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Hernandez E, Abdulahi MM, Hunsader P, Alshi A, Ufearo S, Reed A, Spencer S. Therapeutic effects of metformin on cocaine conditioned place preference and locomotion. Behav Neurosci 2025; 139:122-136. [PMID: 40014500 PMCID: PMC12053506 DOI: 10.1037/bne0000620] [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] [Indexed: 03/01/2025]
Abstract
Lack of Food and Drug Administration-approved treatments for cocaine use disorder contributes to high rates of treatment attrition, relapse, and overdose. Metformin is a Type 2 diabetes drug being investigated for multiple new therapeutic indications. This study set out to determine whether metformin would impact the conditioned rewarding effects of cocaine in an abbreviated or standard two-chamber conditioned place preference (CPP) assay. Adult male (n = 73) and female (n = 82) Sprague Dawley rats were conditioned in a 7-day (abbreviated: 2 × 30 min sessions daily) or a 12-day timeline (standard: 1 × 30 min sessions daily) alternating control and treatment sessions using an unbiased design. Metformin (175 mg/kg) or saline pretreatment occurred 30 min before conditioning with cocaine (20 mg/kg) or vehicle (saline). Data showed sex differences in physiological responses to cocaine and metformin, as well as variant behavioral patterns with different conditioning paradigms. Metformin pretreatment impaired acquisition of cocaine CPP in abbreviated, but not standard conditioning among male rats only. Cocaine-induced locomotor effects are moderated with metformin pretreatment in both female and male rats in different phases of conditioning, suggesting the potential therapeutic value of symptom alleviation when tapering patients off cocaine use with the goal of abstinence. Sex differences observed highlight the importance in better understanding the unique pharmacological profiles of female and male patients. This study provides evidence supporting the potential repurposing of metformin for disrupting rewarding and psychomotor effects of cocaine, paving the way for safe, low-cost, and accessible treatment. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
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Affiliation(s)
- Edith Hernandez
- Molecular Pharmacology and Therapeutics Program, Department of Pharmacology, University of Minnesota Medical School
| | | | - Peter Hunsader
- Department of Pharmacology, University of Minnesota Medical School
| | - Aditi Alshi
- Department of Pharmacology, University of Minnesota Medical School
| | - Sarah Ufearo
- College of Biological Sciences, University of Minnesota
| | - Ayden Reed
- Department of Pharmacology, University of Minnesota Medical School
| | - Sade Spencer
- Molecular Pharmacology and Therapeutics Program, Department of Pharmacology, University of Minnesota Medical School
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Liu S, Liu T, Li J, Hong J, Moosavi-Movahedi AA, Wei J. Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors. Neurosci Bull 2025; 41:676-690. [PMID: 39754628 PMCID: PMC11978575 DOI: 10.1007/s12264-024-01342-8] [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: 08/10/2024] [Accepted: 10/15/2024] [Indexed: 01/06/2025] Open
Abstract
Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
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Affiliation(s)
- Shufen Liu
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Tingting Liu
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Jingwen Li
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | - Jun Hong
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China
| | | | - Jianshe Wei
- Center for Translational Neuromedicine and Neurology, School of Life Sciences, Institute for Brain Sciences Research, Henan University, Huaihe Hospital of Henan University, Kaifeng, 475004, China.
- School of Life Sciences, Institute for Brain Sciences Research, Henan University, Kaifeng, 475004, China.
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Gharandouq MH, Ismail MA, Saleh T, Zihlif M, Ababneh NA. Metformin Protects Human Induced Pluripotent Stem Cell (hiPSC)-Derived Neurons from Oxidative Damage Through Antioxidant Mechanisms. Neurotox Res 2025; 43:15. [PMID: 40100475 DOI: 10.1007/s12640-025-00734-6] [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: 07/28/2024] [Revised: 02/18/2025] [Accepted: 03/08/2025] [Indexed: 03/20/2025]
Abstract
The antidiabetic drug metformin possesses antioxidant and cell protective effects including in neuronal cells, suggesting its potential use for treating neurodegenerative diseases. This study aimed to assess metformin's effects on viability and antioxidant activity in human-induced pluripotent stem cell (hiPSC)-derived neurons under varying concentrations and stress conditions. Six lines of hiPSC-derived neuronal progenitors derived from healthy human iPSCs were treated with metformin (1-500 µM) on day 18 of differentiation. For mature neurons (day 30), three concentrations (10 µM, 50 µM, and 100 µM) were used to assess cytotoxicity. MG132 proteasomal inhibitor and sodium arsenite (NaArs) were used to investigate oxidative stress, and 50 µM of metformin was tested for its protective effects against oxidative stress in hiPSC-derived neurons. Metformin treatment did not affect cell viability, neuronal differentiation, or trigger reactive oxygen species (ROS) generation in healthy hiPSC-derived motor neurons. Additionally, mitochondrial membrane potential (MMP) loss was not observed at 50 µM metformin. Metformin effectively protected neurons from stress agents and elevated the expression of antioxidant genes when treated with MG132. However, an interplay between MG132 and metformin resulted in lower expression of Nrf2 and NQO1 compared to the MG132 group alone, indicating reduced JC-1 aggregate levels due to MG132 proteasomal inhibition. Metformin upregulated antioxidant genes in hiPSC-derived neurons under stress conditions and protected the cells from oxidative damage.
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Affiliation(s)
- Mohammad H Gharandouq
- Faculty of Biological Sciences, The University of Jordan, Amman, Jordan
- Cell Therapy Center, The University of Jordan, Queen Rania Street, Amman, 11942, Jordan
| | - Mohammad A Ismail
- Cell Therapy Center, The University of Jordan, Queen Rania Street, Amman, 11942, Jordan
- South Australian ImmunoGENomics Cancer Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
| | - Tareq Saleh
- Department of Pharmacology and Public Health, Faculty of Medicine, The Hashemite University, Zarqa, 13133, Jordan
- Department of Pharmacology & Therapeutics, College of Medicine & Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Malik Zihlif
- Department of Pharmaceutical Sciences, School of Medicine, University of Jordan, Amman, Jordan
| | - Nidaa A Ababneh
- Cell Therapy Center, The University of Jordan, Queen Rania Street, Amman, 11942, Jordan.
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Mohammadi M, Salehi S, Habibzadeh A, Mohammadi A, Mirzaasgari Z. Neuroprotective Effects of Metformin in Stroke Patients: A Systematic Review and Meta-analysis of Cohort Studies. Clin Neuropharmacol 2025; 48:51-59. [PMID: 40072880 DOI: 10.1097/wnf.0000000000000625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2025]
Abstract
OBJECTIVES People with diabetes are 1.5 times more likely to experience stroke than those without diabetes, underlining the urgent need to address this issue. Metformin is often the initial medication chosen to manage diabetes mellitus (DM). The purpose of our systematic review and meta-analysis is to explore the potential neuroprotective effects of metformin in individuals who have received it prior to stroke. METHOD Our study encompassed cohort studies that drew a comparison between the severity and diverse outcomes of stroke among individuals with DM who were administered metformin prior to the stroke event and those with DM who did not receive the treatment. RESULTS Ten studies met the eligibility criteria. Prestroke metformin use was associated with a significantly lower National Institutes of Health Stroke Scale score (mean difference = -1.29, 95% confidence interval: -2.11 to -0.47) in ischemic stroke. Metformin pretreatment in ischemic stroke was associated with increased odds of favorable outcome (mRS < 2) at 90 days (odds ratio [OR] = 1.45, 95% confidence interval [CI]: 1.06 to 1.99), but it was not significant at discharge. Metformin was found to be associated with reduced mortality (OR = 0.52, 95% CI: 0.42 to 0.64) in ischemic stroke. In hemorrhagic stroke, the results showed a significantly lower intracranial hemorrhage volume in prestroke metformin use (mean difference = -4.77, 95% CI: -6.56 to -2.98). CONCLUSIONS We found that prestroke metformin use in diabetic patients yielded neuroprotective effects. In ischemic strokes, metformin reduces stroke severity and 90-day mortality; it also improves 90-day functional outcomes. In hemorrhagic strokes, prestroke metformin use can also cause less intracranial hemorrhage volume. Further clinical trials are needed to confirm its efficacy and verify its benefits in stroke management.
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Affiliation(s)
| | - Sadaf Salehi
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Aynaz Mohammadi
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Mirzaasgari
- Department of Neurology, Firoozgar Hospital, School of Medicine, Iran University of Medical Science, Fasa, Iran
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Cheng YY, Yao Q, Miao Y, Guan W. Metformin as a potential antidepressant: Mechanisms and therapeutic insights in depression. Biochem Pharmacol 2025; 233:116773. [PMID: 39894309 DOI: 10.1016/j.bcp.2025.116773] [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: 11/21/2024] [Revised: 01/03/2025] [Accepted: 01/21/2025] [Indexed: 02/04/2025]
Abstract
Depression is one of the most disabling psychiatric disorders, whose pathophysiology has not been fully understood. Increasing numbers of preclinical studies have highlighted that metformin, as the first-line hypoglycaemic agent, has a potential pleiotropic effect on depression. Moreover, there is emerging evidence that metformin shows antidepressant activity and improves depressive symptoms in rodent models of depression. However, the exact role and underlying mechanism of metformin in depression remain unclear and still need to be investigated. Recent studies suggest that metformin not only improves neuronal damage and structural plasticity in the hippocampus but also enhances the antidepressant effect of antidepressants. Therefore, in this review, we summarize the existing evidence for the use of metformin as a psychopharmaceutical and elaborate on the underlying mechanisms of metformin in mitigating the onset and progression of depression, as well as the associated biochemical signaling pathways and targets involved in the pathogenesis of depression. After reviewing several studies, we conclude that metformin helps reduce depressive symptoms by targeting multiple pathways, including the regulation of neurotransmitters, enhanced neurogenesis, anti-inflammatory effects, and changes in gut microbiota. We aim to gain a deeper understanding of the mechanism of action of metformin and provide new insights into its clinical value in the prevention and therapy of depression.
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Affiliation(s)
- Yuan-Yuan Cheng
- Department of Pharmacology, Nantong Stomatological Hospital, Nantong 226001 Jiangsu, China
| | - Qi Yao
- Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001 Jiangsu, China
| | - Yang Miao
- Department of Pharmacology, The First People's Hospital of Yancheng, Yancheng 224000 Jiangsu, China.
| | - Wei Guan
- Department of Pharmacology, Pharmacy College, Nantong University, Nantong 226001 Jiangsu, China.
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Liu J, Huang Z, Luo F, Guo Y, Li Y, Wen J, Zhu J. Effect of metformin on the clinical outcomes of stroke in patients with diabetes: a systematic review and meta-analysis. BMJ Open 2025; 15:e092214. [PMID: 39819905 PMCID: PMC11751969 DOI: 10.1136/bmjopen-2024-092214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 12/17/2024] [Indexed: 01/19/2025] Open
Abstract
OBJECTIVES Stroke is a major cause of death and disability globally, especially among diabetic patients. In this study, we aim to scrutinise the effects of metformin on the clinical outcomes of stroke in diabetic patients. DESIGN This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. DATA SOURCES PubMed, Embase and Web of Science databases were searched between their inception and 5 December 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Studies investigating the effect of metformin on the clinical outcomes of stroke in patients with diabetes were included. DATA EXTRACTION AND SYNTHESIS The effect of metformin on the clinical outcomes of stroke in patients with diabetes was identified using combined ORs and 95% CIs. RESULTS A total of 11 studies involving 18 525 participants were included in this review. Pooled analysis has demonstrated that prestroke metformin use could reduce the probability of poor course after stroke by 34% in diabetes mellitus (DM) patients (OR=0.66, 95% CI: 0.61 to 0.72) and reduce the probability of death by 43% (OR=0.57, 95% CI: 0.51 to 0.64). CONCLUSIONS Prestroke metformin use is beneficial for the improvement of clinical outcomes in patients who had a stroke with DM, although the potential bias should be carefully considered. PROSPERO REGISTRATION NUMBER CRD42024496056.
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Affiliation(s)
- Jianyi Liu
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, Hunan, China
| | - Zhihua Huang
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, Hunan, China
| | - Fuqun Luo
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, Hunan, China
| | - Yizhi Guo
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, Hunan, China
| | - Yandeng Li
- Department of Neurology, Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, Hunan, China
| | - Jun Wen
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, Hunan, China
| | - Jianming Zhu
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City), Changde, Hunan, China
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Nag DS, Swain A, Sahu S, Sen B, Vatsala, Parween S. Stroke: Evolution of newer treatment modalities for acute ischemic stroke. World J Clin Cases 2024; 12:6137-6147. [PMID: 39371560 PMCID: PMC11362888 DOI: 10.12998/wjcc.v12.i28.6137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 06/08/2024] [Accepted: 07/03/2024] [Indexed: 08/13/2024] Open
Abstract
Acute ischemic stroke is one of the leading causes of morbidity and mortality worldwide. Restoration of cerebral blood flow to affected ischemic areas has been the cornerstone of therapy for patients for eligible patients as early diagnosis and treatment have shown improved outcomes. However, there has been a paradigm shift in the management approach over the last decade, and with the emphasis currently directed toward including newer modalities such as neuroprotection, stem cell treatment, magnetic stimulation, anti-apoptotic drugs, delayed recanalization, and utilization of artificial intelligence for early diagnosis and suggesting algorithm-based management protocols.
