage in the brain. At present, there is no effective treatment for this complication. Bushen Huoxue prescription (BSHX) is a newly formulated compound Chinese medicine containing 7 components. Previous research indicated that BSHX was neuroprotective against advanced glycosylation end product (AGE)-induced PC12 cell insult; however, the effect of BSHX on AGE-induced cerebral microvascular endothelia injury has not been studied. In the current research, we investigated the protective effects of BSHX on AGE-induced injury in bEnd.3 cells. Our findings revealed that BSHX could effectively protect bEnd.3 cells from apoptosis. Moreover, we analyzed the network regulation effect of BSHX on AGE-induced bEnd.3 cells injury at the proteomic level. The LC-MS/MS-based shotgun proteomics analysis showed BSHX negatively regulated multiple AGE-elicited proteins. Bioinformatics analysis revealed these differential proteins were involved in multiple processes, such as Foxo signaling pathway. Further molecular biology analysis confirmed that BSHX could downregulate the expression of FoxO1/3 protein and inhibit its nuclear transfer and inhibit the expression of downstream apoptotic protein Bim and the activation of caspase, so as to play a protective role in AGE-induced bEnd.3 injury. Taken together, these findings demonstrated the role of BSHX in the management of diabetic cerebral microangiopathy and provide some insights into the proteomics-guided pharmacological mechanism study of traditional Chinese Medicine.
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Raghav A, Singh M, Jeong GB, Giri R, Agarwal S, Kala S. New horizons of biomaterials in treatment of nerve damage in diabetes mellitus: A translational prospective review. Front Endocrinol (Lausanne) 2022; 13:1036220. [PMID: 36387914 PMCID: PMC9647066 DOI: 10.3389/fendo.2022.1036220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 09/28/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Peripheral nerve injury is a serious concern that leads to loss of neuronal communication that impairs the quality of life and, in adverse conditions, causes permanent disability. The limited availability of autografts with associated demerits shifts the paradigm of researchers to use biomaterials as an alternative treatment approach to recover nerve damage. PURPOSE The purpose of this study is to explore the role of biomaterials in translational treatment approaches in diabetic neuropathy. STUDY DESIGN The present study is a prospective review study. METHODS Published literature on the role of biomaterials in therapeutics was searched for. RESULTS Biomaterials can be implemented with desired characteristics to overcome the problem of nerve regeneration. Biomaterials can be further exploited in the treatment of nerve damage especially associated with PDN. These can be modified, customized, and engineered as scaffolds with the potential of mimicking the extracellular matrix of nerve tissue along with axonal regeneration. Due to their beneficial biological deeds, they can expedite tissue repair and serve as carriers of cellular and pharmacological treatments. Therefore, the emerging research area of biomaterials-mediated treatment of nerve damage provides opportunities to explore them as translational biomedical treatment approaches. CONCLUSIONS Pre-clinical and clinical trials in this direction are needed to establish the effective role of several biomaterials in the treatment of other human diseases.
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Affiliation(s)
- Alok Raghav
- Multidisciplinary Research Unit, Department of Health Research, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, India
- *Correspondence: Alok Raghav,
| | - Manish Singh
- Multidisciplinary Research Unit, Department of Health Research, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, India
- Department of Neurosurgery, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, India
| | - Goo-Bo Jeong
- Department of Anatomy and Cell Biology, College of Medicine, Gachon University, Incheon, South Korea
| | - Richa Giri
- Multidisciplinary Research Unit, Department of Health Research, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, India
- Kamlapat Singhania (KPS) Institute of Medicine, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, India
| | - Saurabh Agarwal
- Multidisciplinary Research Unit, Department of Health Research, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, India
- Kamlapat Singhania (KPS) Institute of Medicine, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, India
| | - Sanjay Kala
- Department of Surgery, Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College, Kanpur, India
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Kinscherf NA, Pehar M. Role and Therapeutic Potential of RAGE Signaling in Neurodegeneration. Curr Drug Targets 2022; 23:1191-1209. [PMID: 35702767 PMCID: PMC9589927 DOI: 10.2174/1389450123666220610171005] [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: 02/28/2022] [Revised: 03/29/2022] [Accepted: 04/29/2022] [Indexed: 01/03/2023]
Abstract
Activation of the receptor for advanced glycation end products (RAGE) has been shown to play an active role in the development of multiple neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Although originally identified as a receptor for advanced glycation end products, RAGE is a pattern recognition receptor able to bind multiple ligands. The final outcome of RAGE signaling is defined in a context and cell type specific manner and can exert both neurotoxic and neuroprotective functions. Contributing to the complexity of the RAGE signaling network, different RAGE isoforms with distinctive signaling capabilities have been described. Moreover, multiple RAGE ligands bind other receptors and RAGE antagonism can significantly affect their signaling. Here, we discuss the outcome of celltype specific RAGE signaling in neurodegenerative pathologies. In addition, we will review the different approaches that have been developed to target RAGE signaling and their therapeutic potential. A clear understanding of the outcome of RAGE signaling in a cell type- and disease-specific manner would contribute to advancing the development of new therapies targeting RAGE. The ability to counteract RAGE neurotoxic signaling while preserving its neuroprotective effects would be critical for the success of novel therapies targeting RAGE signaling.