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Affiliation(s)
- Deb Sanjay Nag
- Department of Anaesthesiology, Tata Main Hospital, Jamshedpur 831001, India
| | - Amlan Swain
- Department of Anaesthesiology, Tata Main Hospital, Jamshedpur 831001, India
- Department of Anaesthesiology, Manipal Tata Medical College, Jamshedpur 831017, India
| | - Seelora Sahu
- Department of Anaesthesiology, Tata Main Hospital, Jamshedpur 831001, India
- Department of Anaesthesiology, Manipal Tata Medical College, Jamshedpur 831017, India
| | - Biswajit Sen
- Department of Anaesthesiology, Tata Main Hospital, Jamshedpur 831001, India
| | - Vatsala
- Department of Anaesthesiology, Tata Main Hospital, Jamshedpur 831001, India
| | - Sadiya Parween
- Department of Anaesthesiology, Tata Main Hospital, Jamshedpur 831001, India
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Cai C, Gu C, Meng C, He S, Thashi L, Deji D, Zheng Z, Qiu Q. Therapeutic Effects of Metformin on Central Nervous System Diseases: A Focus on Protection of Neurovascular Unit. Pharm Res 2024; 41:1907-1920. [PMID: 39375240 DOI: 10.1007/s11095-024-03777-0] [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: 02/20/2024] [Accepted: 09/26/2024] [Indexed: 10/09/2024]
Abstract
Metformin is one of the most commonly used oral hypoglycemic drugs in clinical practice, with unique roles in neurodegeneration and vascular lesions. Neurodegeneration and vasculopathy coexist in many diseases and typically affect the neurovascular unit (NVU), a minimal structural and functional unit in the central nervous system. Its components interact with one another and are indispensable for maintaining tissue homeostasis. This review focuses on retinal (diabetic retinopathy, retinitis pigmentosa) and cerebral (ischemic stroke, Alzheimer's disease) diseases to explore the effects of metformin on the NVU. Metformin has a preliminarily confirmed therapeutic effect on the retinal NUV, affecting many of its components, such as photoreceptors (cones and rods), microglia, ganglion, Müller, and vascular endothelial cells. Since it rapidly penetrates the blood-brain barrier (BBB) and accumulates in the brain, metformin also has an extensively studied neuronal protective effect in neuronal diseases. Its mechanism affects various NVU components, including pericytes, astrocytes, microglia, and vascular endothelial cells, mainly serving to protect the BBB. Regulating the inflammatory response in NVU (especially neurons and microglia) may be the main mechanism of metformin in improving central nervous system related diseases. Metformin may be a potential drug for treating diseases associated with NVU deterioration, however, more trials are needed to validate its timing, duration, dose, clinical effects, and side effects.
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Affiliation(s)
- Chunyang Cai
- Department of Ophthalmology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, No. 1111 Xianxia Road, Changning District, Shanghai, 200050, PR China
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai engineering center for precise diagnosis and treatment of eye diseases, Shanghai, PR China
| | - Chufeng Gu
- Department of Ophthalmology, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Shengli Clinical College of Fujian Medical University, Fuzhou, Fujian, PR China
| | - Chunren Meng
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Shuai He
- Department of Ophthalmology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, No. 1111 Xianxia Road, Changning District, Shanghai, 200050, PR China
| | - Lhamo Thashi
- Department of Ophthalmology, Shigatse People's Hospital, Shigatse, Tibet, PR China
| | - Draga Deji
- Department of Ophthalmology, Shigatse People's Hospital, Shigatse, Tibet, PR China
| | - Zhi Zheng
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
- National Clinical Research Center for Eye Diseases; Shanghai Key Laboratory of Ocular Fundus Diseases; Shanghai Engineering Center for Visual Science and Photomedicine; Shanghai engineering center for precise diagnosis and treatment of eye diseases, Shanghai, PR China.
| | - Qinghua Qiu
- Department of Ophthalmology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, No. 1111 Xianxia Road, Changning District, Shanghai, 200050, PR China.
- Department of Ophthalmology, Shigatse People's Hospital, Shigatse, Tibet, PR China.
- High Altitude Ocular Disease Research Center of People's Hospital of Shigatse City and Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Oshitari T. Translational Research and Therapies for Neuroprotection and Regeneration of the Optic Nerve and Retina: A Narrative Review. Int J Mol Sci 2024; 25:10485. [PMID: 39408817 PMCID: PMC11476551 DOI: 10.3390/ijms251910485] [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: 08/23/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Most retinal and optic nerve diseases pose significant threats to vision, primarily due to irreversible retinal neuronal cell death, a permanent change, which is a critical factor in their pathogenesis. Conditions such as glaucoma, retinitis pigmentosa, diabetic retinopathy, and age-related macular degeneration are the top four leading causes of blindness among the elderly in Japan. While standard treatments-including reduction in intraocular pressure, anti-vascular endothelial growth factor therapies, and retinal photocoagulation-can partially delay disease progression, their therapeutic effects remain limited. To address these shortcomings, a range of neuroprotective and regenerative therapies, aimed at preventing retinal neuronal cell loss, have been extensively studied and increasingly integrated into clinical practice over the last two decades. Several of these neuroprotective therapies have achieved on-label usage worldwide. This narrative review introduces several neuroprotective and regenerative therapies for retinal and optic nerve diseases that have been successfully translated into clinical practice, providing foundational knowledge and success stories that serve as valuable references for researchers in the field.
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Affiliation(s)
- Toshiyuki Oshitari
- Department of Ophthalmology and Visual Science, Chiba University Graduate School of Medicine, Inohana 1-8-1, Chuo-ku, Chiba 260-8670, Japan; ; Tel.: +81-43-226-2124; Fax: +81-43-224-4162
- Department of Ophthalmology, International University of Health and Welfare School of Medicine, 4-3 Kozunomori, Narita 286-8686, Japan
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Arnalich-Montiel A, Burgos-Santamaría A, Pazó-Sayós L, Quintana-Villamandos B. Comprehensive Management of Stroke: From Mechanisms to Therapeutic Approaches. Int J Mol Sci 2024; 25:5252. [PMID: 38791292 PMCID: PMC11120719 DOI: 10.3390/ijms25105252] [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: 03/10/2024] [Revised: 04/29/2024] [Accepted: 05/05/2024] [Indexed: 05/26/2024] Open
Abstract
Acute ischemic stroke (AIS) is a challenging disease, which needs urgent comprehensive management. Endovascular thrombectomy (EVT), alone or combined with iv thrombolysis, is currently the most effective therapy for patients with acute ischemic stroke (AIS). However, only a limited number of patients are eligible for this time-sensitive treatment. Even though there is still significant room for improvement in the management of this group of patients, up until now there have been no alternative therapies approved for use in clinical practice. However, there is still hope, as clinical research with novel emerging therapies is now generating promising results. These drugs happen to stop or palliate some of the underlying molecular mechanisms involved in cerebral ischemia and secondary brain damage. The aim of this review is to provide a deep understanding of these mechanisms and the pathogenesis of AIS. Later, we will discuss the potential therapies that have already demonstrated, in preclinical or clinical studies, to improve the outcomes of patients with AIS.
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Affiliation(s)
- Ana Arnalich-Montiel
- Department of Anaesthesia and Intensive Care, Gregorio Marañón’s University Hospital, 28007 Madrid, Spain; (A.B.-S.); (B.Q.-V.)
- Department of Pharmacology, College of Medicine, Complutense University, 28040 Madrid, Spain
| | - Alba Burgos-Santamaría
- Department of Anaesthesia and Intensive Care, Gregorio Marañón’s University Hospital, 28007 Madrid, Spain; (A.B.-S.); (B.Q.-V.)
| | - Laia Pazó-Sayós
- Department of Anaesthesia and Intensive Care, Gregorio Marañón’s University Hospital, 28007 Madrid, Spain; (A.B.-S.); (B.Q.-V.)
| | - Begoña Quintana-Villamandos
- Department of Anaesthesia and Intensive Care, Gregorio Marañón’s University Hospital, 28007 Madrid, Spain; (A.B.-S.); (B.Q.-V.)
- Department of Pharmacology, College of Medicine, Complutense University, 28040 Madrid, Spain
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Pinoșanu EA, Pîrșcoveanu D, Albu CV, Burada E, Pîrvu A, Surugiu R, Sandu RE, Serb AF. Rhoa/ROCK, mTOR and Secretome-Based Treatments for Ischemic Stroke: New Perspectives. Curr Issues Mol Biol 2024; 46:3484-3501. [PMID: 38666949 PMCID: PMC11049286 DOI: 10.3390/cimb46040219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/11/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024] Open
Abstract
Ischemic stroke triggers a complex cascade of cellular and molecular events leading to neuronal damage and tissue injury. This review explores the potential therapeutic avenues targeting cellular signaling pathways implicated in stroke pathophysiology. Specifically, it focuses on the articles that highlight the roles of RhoA/ROCK and mTOR signaling pathways in ischemic brain injury and their therapeutic implications. The RhoA/ROCK pathway modulates various cellular processes, including cytoskeletal dynamics and inflammation, while mTOR signaling regulates cell growth, proliferation, and autophagy. Preclinical studies have demonstrated the neuroprotective effects of targeting these pathways in stroke models, offering insights into potential treatment strategies. However, challenges such as off-target effects and the need for tissue-specific targeting remain. Furthermore, emerging evidence suggests the therapeutic potential of MSC secretome in stroke treatment, highlighting the importance of exploring alternative approaches. Future research directions include elucidating the precise mechanisms of action, optimizing treatment protocols, and translating preclinical findings into clinical practice for improved stroke outcomes.
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Affiliation(s)
- Elena Anca Pinoșanu
- Department of Neurology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania; (E.A.P.); (D.P.); (C.V.A.)
- Doctoral School, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania
| | - Denisa Pîrșcoveanu
- Department of Neurology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania; (E.A.P.); (D.P.); (C.V.A.)
| | - Carmen Valeria Albu
- Department of Neurology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania; (E.A.P.); (D.P.); (C.V.A.)
| | - Emilia Burada
- Department of Physiology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania;
| | - Andrei Pîrvu
- Dolj County Regional Centre of Medical Genetics, Clinical Emergency County Hospital Craiova, St. Tabaci, No. 1, 200642 Craiova, Romania;
| | - Roxana Surugiu
- Department of Biochemistry, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania;
| | - Raluca Elena Sandu
- Department of Neurology, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania; (E.A.P.); (D.P.); (C.V.A.)
- Department of Biochemistry, University of Medicine and Pharmacy of Craiova, St. Petru Rares, No. 2-4, 200433 Craiova, Romania;
| | - Alina Florina Serb
- Department of Biochemistry and Pharmacology, Biochemistry Discipline, “Victor Babes” University of Medicine and Pharmacy, Eftimie Murgu Sq., No. 2, 300041 Timisoara, Romania;
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Ji XT, Yu WL, Jin MJ, Lu LJ, Yin HP, Wang HH. Possible Role of Cellular Polyamine Metabolism in Neuronal Apoptosis. Curr Med Sci 2024; 44:281-290. [PMID: 38453792 DOI: 10.1007/s11596-024-2843-9] [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: 05/13/2023] [Accepted: 01/19/2024] [Indexed: 03/09/2024]
Abstract
Recent studies have shown that cellular levels of polyamines (PAs) are significantly altered in neurodegenerative diseases. Evidence from in vivo animal and in vitro cell experiments suggests that the cellular levels of various PAs may play important roles in the central nervous system through the regulation of oxidative stress, mitochondrial metabolism, cellular immunity, and ion channel functions. Dysfunction of PA metabolism related enzymes also contributes to neuronal injury and cognitive impairment in many neurodegenerative diseases. Therefore, in the current work, evidence was collected to determine the possible associations between cellular levels of PAs, and related enzymes and the development of several neurodegenerative diseases, which could provide a new idea for the treatment of neurodegenerative diseases in the future.
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Affiliation(s)
- Xin-Tong Ji
- School of Basic Medical Sciences, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, China
- School of Medicine, Chongqing University, Chongqing, 400030, China
| | - Wen-Lei Yu
- School of Basic Medical Sciences, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, China
- Department of Stomatology, Huzhou Wuxing District People's Hospital, Huzhou Wuxing District Maternal and Child Health Hospital, Huzhou, 313008, China
| | - Meng-Jia Jin
- School of Basic Medical Sciences, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, China
- School of Pharmacy, Zhejiang University, Hangzhou, 310030, China
| | - Lin-Jie Lu
- School of Basic Medical Sciences, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, China
- Department of Stomatology, Haining Hospital of Traditional Chinese Medicine, Jiaxing, 314400, China
| | - Hong-Ping Yin
- School of Basic Medical Sciences, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, China
| | - Huan-Huan Wang
- School of Basic Medical Sciences, Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, 311121, China.
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13
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Kim C, Kim Y, Sohn JH, Sung JH, Han SW, Lee M, Kim Y, Lee JJ, Mo HJ, Yu KH, Lee SH. Effects of Prior Metformin Use on Stroke Outcomes in Diabetes Patients with Acute Ischemic Stroke Receiving Endovascular Treatment. Biomedicines 2024; 12:745. [PMID: 38672100 PMCID: PMC11048027 DOI: 10.3390/biomedicines12040745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/19/2024] [Accepted: 03/24/2024] [Indexed: 04/28/2024] Open
Abstract
Diabetes mellitus (DM) predisposes individuals to vascular injury, leading to poor outcomes after ischemic stroke and symptomatic hemorrhagic transformation (SHT) after thrombolytic and endovascular treatment (EVT). Metformin (MET), an oral antidiabetic drug, has shown potential neuroprotective effects, but its impact on stroke prognosis in DM patients undergoing EVT remains unclear. In a multicenter study, 231 patients with DM undergoing EVT for acute ischemic stroke were enrolled. Prior MET use was identified, and patients were stratified into MET+ and MET- groups. Demographics, clinical data, and outcomes were compared between groups. Multivariate analysis was used to assess the effect of MET on stroke prognosis. Of the enrolled patients, 59.3% were previously on MET. MET+ patients had lower initial infarct volumes and NIHSS scores compared to MET-taking patients. Multivariate analysis showed that MET+ was associated with a lower risk of stroke progression and SHT (with stroke progression as follows: odd ratio [OR] 0.24, 95% confidence interval [CI] [0.12-0.48], p < 0.001; SHT: OR 0.33, 95% CI [0.14-0.75], p = 0.01) and was also associated with better 3-month functional outcomes (mRS 0-2) after EVT. Prestroke MET use in DM patients undergoing EVT is associated with improved stroke prognosis, including reduced risk of stroke progression and SHT and better functional outcomes. These findings suggest the potential neuroprotective role of MET in this population and highlight its clinical utility as an adjunctive therapy in the management of ischemic stroke. Further research is warranted to elucidate the underlying mechanisms and to optimize MET therapy in this setting.
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Affiliation(s)
- Chulho Kim
- Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; (C.K.); (J.-H.S.); (J.H.S.); (S.-W.H.)
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (Y.K.); (J.J.L.)
| | - Yejin Kim
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (Y.K.); (J.J.L.)
| | - Jong-Hee Sohn
- Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; (C.K.); (J.-H.S.); (J.H.S.); (S.-W.H.)
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (Y.K.); (J.J.L.)
| | - Joo Hye Sung
- Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; (C.K.); (J.-H.S.); (J.H.S.); (S.-W.H.)
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (Y.K.); (J.J.L.)
| | - Sang-Won Han
- Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; (C.K.); (J.-H.S.); (J.H.S.); (S.-W.H.)
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (Y.K.); (J.J.L.)
| | - Minwoo Lee
- Department of Neurology, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068, Republic of Korea; (M.L.); (K.-H.Y.)
| | - Yerim Kim
- Department of Neurology, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul 05355, Republic of Korea;
| | - Jae Jun Lee
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (Y.K.); (J.J.L.)
- Department of Anesthesiology and Pain Medicine, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea
| | - Hee Jung Mo
- Department of Neurology, Dongtan Sacred Heart Hospital, Hallym University College of Medicine, Hwaseong 18450, Republic of Korea;
| | - Kyung-Ho Yu
- Department of Neurology, Hallym Sacred Heart Hospital, Hallym University College of Medicine, Anyang 14068, Republic of Korea; (M.L.); (K.-H.Y.)
| | - Sang-Hwa Lee
- Department of Neurology, Chuncheon Sacred Heart Hospital, Hallym University College of Medicine, Chuncheon 24252, Republic of Korea; (C.K.); (J.-H.S.); (J.H.S.); (S.-W.H.)
- Institute of New Frontier Research Team, Hallym University, Chuncheon 24252, Republic of Korea; (Y.K.); (J.J.L.)
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Ale Mahmoud Mehraban R, Babaei P, Rohampour K, Jafari A, Golipoor Z. Metformin improves memory via AMPK/mTOR-dependent route in a rat model of Alzheimer's disease. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2024; 27:360-365. [PMID: 38333746 PMCID: PMC10849203 DOI: 10.22038/ijbms.2023.73075.15879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/18/2023] [Indexed: 02/10/2024]
Abstract
Objectives Metformin, as an insulin sensitizer, is a familiar antidiabetic drug. Increasing evidence points to metformin's protective effects against Alzheimer's disease (AD). However, the mechanism is not well understood. The present study evaluated whether inhibiting AMPK and activating mTOR could stop metformin from improving memory in rats with streptozotocin (STZ) -induced Alzheimer's disease. Materials and Methods Twelve-week-old Wistar rats, were injected 3 mg/kg STZ intracerebroventricularly on days 1 and 3 to develop the animal model. Metformin was applied orally at 100 mg/kg (17 days). Forty-five min before the retrieval phase, dorsomorphin (DM; AMPK inhibitor, 2 M) and MHY (mTOR activator, 0.1 M) were administered. Morris Water Maze (MWM) and shuttle box were utilized to measure spatial and passive avoidance memory, respectively. Congo red staining was used to identify cortical amyloid deposition. Results The findings exhibited a considerable enhancement in spatial learning and memory in the metformin treatment group (P≤0.05). Injection of DM and MHY alone could not significantly change MWM and passive avoidance. Additionally, co-administration of DM and MHY increased escape latency (P≤0.001) and reduced the total time spent in the target quadrant (TTS) (P≤0.05) compared to the STZ+MET group during retrieval of MWM. Also, co-injection of DM and MHY increased step-through latency (STL) and decreased time spent in the dark compartment (TDC) compared to the STZ+MET group (P≤0.001). Conclusion Metformin appears to have a therapeutic impact by activating AMPK and inactivating mTOR. As a result, it could be used as an Alzheimer's treatment strategy.
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Affiliation(s)
- Reza Ale Mahmoud Mehraban
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Parvin Babaei
- Cellular and Molecular Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Kambiz Rohampour
- Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Adele Jafari
- Department of Physiology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Zoleikha Golipoor
- Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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15
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Lotfimehr H, Mardi N, Narimani S, Nasrabadi HT, Karimipour M, Sokullu E, Rahbarghazi R. mTOR signalling pathway in stem cell bioactivities and angiogenesis potential. Cell Prolif 2023; 56:e13499. [PMID: 37156724 PMCID: PMC10693190 DOI: 10.1111/cpr.13499] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 04/14/2023] [Accepted: 04/26/2023] [Indexed: 05/10/2023] Open
Abstract
The mammalian target of rapamycin (mTOR) is a protein kinase that responds to different stimuli such as stresses, starvation and hypoxic conditions. The modulation of this effector can lead to the alteration of cell dynamic growth, proliferation, basal metabolism and other bioactivities. Considering this fact, the mTOR pathway is believed to regulate the diverse functions in several cell lineages. Due to the pleiotropic effects of the mTOR, we here, hypothesize that this effector can also regulate the bioactivity of stem cells in response to external stimuli pathways under physiological and pathological conditions. As a correlation, we aimed to highlight the close relationship between the mTOR signalling axis and the regenerative potential of stem cells in a different milieu. The relevant publications were included in this study using electronic searches of the PubMed database from inception to February 2023. We noted that the mTOR signalling cascade can affect different stem cell bioactivities, especially angiogenesis under physiological and pathological conditions. Modulation of mTOR signalling pathways is thought of as an effective strategy to modulate the angiogenic properties of stem cells.
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Affiliation(s)
- Hamid Lotfimehr
- Stem Cell Research CenterTabriz University of Medical SciencesTabrizIran
- Department of Applied Cell Sciences, Faculty of Advanced Medical SciencesTabriz University of Medical SciencesTabrizIran
| | - Narges Mardi
- Student Research CommitteeTabriz University of Medical SciencesTabrizIran
| | - Samaneh Narimani
- Department of Applied Cell Sciences, Faculty of Advanced Medical SciencesTabriz University of Medical SciencesTabrizIran
| | - Hamid Tayefi Nasrabadi
- Stem Cell Research CenterTabriz University of Medical SciencesTabrizIran
- Department of Applied Cell Sciences, Faculty of Advanced Medical SciencesTabriz University of Medical SciencesTabrizIran
| | - Mohammad Karimipour
- Department of Applied Cell Sciences, Faculty of Advanced Medical SciencesTabriz University of Medical SciencesTabrizIran
| | - Emel Sokullu
- Koç University Research Center for Translational Medicine (KUTTAM)IstanbulTurkey
| | - Reza Rahbarghazi
- Stem Cell Research CenterTabriz University of Medical SciencesTabrizIran
- Department of Applied Cell Sciences, Faculty of Advanced Medical SciencesTabriz University of Medical SciencesTabrizIran
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An JR, Wang QF, Sun GY, Su JN, Liu JT, Zhang C, Wang L, Teng D, Yang YF, Shi Y. The Role of Iron Overload in Diabetic Cognitive Impairment: A Review. Diabetes Metab Syndr Obes 2023; 16:3235-3247. [PMID: 37872972 PMCID: PMC10590583 DOI: 10.2147/dmso.s432858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 09/29/2023] [Indexed: 10/25/2023] Open
Abstract
It is well documented that diabetes mellitus (DM) is strongly associated with cognitive decline and structural damage to the brain. Cognitive deficits appear early in DM and continue to worsen as the disease progresses, possibly due to different underlying mechanisms. Normal iron metabolism is necessary to maintain normal physiological functions of the brain, but iron deposition is one of the causes of some neurodegenerative diseases. Increasing evidence shows that iron overload not only increases the risk of DM, but also contributes to the development of cognitive impairment. The current review highlights the role of iron overload in diabetic cognitive impairment (DCI), including the specific location and regulation mechanism of iron deposition in the diabetic brain, the factors that trigger iron deposition, and the consequences of iron deposition. Finally, we also discuss possible therapies to improve DCI and brain iron deposition.
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Affiliation(s)
- Ji-Ren An
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
- College of Integrative Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, 050200, People’s Republic of China
| | - Qing-Feng Wang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Gui-Yan Sun
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Jia-Nan Su
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Jun-Tong Liu
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Chi Zhang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Li Wang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Dan Teng
- He University, Shenyang, 110163, People’s Republic of China
| | - Yu-Feng Yang
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
| | - Yan Shi
- Liaoning Key Laboratory of Chinese Medicine Combining Disease and Syndrome of Diabetes, Liaoning University of Traditional Chinese Medicine, Shenyang, 110847, People’s Republic of China
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17
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Huang Z, Shen Y, Fan X, Guo Q, Ma W. Yinzhihuang injection induces apoptosis and suppresses tumor growth in acute myeloid leukemia cells. PLoS One 2023; 18:e0289697. [PMID: 37816017 PMCID: PMC10564230 DOI: 10.1371/journal.pone.0289697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/23/2023] [Indexed: 10/12/2023] Open
Abstract
BACKGROUND The unmet needs in treating acute myeloid leukemia(AML) promote us to look for more effective and less toxic therapies. In this study, we discovered that Yinzhihuang injection(YZHI), a traditional Chinese patent medicine for hepatitis treatment, suppressed the growth of AML cells. METHOD Anti-proliferative activities of YZHI were measured by CCK-8 assay. Cell cycle arrest was evaluated by PI staining, and apoptosis was evaluated by annexin V/PI staining. To explore the cell cycle arrest and cell death mechanism induced by YZHI, we assessed a series of assays, including measurements of the protein expression and cellular ATP. The anti-tumor activity was further demonstrated in nude mice. RESULTS Flow cytometric and biochemical analysis revealed that YZHI caused cell cycle arrest and induced apoptosis in the AML HL-60 cells. Mechanistically, YZHI activated AMPK by promoting phosphorylation of the kinase. The active AMPK negatively regulated the downstream target mTORC1, leading to the inhibition of cell proliferation and induction of apoptosis. Pretreatment with the AMPK inhibitor compound C rescued YZHI induced apoptosis and partially restored cell proliferation of HL-60. Consistent with the data in vitro, YZHI obviously suppressed subcutaneous xenograft growth in nude mice. CONCLUSIONS In a word, our data suggest that YZHI can be repurposed for the treatment of AML, which is worthy of further clinical evaluation.