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Affiliation(s)
- Noah Alexander Kinscherf
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Mariana Pehar
- Division of Geriatrics and Gerontology, Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.,Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, WI, USA
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Liver fibrosis indices are related to diabetic peripheral neuropathy in individuals with type 2 diabetes. Sci Rep 2021; 11:24372. [PMID: 34934162 PMCID: PMC8692472 DOI: 10.1038/s41598-021-03870-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 12/02/2021] [Indexed: 12/17/2022] Open
Abstract
The association between nonalcoholic fatty liver (NAFL) or liver fibrosis and diabetic peripheral neuropathy (DPN) has not been well studied. We aimed to investigate the association of NAFL or liver fibrosis indices and DPN in individuals with type 2 diabetes. In this observational study, we included 264 individuals with type 2 diabetes, and calculated non-alcoholic fatty liver disease (NAFLD) liver fat score, NAFLD fibrosis score, and Fibrosis-4 (FIB-4) index to evaluate the status of NAFLD or liver fibrosis. DPN was diagnosed when the Michigan Neuropathy Screening Instrument—Physical Examination score was ≥ 2.5. The NAFLD fibrosis score and FIB-4 index were significantly higher in individuals with DPN than in those without DPN. Logistic analyses showed that the NAFLD fibrosis score and FIB-4 index were associated with DPN after adjustment for covariates (adjusted odds ratio 1.474 and 1.961, respectively). In the subgroup analysis, this association was only significant in the group with a high NAFLD liver fat score (> − 0.640). Serum levels of fetuin-A, a hepatokine, were decreased in individuals with abnormal vibration perception or 10-g monofilament tests compared with their counterparts. The present study suggests that liver fibrosis might be associated with DPN in individuals with type 2 diabetes.
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Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 2021; 17:400-420. [PMID: 34050323 DOI: 10.1038/s41574-021-00496-z] [Citation(s) in RCA: 238] [Impact Index Per Article: 59.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 02/08/2023]
Abstract
Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
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Kale MB, Bajaj K, Umare M, Wankhede NL, Taksande BG, Umekar MJ, Upaganlawar A. Exercise and Nutraceuticals: Eminent approach for Diabetic Neuropathy. Curr Mol Pharmacol 2021; 15:108-128. [PMID: 34191703 DOI: 10.2174/1874467214666210629123010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/28/2021] [Accepted: 03/05/2021] [Indexed: 11/22/2022]
Abstract
Diabetic neuropathy is an incapacitating chronic pathological condition that encompasses a large group of diseases and manifestations of nerve damage. It affects approximately 50% of patients with diabetes mellitus. Autonomic, sensory, and motor neurons are affected. Disabilities are severe, along with poor recovery and diverse pathophysiology. Physical exercise and herbal-based therapies have the potential to decrease the disabilities associated with diabetic neuropathy. Aerobic exercises like walking, weight lifting, the use of nutraceuticals and herbal extracts are found to be effective. Literature from the public domain was studied emphasizing various beneficial effects of different exercises, use of herbal and nutraceuticals for their therapeutic action in diabetic neuropathy. Routine exercises and administration of herbal and nutraceuticals, either the extract of plant material containing the active phytoconstituent or isolated phytoconstituent at safe concentration, have been shown to have promising positive action in the treatment of diabetic neuropathy. Exercise has shown promising effects on vascular and neuronal health and has proven to be well effective in the treatment as well as prevention of diabetic neuropathy by various novel mechanisms, including herbal and nutraceuticals therapy is also beneficial for the condition. They primarily show the anti-oxidant effect, secretagogue, anti-inflammatory, analgesic, and neuroprotective action. Severe adverse events are rare with these therapies. The current review investigates the benefits of exercise and nutraceutical therapies in the treatment of diabetic neuropathy.