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Affiliation(s)
- Zhe Huang
- Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Sichuan Clinical Research Center for Birth Defects, Luzhou, Sichuan, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Yunfu Shen
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Xianming Fan
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qulian Guo
- Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Sichuan Clinical Research Center for Birth Defects, Luzhou, Sichuan, China
| | - Wenzhe Ma
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
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Wang X, Wang H, Yi P, Baker C, Casey G, Xie X, Luo H, Cai J, Fan X, Soong L, Hu H, Shi PY, Liang Y, Sun J. Metformin restrains ZIKV replication and alleviates virus-induced inflammatory responses in microglia. Int Immunopharmacol 2023; 121:110512. [PMID: 37343373 DOI: 10.1016/j.intimp.2023.110512] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 06/23/2023]
Abstract
The re-emergence of Zika virus (ZIKV) remains a major public health threat that has raised worldwide attention. Accumulating evidence suggests that ZIKV can cause serious pathological changes to the human nervous system, including microcephaly in newborns. Recent studies suggest that metformin, an established treatment for diabetes may play a role in viral infection; however, little is known about the interactions between ZIKV infection and metformin administration. Using fluorescent ZIKV by flow cytometry and immunofluorescence imaging, we found that ZIKV can infect microglia in a dose-dependent manner. Metformin diminished ZIKV replication without the alteration of viral entry and phagocytosis. Our study demonstrated that metformin downregulated ZIKV-induced inflammatory response in microglia in a time- and dose-dependent manner. Our RNA-Seq and qRT-PCR analysis found that type I and III interferons (IFN), such as IFNα2, IFNβ1 and IFNλ3 were upregulated in ZIKV-infected cells by metformin treatment, accompanied with the downregulation of GBP4, OAS1, MX1 and ISG15. Together, our results suggest that metformin-mediated modulation in multiple pathways may attribute to restraining ZIKV infection in microglia, which may provide a potential tool to consider for use in unique clinical circumstances.
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Affiliation(s)
- Xiaofang Wang
- Department of Infectious Disease, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan 410005, China; Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Hui Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Panpan Yi
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Coleman Baker
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Gonzales Casey
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Xuping Xie
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Huanle Luo
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Jiyang Cai
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Xuegong Fan
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lynn Soong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Haitao Hu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Pei-Yong Shi
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
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Xie Y, Lei X, Zhao G, Guo R, Cui N. mTOR in programmed cell death and its therapeutic implications. Cytokine Growth Factor Rev 2023; 71-72:66-81. [PMID: 37380596 DOI: 10.1016/j.cytogfr.2023.06.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/12/2023] [Accepted: 06/19/2023] [Indexed: 06/30/2023]
Abstract
Mechanistic target of rapamycin (mTOR), a highly conserved serine/threonine kinase, is involved in cellular metabolism, protein synthesis, and cell death. Programmed cell death (PCD) assists in eliminating aging, damaged, or neoplastic cells, and is indispensable for sustaining normal growth, fighting pathogenic microorganisms, and maintaining body homeostasis. mTOR has crucial functions in the intricate signaling pathway network of multiple forms of PCD. mTOR can inhibit autophagy, which is part of PCD regulation. Cell survival is affected by mTOR through autophagy to control reactive oxygen species production and the degradation of pertinent proteins. Additionally, mTOR can regulate PCD in an autophagy-independent manner by affecting the expression levels of related genes and phosphorylating proteins. Therefore, mTOR acts through both autophagy-dependent and -independent pathways to regulate PCD. It is conceivable that mTOR exerts bidirectional regulation of PCD, such as ferroptosis, according to the complexity of signaling pathway networks, but the underlying mechanisms have not been fully explained. This review summarizes the recent advances in understanding mTOR-mediated regulatory mechanisms in PCD. Rigorous investigations into PCD-related signaling pathways have provided prospective therapeutic targets that may be clinically beneficial for treating various diseases.
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Affiliation(s)
- Yawen Xie
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Xianli Lei
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Guoyu Zhao
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Ran Guo
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
| | - Na Cui
- Department of Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
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Shabab S, Mahmoudabady M, Hosseini M, Gholamnezhad Z, Fouladi M, Asghari AA. The effects of endurance exercise and metformin on memory impairment caused by diabetes. Horm Mol Biol Clin Investig 2023; 44:187-197. [PMID: 36751729 DOI: 10.1515/hmbci-2022-0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 01/20/2023] [Indexed: 02/09/2023]
Abstract
OBJECTIVES Diabetes has a negative effect on learning and memory performance, and it is a risk factor for Alzheimer's disease and dementia development. The present study aims to investigate the effects of two kinds of endurance exercise including high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) as well as metformin on impaired memory and learning related to streptozotocin (STZ) induced diabetes in rats. METHODS Forty adult male rats (250 ± 20 g weight) were divided into five groups (n=8), including control, diabetic, as well as diabetic rats treated with metformin (300 mg/kg), and HIIT (20 m/min), and MICT (15 m/min) exercises. Diabetes was induced by STZ (60 mg/kg, i.p.). Serum glucose concentration and oxidative stress markers (SOD, CAT, thiol, and MDA) in the cortex and hippocampus were determined by colorimetric assay. Behavioral tests were performed with a passive avoidance test. RESULTS The diabetic groups treated with metformin and both HIIT, and MICT exercises improved the latency and the staying time in the darkroom and lightroom. The entrance frequency into the darkroom also was restored (p<0.01-p<0.001). In both HIIT and MICT exercises as well as metformin groups the oxidative stress induced by diabetes has been reversed and attenuation of the serum glucose level has been observed compared to non-treated diabetic ones (p<0.05-p<0.001). CONCLUSIONS The results of the present study revealed both HIIT and MICT exercises had protective effects against oxidative stress and behavioral impairments induced by diabetes and these effects were comparable to the effects of metformin.
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Affiliation(s)
- Sadegh Shabab
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maryam Mahmoudabady
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Hosseini
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Gholamnezhad
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahtab Fouladi
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Akbar Asghari
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Manica D, Sandri G, da Silva GB, Manica A, da Silva Rosa Bonadiman B, Dos Santos D, Flores ÉMM, Bolzan RC, Barcelos RCS, Tomazoni F, Suthovski G, Bagatini MD, Benvegnú DM. Evaluation of the effects of metformin on antioxidant biomarkers and mineral levels in patients with type II diabetes mellitus: A cross-sectional study. J Diabetes Complications 2023; 37:108497. [PMID: 37209504 DOI: 10.1016/j.jdiacomp.2023.108497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 05/03/2023] [Accepted: 05/10/2023] [Indexed: 05/22/2023]
Abstract
Diabetes mellitus (DM) and arterial hypertension are considered serious public health problems. Several studies have shown that oxidative stress is usually related to the onset of DM and hypertension, as well their associated complications. Moreover, the levels of some minerals are closely related to the pathophysiology of these diseases. Thus, in this study we aimed to evaluate the effect of metformin on the redox profile and mineral levels in the serum of patients with DM type 2 and hypertension. We also tested the effect of metformin on the viability and redox profile of peripheral blood mononuclear cells (PBMCs) for 24 h. As expected, we found that patients with type 2 DM and hypertension + type 2 DM had higher fasting glucose and triglyceride levels. As groundbreaking research, we found that both patients DM type 2 and Hypertension + DM type 2 had reduced myeloperoxidase (MPO) activity. On the other hand, the levels of total thiols (PSH) and vitamin C were increased. There was no statistical significance for the alterations in mineral levels. In addition, metformin treatment had no cytotoxic effect on PBMCs. Similarly, in patients of both groups, MPO activity was reduced and PSH levels were increased in PBMCs. We have shown that metformin is a drug with a protective effect in patients with DM type 2 against oxidative stress by reducing MPO activity and improving the levels of PSH and antioxidant defenders such as vitamin C. The results of in vitro assays support the antioxidant effect of metformin. Furthermore, we suggest studies to assess the biochemical mechanisms of metformin and how it can be used in a pharmacological therapeutic perspective against oxidative damage.
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Affiliation(s)
- Daiane Manica
- Post-graduate Program in Biochemistry, Federal University of Santa Catarina, Florianópolis, SC, Brazil
| | - Gabriela Sandri
- Post Graduate Program of Health, Welfare and Sustainable Animal Production on Fronteira Sul, Federal University of Fronteira Sul, Realeza, PR, Brazil
| | - Gilnei Bruno da Silva
- Multicentric Postgraduate Program in Biochemistry and Molecular Biology, State University of Santa Catarina, Lages, SC, Brazil
| | - Aline Manica
- Post Graduate Program in Health Sciences of the Community University of Chapecó Region - Unochapecó, Chapecó, SC, Brazil
| | - Beatriz da Silva Rosa Bonadiman
- School of Health, Area of Biological and Health Sciences, Community University of Chapecó Region - Unochapecó, Chapecó, SC, Brazil
| | - Daniel Dos Santos
- Graduate Program in Chemical Engineering, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | | | | | | | - Fernanda Tomazoni
- Graduate Program in Dental Science, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Gabriela Suthovski
- Post Graduate Program of Health, Welfare and Sustainable Animal Production on Fronteira Sul, Federal University of Fronteira Sul, Realeza, PR, Brazil
| | - Margarete Dulce Bagatini
- Post Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Chapecó, SC, Brazil.
| | - Dalila Moter Benvegnú
- Post Graduate Program of Health, Welfare and Sustainable Animal Production on Fronteira Sul, Federal University of Fronteira Sul, Realeza, PR, Brazil
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22
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Kalra P, Khan H, Singh TG, Grewal AK. Mechanistic insights on impact of Adenosine monophosphate-activated protein kinase (AMPK) mediated signalling pathways on cerebral ischemic injury. Neurosci Res 2023; 190:17-28. [PMID: 36403790 DOI: 10.1016/j.neures.2022.11.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 09/23/2022] [Accepted: 11/13/2022] [Indexed: 11/18/2022]
Abstract
Cerebral ischemia is the primary cause of morbidity and mortality worldwide due to the perturbations in the blood supply to the brain. The brain triggers a cascade of complex metabolic and cellular defects in response to ischemic stress. However, due to the disease heterogeneity and complexity, ischemic injury's metabolic and cellular pathologies remain elusive, and the link between various pathological mechanisms is difficult to determine. Efforts to develop effective treatments for these disorders have yielded limited efficacy, with no proper cure available to date. Recent clinical and experimental research indicates that several neuronal diseases commonly coexist with metabolic dysfunction, which may aggravate neurological symptoms. As a result, it stands to a reason that metabolic hormones could be a potential therapeutic target for major NDDs. Moreover, fasting signals also influence the circadian clock, as AMPK phosphorylates and promotes the degradation of the photo-sensing receptor (cryptochrome). Here, the interplay of AMPK signaling between metabolic regulation and neuronal death and its role for pathogenesis and therapeutics has been studied. We have also highlighted a significant signaling pathway, i.e., the adenosine monophosphate-activated protein kinase (AMPK) involved in the relationship between the metabolism and ischemia, which could be used as a target for future studies therapeutics, and review some of the clinical progress in this area.
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Affiliation(s)
- Palak Kalra
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
| | - Heena Khan
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India.
| | - Amarjot Kaur Grewal
- Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India
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23
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Huang KH, Tsai YF, Lee CB, Gau SY, Tsai TH, Chung NJ, Lee CY. The Correlation between Metformin Use and Incident Dementia in Patients with New-Onset Diabetes Mellitus: A Population-Based Study. J Pers Med 2023; 13:jpm13050738. [PMID: 37240908 DOI: 10.3390/jpm13050738] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
The evidence of metformin's effect on dementia is conflicting. This study investigates the association between metformin use and the risk of dementia among patients with diabetes mellitus (DM). This study included patients with new-onset DM between 2002 and 2013. We divided the patients into patients who used metformin and patients who did not. Two models were used to assess metformin use: the cumulative defined daily dose (cDDD) of metformin use and the intensity of metformin use. This study with 3-year and 5-year follow-ups investigated the risk of dementia among patients with DM who used metformin. At the 3-year follow-up, patients who received cDDD < 300 had an odds ratio (OR) of developing dementia of 0.92 (95% confidence interval [CI] = 0.89-0.96); patients who used metformin at intensities <10 and 10-25 DDD/month had ORs of 0.92 (95% CI: 0.87-0.97) and 0.92 (95% CI: 0.85-1.00), respectively. Metformin use at cDDD 300-500 (OR = 0.80, 95% CI = 0.56-1.15) or >500 (OR = 1.48, 95% CI = 0.48-4.60) or at an intensity >25 DDD/month (OR = 0.84, 95% CI = 0.60-1.18) were not associated with an incident of dementia. There were similar results at the 5-year follow-up. Patients with a low intensity of metformin use had a lower risk of dementia. However, higher doses of metformin with higher intensity exhibited no protective role in dementia. Prospective clinical trials are warranted to evaluate the actual underlying mechanisms between metformin dosage and the risk of dementia.