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Affiliation(s)
- Mayur Bhimrao Kale
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Komal Bajaj
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Mohit Umare
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Nitu L Wankhede
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | | | - Milind Janrao Umekar
- Shrimati Kishoritai Bhoyar College of Pharmacy, New Kamptee, Nagpur 441002, Maharashtra, India
| | - Aman Upaganlawar
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad-42310, Nasik, Maharashtra, India
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Lindhout IA, Murray TE, Richards CM, Klegeris A. Potential neurotoxic activity of diverse molecules released by microglia. Neurochem Int 2021; 148:105117. [PMID: 34186114 DOI: 10.1016/j.neuint.2021.105117] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 05/18/2021] [Accepted: 06/24/2021] [Indexed: 01/02/2023]
Abstract
Microglia are the professional immune cells of the brain, which support numerous physiological processes. One of the defensive functions provided by microglia involves secretion of cytotoxins aimed at destroying invading pathogens. It is also recognized that the adverse activation of microglia in diseased brains may lead to secretion of cytotoxic molecules, which could be damaging to the surrounding cells, including neurons. Several of these toxins, such as reactive oxygen and nitrogen species, L-glutamate, and quinolinic acid, are widely recognized and well-studied. This review is focused on a structurally diverse group of less-established microglia neurotoxins, which were selected by applying the two criteria that these molecules 1) can be released by microglia, and 2) have the potential to be directly harmful to neurons. The following 11 molecules are discussed in detail: amyloid beta peptides (Aβ); cathepsin (Cat)B and CatD; C-X-C motif chemokine ligand (CXCL)10 and CXCL12 (5-67); high mobility group box (HMGB)1; lymphotoxin (LT)-α; matrix metalloproteinase (MMP)-2 and MMP-9; platelet-activating factor (PAF); and prolyl endopeptidase (PEP). Molecular mechanisms of their release by microglia and neurotoxicity, as well as available evidence implicating their involvement in human neuropathologies are summarized. Further studies on several of the above molecules are warranted to confirm either their microglial origin in the brain or direct neurotoxic effects. In addition, investigations into the differential secretion patterns of neurotoxins by microglia in response to diverse stimuli are required. This research could identify novel therapeutic targets for neurological disorders involving adverse microglial activation.
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Affiliation(s)
- Ivan A Lindhout
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Taryn E Murray
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Christy M Richards
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada
| | - Andis Klegeris
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, British Columbia, V1V 1V7, Canada.
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Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors. Int J Mol Sci 2021; 22:ijms22136904. [PMID: 34199060 PMCID: PMC8268101 DOI: 10.3390/ijms22136904] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
Receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily. RAGE binds and mediates cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as AGEs, HMGB1, and S100/calgranulins, and as an innate immune sensor, can recognize microbial PAMPs (pathogen-associated molecular pattern molecules), including bacterial LPS, bacterial DNA, and viral and parasitic proteins. RAGE and its ligands stimulate the activations of diverse pathways, such as p38MAPK, ERK1/2, Cdc42/Rac, and JNK, and trigger cascades of diverse signaling events that are involved in a wide spectrum of diseases, including diabetes mellitus, inflammatory, vascular and neurodegenerative diseases, atherothrombosis, and cancer. Thus, the targeted inhibition of RAGE or its ligands is considered an important strategy for the treatment of cancer and chronic inflammatory diseases.