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Affiliation(s)
- Kuang-Hua Huang
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Ya-Fang Tsai
- Department of Health Policy and Management, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Chiachi Bonnie Lee
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Shuo-Yan Gau
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Tung-Han Tsai
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan
| | - Ning-Jen Chung
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
| | - Chien-Ying Lee
- Department of Pharmacology, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
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24
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Karami F, Jamaati H, Coleman-Fuller N, Zeini MS, Hayes AW, Gholami M, Salehirad M, Darabi M, Motaghinejad M. Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis. Pharmacol Rep 2023; 75:511-543. [PMID: 37093496 DOI: 10.1007/s43440-023-00469-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 02/21/2023] [Accepted: 02/23/2023] [Indexed: 04/25/2023]
Abstract
Diabetes mellitus (DM) is a metabolic disease that activates several molecular pathways involved in neurodegenerative disorders. Metformin, an anti-hyperglycemic drug used for treating DM, has the potential to exert a significant neuroprotective role against the detrimental effects of DM. This review discusses recent clinical and laboratory studies investigating the neuroprotective properties of metformin against DM-induced neurodegeneration and the roles of various molecular pathways, including mitochondrial dysfunction, oxidative stress, inflammation, apoptosis, and its related cascades. A literature search was conducted from January 2000 to December 2022 using multiple databases including Web of Science, Wiley, Springer, PubMed, Elsevier Science Direct, Google Scholar, the Core Collection, Scopus, and the Cochrane Library to collect and evaluate peer-reviewed literature regarding the neuroprotective role of metformin against DM-induced neurodegenerative events. The literature search supports the conclusion that metformin is neuroprotective against DM-induced neuronal cell degeneration in both peripheral and central nervous systems, and this effect is likely mediated via modulation of oxidative stress, inflammation, and cell death pathways.
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Affiliation(s)
- Fatemeh Karami
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Jamaati
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Natalie Coleman-Fuller
- Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, MN, 55108, USA
| | - Maryam Shokrian Zeini
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - A Wallace Hayes
- University of South Florida College of Public Health and Institute for Integrative Toxicology, Michigan State University, East Lansing, USA
| | - Mina Gholami
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Salehirad
- Cognitive and Neuroscience Research Center (CNRC), Amir-Almomenin Hospital, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mohammad Darabi
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Motaghinejad
- Chronic Respiratory Disease Research Center (CRDRC), National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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25
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Huang A, Ji L, Li Y, Li Y, Yu Q. Gut microbiome plays a vital role in post-stroke injury repair by mediating neuroinflammation. Int Immunopharmacol 2023; 118:110126. [PMID: 37031605 DOI: 10.1016/j.intimp.2023.110126] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 03/18/2023] [Accepted: 03/29/2023] [Indexed: 04/11/2023]
Abstract
Cerebral stroke is a common neurological disease and often causes severe neurological deficits. With high morbidity, mortality, and disability rates, stroke threatens patients' life quality and brings a heavy economic burden on society. Ischemic cerebral lesions incur pathological changes as well as spontaneous nerve repair following stroke. Strategies such as drug therapy, physical therapy, and surgical treatment, can ameliorate blood and oxygen supply in the brain, hamper the inflammatory responses and maintain the structural and functional integrity of the brain. The gut microbiome, referred to as the "second genome" of the human body, participates in the regulation of multiple physiological functions including metabolism, digestion, inflammation, and immunity. The gut microbiome is not only inextricably associated with dangerous factors pertaining to stroke, including high blood pressure, diabetes, obesity, and atherosclerosis, but also influences stroke occurrence and prognosis. AMPK functions as a hub of metabolic control and is responsible for the regulation of metabolic events under physiological and pathological conditions. The AMPK mediators have been found to exert dual roles in regulating gut microbiota and neuroinflammation/neuronal apoptosis in stroke. In this study, we reviewed the role of the gut microbiome in cerebral stroke and the underlying mechanism of the AMPK signaling pathway in stroke. AMPK mediators in nerve repair and the regulation of intestinal microbial balance were also summarized.
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Affiliation(s)
- Airu Huang
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
| | - Ling Ji
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
| | - Yamei Li
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China
| | - Yufeng Li
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China.
| | - Qian Yu
- Department of Rehabilitation Medicine, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China.
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26
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Díaz A, Vázquez-Roque R, Carreto-Meneses K, Moroni-González D, Moreno-Rodríguez JA, Treviño S. Polyoxidovanadates as a pharmacological option against brain aging. J Chem Neuroanat 2023; 129:102256. [PMID: 36921908 DOI: 10.1016/j.jchemneu.2023.102256] [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: 10/26/2022] [Revised: 03/10/2023] [Accepted: 03/11/2023] [Indexed: 03/14/2023]
Abstract
The world population is aging rapidly, and chronic diseases associated are cardiometabolic syndrome, cancer, and neurodegenerative diseases. Oxidative stress and inflammation are typical hallmarks in them. Polyoxidovanadates (POVs) have shown interesting pharmacological actions against chronic diseases. This work aimed to evaluate the POV effect on hippocampal neuroinflammation, redox balance, and recognition memory in the aging of rats. Rats 18 months old were administered a daily dose of sodium metavanadate (MV), decavanadate (DV), Metformin (Metf), or MetfDeca for two months. Results showed that short-term and long-term recognition memory improved by 28 % and 16 % (DV), 19 % and 20 % (Metf), and 21 % and 27 % (MetfDeca). In hippocampi, reactive oxygen species, IL-1β, and TNF-α, after DV, Metf, and MetfDeca decreased at similar concentrations to young adult control, while lipid peroxidation substantially ameliorated. Additionally, superoxide dismutase and catalase activity increased by 41 % and 42 % (DV), 39 % and 41 % (Metf), and 75 % and 73 % (MetfDeca). POV treatments reduced Nrf2 and GFAP immunoreactivity in CA1 (70-87.5 %), CA3 (60-80 %), and DG (57-89 %). Metformin treatment showed a minor effect, while MV treatment did not improve any parameters. Although DV, Metf, and MetfDeca treatments showed similar results, POVs doses were 16-fold fewer than Metformin. In conclusion, DV and MetfDeca could be pharmacological options to reduce age-related neuronal damage.
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Affiliation(s)
- Alfonso Díaz
- Department of Pharmacy, Faculty of Chemistry Science, University Autonomous of Puebla, 22 South. FC91, University City, Puebla C.P. 72560, Mexico
| | - Rubén Vázquez-Roque
- Neuropsychiatry laboratory, Physiology Institute, University Autonomous of Puebla, 14 South. University City, Puebla C.P. 72560, Mexico
| | - Karen Carreto-Meneses
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, University Autonomous of Puebla, 14 South. FCQ1, University City, Puebla C.P. 72560, Mexico
| | - Diana Moroni-González
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, University Autonomous of Puebla, 14 South. FCQ1, University City, Puebla C.P. 72560, Mexico
| | - José Albino Moreno-Rodríguez
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, University Autonomous of Puebla, 14 South. FCQ1, University City, Puebla C.P. 72560, Mexico
| | - Samuel Treviño
- Laboratory of Chemical-Clinical Investigations, Department of Clinical Chemistry, Faculty of Chemistry Science, University Autonomous of Puebla, 14 South. FCQ1, University City, Puebla C.P. 72560, Mexico.
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27
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Dietary energy restriction in neurological diseases: what's new? Eur J Nutr 2023; 62:573-588. [PMID: 36369305 DOI: 10.1007/s00394-022-03036-1] [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: 03/15/2022] [Accepted: 10/11/2022] [Indexed: 11/13/2022]
Abstract
Energy-restricted diet is a specific dietary regimen, including the continuous energy-restricted diet and the intermittent energy-restricted diet. It has been proven effective not only to reduce weight and extend the lifespan in animal models, but also to regulate the development and progression of various neurological diseases such as epilepsy, cerebrovascular diseases (stroke), neurodegenerative disorders (Alzheimer's disease and Parkinson's disease) and autoimmune diseases (multiple sclerosis). However, the mechanism in this field is still not clear and a systematic neurological summary is still missing. In this review, we first give a brief summary of the definition and mainstream strategies of energy restrictions. We then review evidence about the effects of energy-restricted diet from both animal models and human trials, and update the current understanding of mechanisms underlying the biological role of energy-restricted diet in the fight against neurological diseases. Our review thus contributes to the modification of dietary regimen and the search for special diet mimics.
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28
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Advanced Glycation End-Products and Diabetic Neuropathy of the Retina. Int J Mol Sci 2023; 24:ijms24032927. [PMID: 36769249 PMCID: PMC9917392 DOI: 10.3390/ijms24032927] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/29/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Diabetic retinopathy is a tissue-specific neurovascular impairment of the retina in patients with both type 1 and type 2 diabetes. Several pathological factors are involved in the progressive impairment of the interdependence between cells that consist of the neurovascular units (NVUs). The advanced glycation end-products (AGEs) are one of the major pathological factors that cause the impairments of neurovascular coupling in diabetic retinopathy. Although the exact mechanisms for the toxicities of the AGEs in diabetic retinopathy have not been definitively determined, the AGE-receptor of the AGE (RAGE) axis, production of reactive oxygen species, inflammatory reactions, and the activation of the cell death pathways are associated with the impairment of the NVUs in diabetic retinopathy. More specifically, neuronal cell death is an irreversible change that is directly associated with vision reduction in diabetic patients. Thus, neuroprotective therapies must be established for diabetic retinopathy. The AGEs are one of the therapeutic targets to examine to ameliorate the pathological changes in the NVUs in diabetic retinopathy. This review focuses on the basic and pathological findings of AGE-induced neurovascular abnormalities and the potential therapeutic approaches, including the use of anti-glycated drugs to protect the AGE-induced impairments of the NVUs in diabetic retinopathy.
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Zhang Y, Zhou F, Guan J, Zhou L, Chen B. Action Mechanism of Metformin and Its Application in Hematological Malignancy Treatments: A Review. Biomolecules 2023; 13:250. [PMID: 36830619 PMCID: PMC9953052 DOI: 10.3390/biom13020250] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 01/18/2023] [Accepted: 01/20/2023] [Indexed: 02/03/2023] Open
Abstract
Hematologic malignancies (HMs) mainly include acute and chronic leukemia, lymphoma, myeloma and other heterogeneous tumors that seriously threaten human life and health. The common effective treatments are radiotherapy, chemotherapy and hematopoietic stem cell transplantation (HSCT), which have limited options and are prone to tumor recurrence and (or) drug resistance. Metformin is the first-line drug for the treatment of type 2 diabetes (T2DM). Recently, studies identified the potential anti-cancer ability of metformin in both T2DM patients and patients that are non-diabetic. The latest epidemiological and preclinical studies suggested a potential benefit of metformin in the prevention and treatment of patients with HM. The mechanism may involve the activation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway by metformin as well as other AMPK-independent pathways to exert anti-cancer properties. In addition, combining current conventional anti-cancer drugs with metformin may improve the efficacy and reduce adverse drug reactions. Therefore, metformin can also be used as an adjuvant therapeutic agent for HM. This paper highlights the anti-hyperglycemic effects and potential anti-cancer effects of metformin, and also compiles the in vitro and clinical trials of metformin as an anti-cancer and chemosensitizing agent for the treatment of HM. The need for future research on the use of metformin in the treatment of HM is indicated.
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Affiliation(s)
| | | | | | | | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, China
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30
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Duan H, Yun HJ, Rajah GB, Che F, Wang Y, Liu J, Tong Y, Cheng Z, Cai L, Geng X, Ding Y. Large vessel occlusion stroke outcomes in diabetic vs. non-diabetic patients with acute stress hyperglycemia. Front Neurosci 2023; 17:1073924. [PMID: 36777640 PMCID: PMC9911880 DOI: 10.3389/fnins.2023.1073924] [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: 10/19/2022] [Accepted: 01/06/2023] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE This study assesses whether stress-induced hyperglycemia is a predictor of poor outcome at 3 months for patients with acute ischemic stroke (AIS) treated by endovascular treatment (EVT) and impacted by their previous blood glucose status. METHODS This retrospective study collected data from 576 patients with AIS due to large vessel occlusion (LVO) treated by EVT from March 2019 to June 2022. The sample was composed of 230 and 346 patients with and without diabetes mellitus (DM), respectively, based on their premorbid diabetic status. Prognosis was assessed with modified Rankin Scale (mRS) at 3-month after AIS. Poor prognosis was defined as mRS>2. Stress-induced hyperglycemia was assessed by fasting glucose-to-glycated hemoglobin ratio (GAR). Each group was stratified into four groups by quartiles of GAR (Q1-Q4). Binary logistic regression analysis was used to identify relationship between different GAR quartiles and clinical outcome after EVT. RESULTS In DM group, a poor prognosis was seen in 122 (53%) patients and GAR level was 1.27 ± 0.44. These variables were higher than non-DM group and the differences were statistically significant (p < 0.05, respectively). Patients with severe stress-induced hyperglycemia demonstrated greater incidence of 3-month poor prognosis (DM: Q1, 39.7%; Q2, 45.6%; Q3, 58.6%; Q4, 68.4%; p = 0.009. Non-DM: Q1, 31%; Q2, 32.6%; Q3, 42.5%; Q4, 64%; p < 0.001). However, the highest quartile of GAR was independently associated with poor prognosis at 3 months (OR 3.39, 95% CI 1.66-6.96, p = 0.001), compared to the lowest quartile in non-DM patients after logistic regression. This association was not observed from DM patients. CONCLUSION The outcome of patients with acute LVO stroke treated with EVT appears to be influenced by premorbid diabetes status. However, the poor prognosis at 3-month in patients with DM is not independently correlated with stress-induced hyperglycemia. This could be due to the long-term damage of persistent hyperglycemia and diabetic patients' adaptive response to stress following acute ischemic damage to the brain.
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Affiliation(s)
- Honglian Duan
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Ho Jun Yun
- Department of Neurosurgery, School of Medicine, Wayne State University, Detroit, MI, United States
| | - Gary Benjamin Rajah
- Department of Neurosurgery, Munson Healthcare, Munson Medical Center, Traverse City, MI, United States
| | - Fengli Che
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Yanling Wang
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Jing Liu
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Yanna Tong
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Zhe Cheng
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Lipeng Cai
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Xiaokun Geng
- Department of Neurology, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Yuchuan Ding
- Department of Neurosurgery, School of Medicine, Wayne State University, Detroit, MI, United States
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31
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Sheng S, Liu W, Xue Y, Pan Z, Zhao L, Wang F, Qi X. Follicle-Stimulating Hormone Promotes the Development of Endometrial Cancer In Vitro and In Vivo. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph192215344. [PMID: 36430063 PMCID: PMC9696221 DOI: 10.3390/ijerph192215344] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 05/26/2023]
Abstract
Endocrine disruptors as risk factors for endometrial cancer (EC) are positively correlated with serum follicle-stimulating hormone (FSH) levels. Additionally, increased FSH is associated with EC. However, its exact mechanism is not yet clear. Therefore, this study investigated how FSH affects the occurrence of EC. Using immunohistochemistry (IHC), immunofluorescence (IF), and Western blot (WB), we found that FSH receptor (FSHR) was expressed in both EC tissues and cell lines. To explore the effect of FSH on EC in vitro, Ishikawa (ISK) cells were cultured in different doses of FSH, and it was found that FSH could promote the proliferation and migration of ISK cells. Furthermore, the detection of key molecules of migration and apoptosis by WB showed that FSH promoted cell migration and inhibited apoptosis. Additionally, FSH decreased AMPK activation. To clarify the effect of FSH on EC in vivo, we subcutaneously planted ISK cells into ovariectomized mice and then gave two of the groups oestradiol (E2). In comparison with the OE (ovariectomy plus E2) and sham groups, the growth rates and weights of the tumors in the OE plus FSH group were significantly higher. The findings above suggest that FSH promotes the proliferation and metastasis of EC, providing a new strategy for the treatment of EC.
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Affiliation(s)
- Shuman Sheng
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan 250021, China
| | - Wei Liu
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, 324 Jingwu Road, Jinan 250021, China
| | - Yafei Xue
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan 250021, China
| | - Zhengwu Pan
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan 250021, China
| | - Lanlan Zhao
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan 250021, China
| | - Fei Wang
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan 250021, China
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, 324 Jingwu Road, Jinan 250021, China
| | - Xiaoyi Qi
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 324 Jingwu Road, Jinan 250021, China
- Department of Obstetrics and Gynecology, Shandong Provincial Hospital, Shandong University, 324 Jingwu Road, Jinan 250021, China
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Chen H, Zhou J, Zhang G, Luo Z, Li L, Kang X. Emerging role and therapeutic implication of mTOR signalling in intervertebral disc degeneration. Cell Prolif 2022; 56:e13338. [PMID: 36193577 PMCID: PMC9816935 DOI: 10.1111/cpr.13338] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/16/2022] [Accepted: 09/01/2022] [Indexed: 01/11/2023] Open
Abstract
Intervertebral disc degeneration (IDD), an important cause of chronic low back pain (LBP), is considered the pathological basis for various spinal degenerative diseases. A series of factors, including inflammatory response, oxidative stress, autophagy, abnormal mechanical stress, nutritional deficiency, and genetics, lead to reduced extracellular matrix (ECM) synthesis by intervertebral disc (IVD) cells and accelerate IDD progression. Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that plays a vital role in diverse degenerative diseases. Recent studies have shown that mTOR signalling is involved in the regulation of autophagy, oxidative stress, inflammatory responses, ECM homeostasis, cellular senescence, and apoptosis in IVD cells. Accordingly, we reviewed the mechanism of mTOR signalling in the pathogenesis of IDD to provide innovative ideas for future research and IDD treatment.
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Affiliation(s)
- Hai‐Wei Chen
- Department of OrthopaedicsLanzhou University Second HospitalLanzhouGansuPeople's Republic of China,The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuPeople's Republic of China
| | - Jian‐Wei Zhou
- Department of OrthopaedicsLanzhou University Second HospitalLanzhouGansuPeople's Republic of China,Key Laboratory of Orthopaedics Disease of Gansu ProvinceLanzhou University Second HospitalLanzhouGansu ProvincePeople's Republic of China
| | - Guang‐Zhi Zhang
- Department of OrthopaedicsLanzhou University Second HospitalLanzhouGansuPeople's Republic of China,The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuPeople's Republic of China
| | - Zhang‐Bin Luo
- Department of OrthopaedicsLanzhou University Second HospitalLanzhouGansuPeople's Republic of China,The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuPeople's Republic of China
| | - Lei Li
- Department of OrthopaedicsLanzhou University Second HospitalLanzhouGansuPeople's Republic of China,The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuPeople's Republic of China
| | - Xue‐Wen Kang
- Department of OrthopaedicsLanzhou University Second HospitalLanzhouGansuPeople's Republic of China,The Second Clinical Medical CollegeLanzhou UniversityLanzhouGansuPeople's Republic of China,Key Laboratory of Orthopaedics Disease of Gansu ProvinceLanzhou University Second HospitalLanzhouGansu ProvincePeople's Republic of China
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Shu M, Xiang C. Relationship between Peripheral Blood miR-181c, miR-101, and Cognitive Impairment in Patients with Diabetes Mellitus Complicated with Acute Stroke. Emerg Med Int 2022; 2022:5777106. [PMID: 36212996 PMCID: PMC9546670 DOI: 10.1155/2022/5777106] [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: 08/04/2022] [Accepted: 09/07/2022] [Indexed: 12/05/2022] Open
Abstract
Objectives To explore the relationship between peripheral blood microRNA-181c (miR-181c), microRNA-101 (miR-101), and cognitive impairment (CI) in patients with diabetes mellitus (DM) complicated with acute stroke (AS). Methods A retrospective analysis was performed on 70 patients with DM complicated with AS admitted to the hospital between January 2019 and December 2021. According to presence or absence of CI, they were divided into CI group (41 cases) and non-CI group (29 cases). The clinical characteristics and general data (blood glucose and blood lipid) of patients were statistically analyzed. The relative expression levels of miR-181c and miR-101 in peripheral blood were detected by real-time fluorescence quantitative PCR. The risk factors of CI were analyzed by logistic regression analysis. The diagnostic value of peripheral blood miR-181c and miR-101 for CI was evaluated by receiver operating characteristic (ROC) curves. Results The relative expression levels of peripheral blood miR-181c and miR-101 in the CI group were lower than those in the non-CI group (P < 0.05). The occurrence of CI was related to age, course of DM, AS location, time from onset to admission, HbA1c, TG, UA, and Hcy levels (P < 0.05). Logistic regression analysis showed that age, AS location, HbA1c, miR-181c, and miR-101 were related influencing factors of CI in patients with DM complicated with AS (P < 0.05). The results of ROC curves analysis showed that AUC, sensitivity, and specificity of miR-181c combined with miR-101 for predicting CI were 0.865, 73.17%, and 89.66%, respectively (P < 0.05). Conclusions The peripheral blood miR-181c and miR-101 are low expressed in patients with DM complicated with AS, and advanced age, intracortical AS lesions, increased HbA1c, and low expression of miR-181c and miR-101 are all independent risk factors for CI in patients with DM complicated with AS. Besides, the combined detection of miR-181c and miR-101 expression has a good diagnostic value for CI.
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Affiliation(s)
- Mengxian Shu
- Department of Pulmonary Disease Diabetes Mellitus, The Central Hospital of Enshi Autonomous Prefecture, Enshi, Hubei 445000, China
| | - Chunhui Xiang
- Department of Neurosurgery, The Central Hospital of Enshi Autonomous Prefecture, Enshi, Hubei 445000, China
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Hu X, Wang Y, Du W, Liang LJ, Wang W, Jin X. Role of Glial Cell-Derived Oxidative Stress in Blood-Brain Barrier Damage after Acute Ischemic Stroke. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7762078. [PMID: 36092167 PMCID: PMC9463007 DOI: 10.1155/2022/7762078] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/13/2022] [Indexed: 11/18/2022]
Abstract
The integrity of the blood-brain barrier (BBB) is mainly maintained by endothelial cells and basement membrane and could be regulated by pericytes, neurons, and glial cells including astrocytes, microglia, oligodendrocytes (OLs), and oligodendrocyte progenitor cells (OPCs). BBB damage is the main pathological basis of hemorrhage transformation (HT) and vasogenic edema after stroke. In addition, BBB damage-induced HT and vasogenic edema will aggravate the secondary brain tissue damage. Of note, after reperfusion, oxidative stress-initiated cascade plays a critical role in the BBB damage after acute ischemic stroke (AIS). Although endothelial cells are the target of oxidative stress, the role of glial cell-derived oxidative stress in BBB damage after AIS also should receive more attention. In the current review, we first introduce the physiology and pathophysiology of the BBB, then we summarize the possible mechanisms related to BBB damage after AIS. We aim to characterize the role of glial cell-derived oxidative stress in BBB damage after AIS and discuss the role of oxidative stress in astrocytes, microglia cells and oligodendrocytes in after AIS, respectively.
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Affiliation(s)
- Xiaoyan Hu
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Yanping Wang
- Department of Neurology, The Second Hospital of Jiaxing City, Jiaxing, 314000 Zhejiang, China
| | - Weihong Du
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
| | - Li-Jun Liang
- Children's Hospital of Shanxi Province, Taiyuan, Shanxi Province, China
| | - Wei Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Xinchun Jin
- Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Histology and Embryology, School of Basic Medical Sciences, Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing 100069, China
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Xu L, Wang W, Song W. A combination of metformin and insulin improve cardiovascular and cerebrovascular risk factors in individuals with type 1 diabetes mellitus. Diabetes Res Clin Pract 2022; 191:110073. [PMID: 36075464 DOI: 10.1016/j.diabres.2022.110073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/14/2022] [Accepted: 08/31/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND This study aims to further clarify whether the addition of metformin to insulin treatment improve cardiovascular and cerebrovascular risk factors in individuals with T1DM. METHODS Electronic databases were searched for randomized controlled trials in which the efficacy and safety of metformin were compared with those of a placebo for risk factors of cardiovascular and cerebrovascular disease among individuals with T1DM, and a meta-analysis was conducted. RESULTS Thirteen cardiovascular studies were identified. In the metformin group, mean carotid intimal media thickness was significantly reduced by 0.03 mm, ascending aortic pulse wave velocity by 6.3 m/s, descending aortic wall shear stress by 1.77 dyn/cm2 (P = 0.02), insulin daily dose by 0.05 U/kg/d, body weight by 2.27 kg, fat-free mass by 1.32 kg, body mass index by 0.58 kg/m2, hip circumference by 0.29 m, and low-density lipoprotein by 0.16 mmol/L, all above are P < 0.05. In the metformin group, flow-mediated dilation was increased by 1.29 %, glucose infusion rate/insulin by 18.22 mg/(kg⋅min)/μIU/μL, and waist-to-hip ratio by 0.02, all above are P < 0.00001. The metformin group showed no differences in blood pressure, reactive hyperemia index, waist circumference, triglyceride, total cholesterol, high-density lipoprotein cholesterol, or body mass index Z score. For cerebrovascular studies were identified. But none of them had a risk factor assessment. CONCLUSIONS Metformin can ameliorate cardiovascular and cerebrovascular risk factors through non-hypoglycemic multiple pathways in individuals with T1DM.
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Affiliation(s)
- Linlin Xu
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Wang
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Song
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
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Effect of metformin on outcome after acute ischemic stroke in patients with type 2 diabetes mellitus. J Stroke Cerebrovasc Dis 2022; 31:106648. [PMID: 35863262 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 07/09/2022] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION Diabetes mellitus is a well-known risk factor for ischemic stroke and is associated with unfavorable outcome after stroke. Metformin is recommended as first-line treatment in these patients. Pre-stroke metformin use might have neuroprotective properties resulting in reduced stroke severity. However, results of the effects of pre-stroke metformin use on functional outcome are conflicting and has not been previously described in patients with type 2 diabetes mellitus regardless of stroke severity or revascularization treatment. In this study, we aimed to assess the association between metformin use and functional outcome in patients with type 2 diabetes mellitus and acute ischemic stroke. METHODS We used data from patients with known type 2 diabetes mellitus who were admitted with acute ischemic stroke between 2017 and 2021 in the Isala Hospital Zwolle and Medisch Spectrum Twente (MST) Enschede, the Netherlands. The association between pre-stroke metformin use and favorable functional outcome at 3 months (defined as modified Rankin Scale (mRS) < 3) was expressed as Odds Ratios (ORs) with corresponding confidence intervals (CIs). Adjustments were made for age, sex, hyperglycemia on admission and revascularization treatment by means of multiple logistic regression. RESULTS Nine hundred thirty seven patients were included of whom 592 patients (63%) used metformin. Six hundred seventy eight (74%) patients were hyperglycemic on admission. Median mRS was 3 (IQR 2-6) and 593 patients (63%) had a favorable outcome. Pre-stroke metformin use was associated with favorable outcome (aOR of 1.94 (95%- CI 1.45-2.59)). CONCLUSION In this study, we showed that pre-stroke metformin use was associated with favorable outcome after acute ischemic stroke in patients with diabetes mellitus type 2.