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The parp-1 and bax genes as potential targets for treatment of the heart functioning impairments induced by type 1 diabetes mellitus. Endocr Regul 2021; 55:61-71. [PMID: 34020532 DOI: 10.2478/enr-2021-0008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objectives. The present study was designed to assess whether apoptosis-related genes as parp-1 and bax could be targets for treatment of diabetes mellitus and whether vitamin D may exert beneficial effects. Methods. Vitamin D3 treatment for 4 weeks, starting after 4 weeks of the diabetes duration. The expression of parp-1 and bax genes was estimated on mRNA levels using real time quantitative polymerase chain reaction. Results. After 8 weeks, diabetic rats had weight loss, while blood glucose was increased about 4.9-fold compared to control group. Vitamin D3 administration to diabetic animals had no effect on these parameters. It was found that total serum alkaline phosphatase activity was significantly elevated in diabetic rats as compared to control animals and was restored by vitamin D3. Diabetes was accompanied by reduction of nicotinamidadenindinucleotide, a substrate of poly-ADP-ribosylation, level by 31.7% as compared to control rats, which was not reversed in response to vitamin D3 treatment. In diabetic hearts, the mRNA expression level of parp-1 gene was 2.8-fold higher compared to control rats and partially decreased by vitamin D3 treatment. Less significant alterations were observed in diabetic hearts for the mRNA expression level of bax gene that was 2.0-fold higher compared to control animals and vitamin D3 normalized it. These results indicate that cardiomyocytes have a tendency to apoptosis. Conclusions. The findings suggest that investigated genes can be targets at the transcriptional level for vitamin D action that may be contributed to the improving metabolic/signaling pathways induced by diabetes mellitus.
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Nair M, Jagadeeshan S, Katselis G, Luan X, Momeni Z, Henao-Romero N, Chumala P, Tam JS, Yamamoto Y, Ianowski JP, Campanucci VA. Lipopolysaccharides induce a RAGE-mediated sensitization of sensory neurons and fluid hypersecretion in the upper airways. Sci Rep 2021; 11:8336. [PMID: 33863932 PMCID: PMC8052339 DOI: 10.1038/s41598-021-86069-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 03/02/2021] [Indexed: 02/07/2023] Open
Abstract
Thoracic dorsal root ganglia (tDRG) contribute to fluid secretion in the upper airways. Inflammation potentiates DRG responses, but the mechanisms remain under investigation. The receptor for advanced glycation end-products (RAGE) underlies potentiation of DRG responses in pain pathologies; however, its role in other sensory modalities is less understood. We hypothesize that RAGE contributes to electrophysiological and biochemical changes in tDRGs during inflammation. We used tDRGs and tracheas from wild types (WT), RAGE knock-out (RAGE-KO), and with the RAGE antagonist FPS-ZM1, and exposed them to lipopolysaccharides (LPS). We studied: capsaicin (CAP)-evoked currents and action potentials (AP), tracheal submucosal gland secretion, RAGE expression and downstream pathways. In WT neurons, LPS increased CAP-evoked currents and AP generation, and it caused submucosal gland hypersecretion in tracheas from WT mice exposed to LPS. In contrast, LPS had no effect on tDRG excitability or gland secretion in RAGE-KO mice or mice treated with FPS-ZM1. LPS upregulated full-length RAGE (encoded by Tv1-RAGE) and downregulated a soluble (sRAGE) splice variant (encoded by MmusRAGEv4) in tDRG neurons. These data suggest that sensitization of tDRG neurons contributes to hypersecretion in the upper airways during inflammation. And at least two RAGE variants may be involved in these effects of LPS.
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Affiliation(s)
- Manoj Nair
- Department of Anatomy, Physiology and Pharmacology (APP), College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Santosh Jagadeeshan
- Department of Anatomy, Physiology and Pharmacology (APP), College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - George Katselis
- Department of Medicine, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Xiaojie Luan
- Department of Medicine, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Zeinab Momeni
- Department of Anatomy, Physiology and Pharmacology (APP), College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Nicolas Henao-Romero
- Department of Anatomy, Physiology and Pharmacology (APP), College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Paulos Chumala
- Department of Medicine, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Julian S Tam
- Department of Medicine, Division of Respirology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, 920-8640, Japan
| | - Juan P Ianowski
- Department of Anatomy, Physiology and Pharmacology (APP), College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada
| | - Verónica A Campanucci
- Department of Anatomy, Physiology and Pharmacology (APP), College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK, S7N 5E5, Canada.