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Enriched Environment-Induced Neuroprotection against Cerebral Ischemia-Reperfusion Injury Might Be Mediated via Enhancing Autophagy Flux and Mitophagy Flux. Mediators Inflamm 2022; 2022:2396487. [PMID: 35795405 PMCID: PMC9252718 DOI: 10.1155/2022/2396487] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/09/2022] [Accepted: 06/13/2022] [Indexed: 12/15/2022] Open
Abstract
Background Enriched environment (EE) can protect the brain against damages caused by an ischemic stroke; however, the underlying mechanism remains elusive. Autophagy and mitochondria quality control are instrumental in the pathogenesis of ischemic stroke. In this study, we investigated whether and how autophagy and mitochondria quality control contribute to the protective effect of EE in the acute phase of cerebral ischemia–reperfusion injury. Methods We exposed transient middle cerebral artery occlusion (tMCAO) mice to EE or standard condition (SC) for 7 days and then studied them for neurological deficits, autophagy and inflammation-related proteins, and mitochondrial morphology and function. Results Compared to tMCAO mice in the SC group, those in the EE group showed fewer neurological deficits, relatively downregulated inflammation, higher LC3 expression, higher mitochondrial Parkin levels, higher mitochondrial fission factor dynamin-related protein-1 (Drp1) levels, lower p62 expression, and lower autophagy inhibitor mTOR expression. Furthermore, we found that the EE group showed a higher number of mitophagosomes and normal mitochondria, fewer mitolysosomes, and relatively increased mitochondrial membrane potential. Conclusion These results suggested that EE enhances autophagy flux by inhibiting mTOR and enhances mitophagy flux via recruiting Drp1 and Parkin to eliminate dysfunctional mitochondria, which in turn inhibits inflammation and alleviates neurological deficits. Limitations. The specific mechanisms through which EE promotes autophagy and mitophagy and the signaling pathways that link them with inflammation need further study.
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Zhang G, Chen S, Jia J, Liu C, Wang W, Zhang H, Zhen X. Development and Evaluation of Novel Metformin Derivative Metformin Threonate for Brain Ischemia Treatment. Front Pharmacol 2022; 13:879690. [PMID: 35800435 PMCID: PMC9253272 DOI: 10.3389/fphar.2022.879690] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/11/2022] [Indexed: 11/25/2022] Open
Abstract
Epidemiologic data reveal that diabetes patients taking metformin exhibit lower incidence of stroke and better functional outcomes during post-stroke neurologic recovery. We previously demonstrated that chronic post-ischemic administration of metformin improved functional recovery in experimental cerebral ischemia. However, few beneficial effects of metformin on the acute phase of cerebral ischemia were reported either in experimental animals or in stroke patients, which limits the application of metformin in stroke. We hypothesized that slow cellular uptake of metformin hydrochloride may contribute to the lack of efficacy in acute stroke. We recently developed and patented a novel metformin derivative, metformin threonate (SHY-01). Pharmacokinetic profile in vivo and in cultured cells revealed that metformin is more rapidly uptaken and accumulated from SHY-01 than metformin hydrochloride. Accordingly, SHY-01 treatment exhibited more potent and rapid activation of AMP-activated protein kinase (AMPK). Furthermore, SHY-01 elicited a stronger inhibition of microglia activation and more potent neuroprotection when compared to metformin hydrochloride. SHY-01 administration also had superior beneficial effects on neurologic functional recovery in experimental stroke and offered strong protection against acute cerebral ischemia with reduced infarct volume and mortality, as well as the improved sensorimotor and cognitive functions in rats. Collectively, these results indicated that SHY-01 had an improved pharmacokinetic and pharmacological profile and produced more potent protective effects on acute stroke and long-term neurological damage. We propose that SHY-01 is a very promising therapeutic candidate for cerebral ischemic stroke.
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Affiliation(s)
- Gufang Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- *Correspondence: Xuechu Zhen, ; Gufang Zhang,
| | - Shuangshuang Chen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Jia Jia
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Chun Liu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Weipeng Wang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Hongjian Zhang
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- Department of Pharmaceutical Analysis, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Xuechu Zhen
- Jiangsu Key Laboratory of Neuropsychiatric Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
- *Correspondence: Xuechu Zhen, ; Gufang Zhang,
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Rahman MO, Ahmed S, Mazumder T, Salam MA, Baral PK, Rana MF, Mitra S, Hossain S, Rahman R, Hussain MS. A comparative evaluation of cardiac and neurological safety status of two commonly used oral hypoglycaemic agents in T2-DM Swiss albino mice model. Metabol Open 2022; 14:100191. [PMID: 35651883 PMCID: PMC9149180 DOI: 10.1016/j.metop.2022.100191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 05/16/2022] [Accepted: 05/19/2022] [Indexed: 11/06/2022] Open
Abstract
Background Diabetes mellitus (DM), along with its associated complications, including diabetic neuropathy and hyperlipidemia, has become a global concern in the last few decades. The main objective of our study is to evaluate the comparative neuro-safety status, serum plasma glucose, and lipid-lowering potential of two widely recognized antidiabetic drugs named metformin and glimepiride. Methods The neurological evaluation was done by open field test, hole board test, forced swimming test, dark and lighthouse test, and elevated plus maze test by employing diazepam as standard. Serum blood glucose level of streptozotocin (STZ)-induced diabetic mice was determined by glucose oxidizing method using a glucometer. Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very-low-density lipoprotein cholesterol (VLDL-C) levels were estimated by using the reference method where atorvastatin was used as standard. Results In neurological evaluation, both drugs produce almost the same anxiolytic activity in the open field test, hole board test, light and dark house test, and elevated plus maze test. However, in the forced swimming test, glimepiride produced more antidepressant activity than metformin. Glimepiride was found to remarkably reduce serum glucose and VLDL-C levels more than metformin, whereas, for other parameters, metformin takes over glimepiride sometimes took over the standard atorvastatin. Conclusions The results of our study indicate that both oral hypoglycaemic drugs alter the lipid index while producing some anxiolytic effects on the central nervous system. Thus, recommended to be carefully administered to patients with low BMI and might be beneficial to patients suffering from peripheral nerve function and anxiety.
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Molecular Evidence on the Inhibitory Potential of Metformin against Chlorpyrifos-Induced Neurotoxicity. TOXICS 2022; 10:toxics10040197. [PMID: 35448458 PMCID: PMC9029213 DOI: 10.3390/toxics10040197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/07/2022] [Accepted: 04/17/2022] [Indexed: 02/06/2023]
Abstract
Chlorpyrifos (CPF) is an organophosphorus (OP) pesticide, resulting in various health complications as the result of ingestion, inhalation, or skin absorption, and leads to DNA damage and increased oxidative stress. Metformin, derived from Galega officinalis, is reported to have anti-inflammatory and anti-apoptotic properties; thus, this study aimed to investigate the beneficial role of metformin in neurotoxicity induced by sub-acute exposure to CPF in Wistar rats. In this study, animals were divided into nine groups and were treated with different combinations of metformin and CPF. Following the 28 days of CPF and metformin administration, brain tissues were separated. The levels of inflammatory biomarkers such as tumor necrosis factor alpha (TNFα) and interleukin 1β (IL-1β), as well as the expression of 5HT1 and 5HT2 genes, were analyzed. Moreover, the levels of malondialdehyde (MDA), reactive oxygen species (ROS), and the ADP/ATP ratio, in addition to the activity of acetylcholinesterase (AChE) and superoxide dismutase (SOD), were tested through in vitro experiments. This study demonstrated the potential role of metformin in alleviating the mentioned biomarkers, which can be altered negatively as a result of CPF toxicity. Moreover, metformin showed protective potential in modulating inflammation, as well as oxidative stress, the expression of genes, and histological analysis, in a concentration-dependent manner.
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Shao Y, Wang M, Zhu Y, Li X, Liu J. Association of metformin treatment with enhanced effect of anti-VEGF agents in diabetic macular edema patients. Acta Diabetol 2022; 59:553-559. [PMID: 35034186 DOI: 10.1007/s00592-021-01833-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 11/25/2021] [Indexed: 11/01/2022]
Abstract
PURPOSE To investigate the effect of metformin combined with anti-VEGF agents in patients with diabetic macular edema (DME). METHODS This study was a prospective, nonrandomized case-control study. Patients were included in with a diagnosis of DME who received anti-VEGF agents injection. Basic information, medical history, best-corrected visual acuity (BCVA), central macular thickness (CMT), the number of intravitreal injections, panretinal photocoagulation (PRP), and macular grid photocoagulation treatment during the 6-month follow-up, were recorded for each patient. RESULTS A total of 50 DME patients were collected (24 patients with a history of oral metformin ≥ 6 months and 26 patients who had not taken metformin). The BCVA and the CMT were significantly improved after anti-VEGF treatment in two groups (F1 = 19.35, F2 = 26.78; F1 = 65.45, F2 = 76.23; P < 0.05). The BCVA in the metformin group was better than that in non-metformin group at every point after treatment (F = 34.45, P < 0.05). The CMT in metformin group decreased much more than that in non-metformin group during the follow-up period (F = 87.05, P < 0.05). The injection numbers decreased in the metformin group compared with the non-metformin group (t = 5.14, P < 0.05). However, there was no difference in PRP and macular grid photocoagulation therapy between the two groups during the 6-month follow-up. CONCLUSION Metformin can enhance the therapeutic effect of anti-VEGF agents on DME patients to improve their visual acuity, improve the structure of the macular area, and reduce the number of intravitreal injections 90.
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Affiliation(s)
- Yan Shao
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin, China
- Tianjin Branch of National Clinical Research Center for Ocular Disease, Tianjin, China
- Eye Institute and School of Optometry, Tianjin, China
- Tianjin Medical University Eye Hospital, Tianjin, China
| | - Manqiao Wang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin, China
- Tianjin Branch of National Clinical Research Center for Ocular Disease, Tianjin, China
- Eye Institute and School of Optometry, Tianjin, China
- Tianjin Medical University Eye Hospital, Tianjin, China
| | - Yimeng Zhu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin, China
- Tianjin Branch of National Clinical Research Center for Ocular Disease, Tianjin, China
- Eye Institute and School of Optometry, Tianjin, China
- Tianjin Medical University Eye Hospital, Tianjin, China
| | - Xiaorong Li
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin, China.
- Tianjin Branch of National Clinical Research Center for Ocular Disease, Tianjin, China.
- Eye Institute and School of Optometry, Tianjin, China.
- Tianjin Medical University Eye Hospital, Tianjin, China.
| | - Juping Liu
- Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin, China.
- Tianjin Branch of National Clinical Research Center for Ocular Disease, Tianjin, China.
- Eye Institute and School of Optometry, Tianjin, China.
- Tianjin Medical University Eye Hospital, Tianjin, China.
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Metformin Protects against Spinal Cord Injury and Cell Pyroptosis via AMPK/NLRP3 Inflammasome Pathway. Anal Cell Pathol 2022; 2022:3634908. [PMID: 35387358 PMCID: PMC8977347 DOI: 10.1155/2022/3634908] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 02/13/2022] [Accepted: 03/16/2022] [Indexed: 11/17/2022] Open
Abstract
Spinal cord injury (SCI) is an extreme neurological impairment with few effective drug treatments. Pyroptosis is a recently found and proven type of programmed cell death that is characterized by a reliance on inflammatory caspases and the release of a large number of proinflammatory chemicals. Pyroptosis differs from other cell death mechanisms such as apoptosis and necrosis in terms of morphological traits, incidence, and regulatory mechanism. Pyroptosis is widely involved in the occurrence and development of SCI. In-depth research on pyroptosis will help researchers better understand its involvement in the onset, progression, and prognosis of SCI, as well as provide new therapeutic prevention and treatment options. Herein, we investigated the role of AMPK-mediated activation of the NLRP3 inflammasome in the neuroprotection of MET-regulated pyroptosis. We found that MET treatment reduced NLRP3 inflammasome activation by activating phosphorylated AMPK and reduced proinflammatory cytokine (IL-1β, IL-6, and TNF-α) release. At the same time, MET improved motor function recovery in rats after SCI by reducing motor neuron loss in the anterior horn of the spinal cord. Taken together, our study confirmed that MET inhibits neuronal pyroptosis after SCI via the AMPK/NLRP3 signaling pathway, which is mostly dependent on the AMPK pathway increase, hence decreasing NLRP3 inflammasome activation.
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Drug repurposing for stroke intervention. Drug Discov Today 2022; 27:1974-1982. [DOI: 10.1016/j.drudis.2022.03.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023]
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Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, Hashemi M, Hushmandi K, Ashrafizadeh M, Zarrabi A, Ertas YN, Mirzaei S, Samarghandian S. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomed Pharmacother 2022; 146:112563. [PMID: 35062059 DOI: 10.1016/j.biopha.2021.112563] [Citation(s) in RCA: 175] [Impact Index Per Article: 58.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/16/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus (DM) is considered as a main challenge in both developing and developed countries, as lifestyle has changed and its management seems to be vital. Type I and type II diabetes are the main kinds and they result in hyperglycemia in patients and related complications. The gene expression alteration can lead to development of DM and related complications. The AMP-activated protein kinase (AMPK) is an energy sensor with aberrant expression in various diseases including cancer, cardiovascular diseases and DM. The present review focuses on understanding AMPK role in DM. Inducing AMPK signaling promotes glucose in DM that is of importance for ameliorating hyperglycemia. Further investigation reveals the role of AMPK signaling in enhancing insulin sensitivity for treatment of diabetic patients. Furthermore, AMPK upregulation inhibits stress and cell death in β cells that is of importance for preventing type I diabetes development. The clinical studies on diabetic patients have shown the role of AMPK signaling in improving diabetic complications such as brain disorders. Furthermore, AMPK can improve neuropathy, nephropathy, liver diseases and reproductive alterations occurring during DM. For exerting such protective impacts, AMPK signaling interacts with other molecular pathways such as PGC-1α, PI3K/Akt, NOX4 and NF-κB among others. Therefore, providing therapeutics based on AMPK targeting can be beneficial for amelioration of DM.
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Affiliation(s)
- Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Danial Hashemi
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirhossein Zabolian
- Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Golestan, Iran
| | - Shima Mohammadi
- Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Farima Fakhri
- Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonosis, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer 34396, Istanbul, Turkey
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri 38039, Turkey
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Li T, Providencia R, Jiang W, Liu M, Yu L, Gu C, Chang ACY, Ma H. Association of Metformin with the Mortality and Incidence of Cardiovascular Events in Patients with Pre-existing Cardiovascular Diseases. Drugs 2022; 82:311-322. [PMID: 35032305 DOI: 10.1007/s40265-021-01665-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2021] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Whether metformin reduces all-cause cardiovascular mortality and the incidence of cardiovascular events in patients with pre-existing cardiovascular diseases (CVD) remains inconclusive. Some randomised controlled trials (RCTs) and cohort studies have shown that metformin is associated with an increased risk of mortality and cardiovascular events. METHODS We conducted a pooling synthesis to assess the effects of metformin in all-cause cardiovascular mortality and incidence of cardiovascular events in patients with CVD. Studies published up to October 2021 in PubMed or Embase with a registration in PROSPERO (CRD42020189905) were collected. Both RCT and cohort studies were included. Hazard ratios (HR) with 95% CI were pooled across various trials using the random-effects model. RESULTS This study enrolled 35 published studies (in 14 publications) for qualitative synthesis and identified 33 studies (published in 26 publications) for quantitative analysis. We analysed a total of 61,704 patients, among them 58,271 patients were used to calculate all-cause mortality while 12,814 patients were used to calculate cardiovascular mortality. Compared with non-metformin control, metformin usage is associated with a reduction in all-cause mortality (HR: 0.90; 95% CI 0.83, 0.98; p = 0.01), cardiovascular mortality (HR: 0.89; 95% CI 0.85, 0.94; p < 0.0001), incidence of coronary revascularisation (HR: 0.79; 95% CI 0.64, 0.98; p = 0.03), and heart failure (HR: 0.90; 95% CI 0.87, 0.94; p < 0.0001) in patients with pre-existing cardiovascular diseases. CONCLUSION Metformin use is associated with a reduction in all-cause mortality, cardiovascular mortality, incidence of coronary revascularisation, and heart failure in patients with CVD; however, metformin usage was not associated with reduction in the incidence of myocardial infarction, angina, or stroke.
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Affiliation(s)
- Tian Li
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China
| | | | - Wenhua Jiang
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China
| | - Manling Liu
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China
| | - Lu Yu
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Chunhu Gu
- Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China
| | - Alex Chia Yu Chang
- Department of Cardiology and Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 211125, China.
| | - Heng Ma
- Department of Physiology and Pathophysiology, Fourth Military Medical University, No. 169 Changle West Rd, Xi'an, 710032, China.
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Geng X, Duan H, Kohls W, Ilagan R, Ding Y. Mini review: Hyperglycemia in ischemic stroke. ENVIRONMENTAL DISEASE 2022. [DOI: 10.4103/ed.ed_26_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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Agostini F, Masato A, Bubacco L, Bisaglia M. Metformin Repurposing for Parkinson Disease Therapy: Opportunities and Challenges. Int J Mol Sci 2021; 23:ijms23010398. [PMID: 35008822 PMCID: PMC8745385 DOI: 10.3390/ijms23010398] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/23/2021] [Accepted: 12/28/2021] [Indexed: 02/07/2023] Open
Abstract
Parkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally well-tolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological α-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy.
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Affiliation(s)
- Francesco Agostini
- Department of Biology, University of Padova, 35121 Padova, Italy; (F.A.); (A.M.)
| | - Anna Masato
- Department of Biology, University of Padova, 35121 Padova, Italy; (F.A.); (A.M.)
| | - Luigi Bubacco
- Department of Biology, University of Padova, 35121 Padova, Italy; (F.A.); (A.M.)
- Center Study for Neurodegeneration (CESNE), University of Padova, 35121 Padova, Italy
- Correspondence: (L.B.); (M.B.)
| | - Marco Bisaglia
- Department of Biology, University of Padova, 35121 Padova, Italy; (F.A.); (A.M.)
- Center Study for Neurodegeneration (CESNE), University of Padova, 35121 Padova, Italy
- Correspondence: (L.B.); (M.B.)
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Wang Y, Xiong M, Wang M, Chen H, Li W, Zhou X. Quercetin promotes locomotor function recovery and axonal regeneration through induction of autophagy after spinal cord injury. Clin Exp Pharmacol Physiol 2021; 48:1642-1652. [PMID: 34407225 DOI: 10.1111/1440-1681.13573] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 12/22/2022]
Abstract
Quercetin (Que), one of the flavonoids, exerts numerous actions on the central nervous system. However, the roles and underlying mechanism of Que in locomotor function recovery and axonal regeneration following spinal cord injury (SCI) have not been fully elucidated. A rat model of spinal cord injury (SCI) was established at T10 using the modified Allen's method. The results in our study indicated that Basso, Beattie and Bresnahan (BBB) locomotor scores were significantly higher after Que treatment. Additionally, Que administration cut down the latency of somatosensory evoked potentials (SEP) and motor evoked potentials (MEP), increased the amplitude of MEP and SEP following SCI. Hematoxylin-eosin (HE) staining demonstrated that Que administration reduced lesion size and cavity formation. Biotinylated dextran amine (BDA) anterograde tracing revealed that BDA positive fibres were increased by Que following SCI. Immunofluorescence staining revealed that Que elevated 5-hydroxytryptamine (5-HT) positive nerve fibres and neurofilament-200 (NF-200) positive neurons, reduced glial fibrillary acidic protein (GFAP) positive astrocytes. In addition, Que inhibited GFAP expression, increased both NeuN and NF-200 expression and facilitated the spinal cord energy metabolism. Moreover, Que increased 18 F-FDG uptake in a time-dependent manner. Furthermore, Que increased Beclin 1 and LC3 II expression, blocked the phosphorylation of Akt, mTOR and p70S6K. 3-methyladenine (3-MA) partly abolished the neuro-protective roles of Que following SCI. Taken together, our study suggested that Que might promote locomotor function recovery, axonal regeneration and energy metabolism through induction of autophagy via Akt/mTOR/p70S6K pathway.
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Affiliation(s)
- Yeyang Wang
- Department of Spine, Orthopaedic Center, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Man Xiong
- Department of Gastroenterology, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Mingsen Wang
- Department of Orthopedic, Traditional Chinese Medicine Hospital of Puning City, Orthopaedic Hospital of Puning City, Puning, China
| | - Hongdong Chen
- Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Wenjun Li
- Department of Joint, Orthopaedic Center, Guangdong Second Provincial General Hospital, Guangzhou, China
| | - Xiaozhong Zhou
- Department of Spine, Orthopaedic Center, Guangdong Second Provincial General Hospital, Guangzhou, China
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Wang K, Hu H, Cui W, Zhang X, Tang Q, Liu N, Lan X, Pan C. Palliative effects of metformin on testicular damage induced by triptolide in male rats. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 222:112536. [PMID: 34303043 DOI: 10.1016/j.ecoenv.2021.112536] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 06/13/2023]
Abstract
As a widely existing traditional Chinese medicine component, TP (triptolide) has serious reproductive toxicity which causes severe damage to the reproductive system and limits its application prospect. TP and MET (metformin) have shown great potential in combined with each other in anticancer and anti-inflammatory. Whether metformin can resist the reproductive toxicity caused by triptolide, the effects of MET on TP-induced reproductive capacity has not been reported. In this study, metformin was used to investigate the therapeutic effect on reproductive toxicity induced by TP in rat. The results showed that metformin had significant therapeutic effects on oxidative stress damage, destruction of the blood-testosterone barrier and apoptosis. And it proved that its therapeutic effect is mainly to restore the structural and functional stability of testis through antioxidant stress. It will provide guidance for the treatment of reproductive toxicity caused by TP and the adjuvant detoxification of TP application.
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Affiliation(s)
- Ke Wang
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi 712100, PR China.
| | - Huina Hu
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi 712100, PR China.
| | - Wenbo Cui
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi 712100, PR China.
| | - Xuelian Zhang
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi 712100, PR China
| | - Qi Tang
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi 712100, PR China
| | - Nuan Liu
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi 712100, PR China
| | - Xianyong Lan
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi 712100, PR China
| | - Chuanying Pan
- College of Animal Science and Technology, Northwest A&F University, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, Key Laboratory of Animal Biotechnology, Ministry of Agriculture, No. 22 Xinong Road, Yangling, Shaanxi 712100, PR China.
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Tu WJ, Zeng Q, Wang K, Wang Y, Sun BL, Zeng X, Liu Q. Prestroke Metformin Use on the 1-Year Prognosis of Intracerebral Hemorrhage Patients with Type 2 Diabetes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:2027359. [PMID: 34567407 PMCID: PMC8457962 DOI: 10.1155/2021/2027359] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/29/2021] [Accepted: 08/16/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND Although recent studies have focused on the use of metformin in treating ischemic stroke, there is little literature to support whether it can treat intracerebral hemorrhage (ICH). Therefore, this study is aimed at evaluating the possible effects of prestroke metformin (MET) on ICH patients with type 2 diabetes. METHODS From January 2010 to December 2019, all first-ever ICH patients with type 2 diabetes from our hospitals were included. All discharged patients would receive a one-time follow-up at 1 year after admission. Death, disability, and recurrence events were recorded. RESULTS We included 730 patients for analysis (the median age: 65 [IQR, 56-72] years and 57.7% was men). Of those patients, 281 (38.5%) had received MET before ICH (MET+), whereas 449 (61.5%) had not (MET-). MET (+) patients had a lower median baseline hematoma volume than did MET (-) patients (9.6 ml [IQR, 5.3-22.4 ml] vs. 14.7 ml [IQR, 7.9-28.6 ml]; P < 0.001). The inhospital mortality events were not significantly reduced in the MET (+) group compared with the MET (-) group (6.4% vs 8.9%, respectively; absolute difference, -2.5% [95% CI, -3.9% to -0.7%]; OR, 0.70 [95% CI, 0.39 to 1.27]; P = 0.22). The 1-year mortality events were not significantly reduced in the MET (+) group compared with the MET (-) group (14.1% vs 17.4%, respectively; absolute difference, -3.3% [95% CI, -5.1% to -1.8%]; OR, 0.73 [95% CI, 0.47 to 1.14]; P = 0.16). The 1-year disability events were not significantly reduced in the MET (+) group compared with the MET (-) group (28.4% vs 34.1%, respectively; absolute difference, -5.7% [95% CI, -8.2% to -3.3%]; OR, 0.77 [95% CI, 0.52 to 1.13]; P = 0.18). Finally, the recurrence rates in those two groups were not significantly different (MET [+] vs. MET [-]: 6.4% vs. 5.9%; absolute difference, 0.5% [95% CI, 0.2% to 1.3%]; OR, 1.08 [95% CI, 0.51 to 2.28]; P = 0.84). CONCLUSIONS Pre-ICH metformin use was not associated with inhospital mortality and 1-year prognosis in diabetic ICH patients.
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Affiliation(s)
- Wen-Jun Tu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Qingjia Zeng
- School of Healthcare Science, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M156GX, UK
| | - Kai Wang
- Department of Neurology, Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yu Wang
- Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Bao-Liang Sun
- Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China
| | - Xianwei Zeng
- Rehabilitation Hospital of the National Research Center for Rehabilitation Technical Aids, Beijing, China
- Department of Neurosurgery, Shandong University Qilu Hospital, Jinan, China
- People's Hospital of Ningjin County, Dezhou, China
| | - Qiang Liu
- Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
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