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Erusalimsky JD. The use of the soluble receptor for advanced glycation-end products (sRAGE) as a potential biomarker of disease risk and adverse outcomes. Redox Biol 2021; 42:101958. [PMID: 33839083 PMCID: PMC8113049 DOI: 10.1016/j.redox.2021.101958] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/21/2021] [Accepted: 03/24/2021] [Indexed: 02/07/2023] Open
Abstract
The soluble receptor for advanced glycation end-products (sRAGE) has been classically considered a sink for pro-inflammatory RAGE ligands and as such has been associated with protection from inflammatory stress and disease. An alternative, though not mutually exclusive view is that high levels of sRAGE in circulation reflect the overstimulation of cell surface RAGE which if persistent, lead to the amplification of pro-inflammatory processes and the exacerbation of pathological states. With these two scenarios in mind this review focuses on the potential role of sRAGE as a prospective biomarker of disease risk and adverse outcomes.
The prognostic value of measuring sRAGE levels in blood is subjected to debate. Raised sRAGE levels may result from the overstimulation of cell surface RAGE. Raised sRAGE may reflect chronic inflammation and multimorbidity rather than a healthy state. sRAGE is a promising biomarker of disease risk and adverse outcomes.
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Affiliation(s)
- Jorge D Erusalimsky
- The Cellular Senescence and Pathophysiology Group, Cardiff Metropolitan University, Cardiff, UK.
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Jiang X, Zhao W, Zhao T, Yang M, Yuan H, Qian J, Xiang Z. S100A4 in Spinal Substantia Gelatinosa from Dorsal Root Ganglia Modulates Neuropathic Pain in a Rodent Spinal Nerve Injury Model. J Pain Res 2021; 14:665-679. [PMID: 33732013 PMCID: PMC7956897 DOI: 10.2147/jpr.s293462] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 02/25/2021] [Indexed: 12/18/2022] Open
Abstract
Purpose To detect the spatio-temporal expression of S100A4 in a spinal nerve ligation (SNL) rat model. Also to figure out which other molecules directly interact with S100A4 to explore the possible mechanisms which might be involved in neuropathic pain. Methods Seven-week-old male SD rats were used for the SNL model construction. Immunofluorescence and Western blotting were used to detect the spatio-temporal expression of S100A4 in the model. S100A4 was co-labeled with a number of related molecules and marker molecules that can distinguish between cell types. After intrathecal injection of S100A4 neutralizing antibody, the behavioral changes of SNL rats were recorded, and molecular changes compared. The direct interaction between S100A4 and other related molecules was verified by co-immunoprecipitation (co-IP) to explore its possible mechanism. Results After spinal nerve ligation, the content of S100A4 in the dorsal root ganglion (DRG) and spinal dorsal horn increased significantly. Intrathecal injection of S100A4 neutralizing antibody could effectively relieve the mechanical pain in rats. co-IP revealed a direct interaction between S100A4 and RAGE. Conclusion The content of S100A4 in the DRG and spinal dorsal horn of SNL rats increased, compared with that of the control group. Intrathecal injection of S100A4 neutralizing antibody could effectively relieve the mechanical pain in SNL rats. S100A4 may be involved in the production of neuropathic pain through RAGE or other ways, but the specific mechanism needs to be further studied.
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Affiliation(s)
- Xin Jiang
- Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai, People's Republic of China
| | - Wenqi Zhao
- Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai, People's Republic of China
| | - Tiantian Zhao
- Department of General Surgery, Affiliated Xinchang Hospital of Shaoxing University, Zhejiang, People's Republic of China
| | - Mei Yang
- Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai, People's Republic of China
| | - Hongbin Yuan
- Department of Anesthesiology, Changzheng Hospital, Naval Medical University, Shanghai, People's Republic of China
| | - Jun Qian
- Department of General Surgery, Affiliated Xinchang Hospital of Shaoxing University, Zhejiang, People's Republic of China
| | - Zhenghua Xiang
- Department of Neurobiology, Key Laboratory of Molecular Neurobiology, Ministry of Education, Naval Medical University, Shanghai, People's Republic of China
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Balança B, Desmurs L, Grelier J, Perret-Liaudet A, Lukaszewicz AC. DAMPs and RAGE Pathophysiology at the Acute Phase of Brain Injury: An Overview. Int J Mol Sci 2021; 22:ijms22052439. [PMID: 33670976 PMCID: PMC7957733 DOI: 10.3390/ijms22052439] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/17/2021] [Accepted: 02/23/2021] [Indexed: 12/14/2022] Open
Abstract
Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for “DAMPs” or “RAGE” or “S100B” and “traumatic brain injury” or “subarachnoid hemorrhage” or “stroke”. We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives
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Affiliation(s)
- Baptiste Balança
- Department of Neurological Anesthesiology and Intensive Care Medicine, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, 69500 Bron, France;
- Team TIGER, Lyon Neuroscience Research Centre, Inserm U1028, CNRS UMR 5292, 69500 Bron, France
- Correspondence: ; Tel.: +33-6-2391-0594
| | - Laurent Desmurs
- Clinical Chemistry and Molecular Biology Laboratory, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, 69500 Bron, France; (L.D.); (A.P.-L.)
| | - Jérémy Grelier
- Department of Neurological Anesthesiology and Intensive Care Medicine, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, 69500 Bron, France;
| | - Armand Perret-Liaudet
- Clinical Chemistry and Molecular Biology Laboratory, Hospices Civils de Lyon, Hôpital Pierre Wertheimer, 69500 Bron, France; (L.D.); (A.P.-L.)
- Team BIORAN, Lyon Neuroscience Research Centre, Inserm U1028, CNRS UMR 5292, 69500 Bron, France
| | - Anne-Claire Lukaszewicz
- Department of Neurological Anesthesiology and Intensive Care Medicine, Hospices Civils de Lyon, Hôpital Edouard Herriot, 69003 Lyon, France;
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Wang X, Li Q, Han X, Gong M, Yu Z, Xu B. Electroacupuncture Alleviates Diabetic Peripheral Neuropathy by Regulating Glycolipid-Related GLO/AGEs/RAGE Axis. Front Endocrinol (Lausanne) 2021; 12:655591. [PMID: 34295304 PMCID: PMC8290521 DOI: 10.3389/fendo.2021.655591] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 05/19/2021] [Indexed: 01/04/2023] Open
Abstract
Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes mellitus (DM) and affects over one-third of all patients. Neuropathic pain and nerve dysfunction induced by DM is related to the increase of advanced glycation end products (AGEs) produced by reactive dicarbonyl compounds in a hyperglycemia environment. AGEs induce the expression of pro-inflammatory cytokines via the main receptor (RAGE), which has been documented to play a crucial role in the pathogenesis of diabetic peripheral neuropathy. Electroacupuncture (EA) has been reported to have a positive effect on paralgesia caused by various diseases, but the mechanism is unclear. In this study, we used high-fat-fed low-dose streptozotocin-induced rats as a model of type 2 diabetes (T2DM). Persistent metabolic disorder led to mechanical and thermal hyperalgesia, as well as intraepidermal nerve fiber density reduction and nerve demyelination. EA improved neurological hyperalgesia, decreased the pro-inflammatory cytokines, reduced the generation of AGEs and RAGE, and regulated the glyoxalase system in the EA group. Taken together, our study suggested that EA plays a role in the treatment of T2DM-induced DPN, and is probably related to the regulation of metabolism and the secondary influence on the GLO/AGE/RAGE axis.
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Affiliation(s)
| | | | | | | | - Zhi Yu
- *Correspondence: Zhi Yu, ; Bin Xu,
| | - Bin Xu
- *Correspondence: Zhi Yu, ; Bin Xu,
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Stino AM, Rumora AE, Kim B, Feldman EL. Evolving concepts on the role of dyslipidemia, bioenergetics, and inflammation in the pathogenesis and treatment of diabetic peripheral neuropathy. J Peripher Nerv Syst 2020; 25:76-84. [PMID: 32412144 PMCID: PMC7375363 DOI: 10.1111/jns.12387] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/11/2020] [Accepted: 05/11/2020] [Indexed: 12/14/2022]
Abstract
Diabetic peripheral neuropathy (DPN) is one of the most widespread and disabling neurological conditions, accounting for half of all neuropathy cases worldwide. Despite its high prevalence, no approved disease modifying therapies exist. There is now a growing body of evidence that DPN secondary to type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) represents different disease processes, with T2DM DPN best understood within the context of metabolic syndrome rather than hyperglycemia. In this review, we highlight currently understood mechanisms of DPN, along with their corresponding potential therapeutic targets. We frame this discussion within a practical overview of how the field evolved from initial human observations to murine pathomechanistic and therapeutic models into ongoing and human clinical trials, with particular emphasis on T2DM DPN and metabolic syndrome.
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Affiliation(s)
- Amro Maher Stino
- Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
- Division of Neuromuscular Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
| | - Amy E. Rumora
- Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
| | - Bhumsoo Kim
- Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
| | - Eva L. Feldman
- Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
- Division of Neuromuscular Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
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Pergolizzi JV, Magnusson P, LeQuang JA, Razmi R, Zampogna G, Taylor R. Statins and Neuropathic Pain: A Narrative Review. Pain Ther 2020; 9:97-111. [PMID: 32020545 PMCID: PMC7203325 DOI: 10.1007/s40122-020-00153-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Indexed: 12/11/2022] Open
Abstract
The frequently prescribed drug class of statins have pleiotropic effects and have been implicated in neuropathic pain syndromes. This narrative review examines studies of statin-induced neuropathic pain which to date have been conducted only in animal models. However, the pathophysiology of diabetic neuropathy in humans may shed some light on the etiology of neuropathic pain. Statins have exhibited a paradoxical effect in that statins appear to reduce neuropathic pain in animals but have been associated with neuropathic pain in humans. While there are certain postulated mechanisms offering elucidation as to how statins might be associated with neuropathic pain, there is, as the American Heart Association stated, to date no definitive association between statins and neuropathic pain. Statins are important drugs that reduce cardiovascular risk factors and should be prescribed to appropriate patients with these risk factors but some of this population is also at elevated risk for neuropathic pain from other causes.
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Affiliation(s)
| | - Peter Magnusson
- Cardiology Research Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
- Centre for Research and Development, Region Gävleborg/Uppsala University, Gävle, Sweden
| | | | - Robin Razmi
- Department of Infectious Disease, Region Gävleborg/Uppsala University, Gävle, Sweden
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50
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Eid SA, El Massry M, Hichor M, Haddad M, Grenier J, Dia B, Barakat R, Boutary S, Chanal J, Aractingi S, Wiesel P, Szyndralewiez C, Azar ST, Boitard C, Zaatari G, Eid AA, Massaad C. Targeting the NADPH Oxidase-4 and Liver X Receptor Pathway Preserves Schwann Cell Integrity in Diabetic Mice. Diabetes 2020; 69:448-464. [PMID: 31882567 DOI: 10.2337/db19-0517] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Accepted: 12/15/2019] [Indexed: 11/13/2022]
Abstract
Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.
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Affiliation(s)
- Stéphanie A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
| | - Mohamed El Massry
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
| | - Mehdi Hichor
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
| | - Mary Haddad
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Julien Grenier
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
| | - Batoul Dia
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Rasha Barakat
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- INSERM U1016, Cochin Institute, University Paris Descartes, Faculty of Medicine, Sorbonne Paris Cité, Paris, France
| | - Suzan Boutary
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Johan Chanal
- INSERM U1016, Cochin Institute, University Paris Descartes, Faculty of Medicine, Sorbonne Paris Cité, Paris, France
| | - Selim Aractingi
- INSERM U1016, Cochin Institute, University Paris Descartes, Faculty of Medicine, Sorbonne Paris Cité, Paris, France
| | | | | | - Sami T Azar
- Department of Internal Medicine, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- AUB Diabetes, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Christian Boitard
- INSERM U1016, Cochin Institute, University Paris Descartes, Faculty of Medicine, Sorbonne Paris Cité, Paris, France
| | - Ghazi Zaatari
- Department of Pathology, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
- AUB Diabetes, American University of Beirut, Faculty of Medicine and Medical Center, Beirut, Lebanon
| | - Charbel Massaad
- INSERM UMR 1124, University Paris Descartes, Faculty of Basic and Biomedical Sciences, Paris, France
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