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Ghayourbabaei F, Farzin M, Keshavarzi Z, Saburi E, Khodadadegan MA, Hajali V. Anxiety-like behaviors in rats exposed to the single and combined program of running exercise and environmental enrichment. Neuroreport 2025; 36:31-38. [PMID: 39651719 DOI: 10.1097/wnr.0000000000002117] [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: 12/11/2024]
Abstract
Exercise (Ex) and environmental enrichment (EE) as the nondrug solutions have positive effects on cognitive behaviors and also increase the ability to cope with anxiety, fear, and stress. In this research, we decided to investigate the simultaneous effect of Ex and EE on anxiety-like behaviors and hippocampal neurogenesis markers in healthy rats. A total of 40 male Wistar rats were divided into four treatment groups: control, EE, Ex, and EE + Ex. Animals in EE groups were housed in large cages (50 × 50 × 50 cm) equipped with toys and objects of different shapes for 3 weeks. Ex-animals were forced to run on a treadmill once a day for 3 consecutive weeks. Open field (OF) and elevated plus maze (EPM) tests were used to evaluate anxiety behaviors. The hippocampal expression of early neurogenesis markers, doublecortin, and sex determining region Y-box 2, were measured using real-time-PCR. Ex and EE animals separately did not show any significant performance in reducing anxiety levels, neither in EPM nor in OF compared with the control group. When animals were treated with EE and Ex simultaneously, they showed significantly reduced anxiety in both EPM and OF tests compared with the control as well as Ex and EE groups separately. Both treatments in combination were also more effective than individual groups in increasing the neurogenesis molecular markers within the hippocampus. This study proposes that Ex in combination with cognitive engagement is more efficient in alleviating anxiety responses and that can develop a nonpharmacological and multidomain policy that may prevent or delay psychophysiological symptoms.
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Affiliation(s)
| | - Mohaya Farzin
- Razi Clinical Research Development Unit, Guilan University of Medical Sciences, Rasht
| | - Zakieh Keshavarzi
- Natural Product and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd
| | - Ehsan Saburi
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad
| | | | - Vahid Hajali
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Abdalla MMI. Insulin resistance as the molecular link between diabetes and Alzheimer's disease. World J Diabetes 2024; 15:1430-1447. [PMID: 39099819 PMCID: PMC11292327 DOI: 10.4239/wjd.v15.i7.1430] [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: 02/14/2024] [Revised: 04/08/2024] [Accepted: 05/06/2024] [Indexed: 07/08/2024] Open
Abstract
Diabetes mellitus (DM) and Alzheimer's disease (AD) are two major health concerns that have seen a rising prevalence worldwide. Recent studies have indicated a possible link between DM and an increased risk of developing AD. Insulin, while primarily known for its role in regulating blood sugar, also plays a vital role in protecting brain functions. Insulin resistance (IR), especially prevalent in type 2 diabetes, is believed to play a significant role in AD's development. When insulin signalling becomes dysfunctional, it can negatively affect various brain functions, making individuals more susceptible to AD's defining features, such as the buildup of beta-amyloid plaques and tau protein tangles. Emerging research suggests that addressing insulin-related issues might help reduce or even reverse the brain changes linked to AD. This review aims to explore the rela-tionship between DM and AD, with a focus on the role of IR. It also explores the molecular mechanisms by which IR might lead to brain changes and assesses current treatments that target IR. Understanding IR's role in the connection between DM and AD offers new possibilities for treatments and highlights the importance of continued research in this interdisciplinary field.
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Affiliation(s)
- Mona Mohamed Ibrahim Abdalla
- Department of Human Biology, School of Medicine, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
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3
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Ren J, Xiao H. Exercise Intervention for Alzheimer's Disease: Unraveling Neurobiological Mechanisms and Assessing Effects. Life (Basel) 2023; 13:2285. [PMID: 38137886 PMCID: PMC10744739 DOI: 10.3390/life13122285] [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: 10/31/2023] [Revised: 11/26/2023] [Accepted: 11/29/2023] [Indexed: 12/24/2023] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease and a major cause of age-related dementia, characterized by cognitive dysfunction and memory impairment. The underlying causes include the accumulation of beta-amyloid protein (Aβ) in the brain, abnormal phosphorylation, and aggregation of tau protein within nerve cells, as well as neuronal damage and death. Currently, there is no cure for AD with drug therapy. Non-pharmacological interventions such as exercise have been widely used to treat AD, but the specific molecular and biological mechanisms are not well understood. In this narrative review, we integrate the biology of AD and summarize the knowledge of the molecular, neural, and physiological mechanisms underlying exercise-induced improvements in AD progression. We discuss various exercise interventions used in AD and show that exercise directly or indirectly affects the brain by regulating crosstalk mechanisms between peripheral organs and the brain, including "bone-brain crosstalk", "muscle-brain crosstalk", and "gut-brain crosstalk". We also summarize the potential role of artificial intelligence and neuroimaging technologies in exercise interventions for AD. We emphasize that moderate-intensity, regular, long-term exercise may improve the progression of Alzheimer's disease through various molecular and biological pathways, with multimodal exercise providing greater benefits. Through in-depth exploration of the molecular and biological mechanisms and effects of exercise interventions in improving AD progression, this review aims to contribute to the existing knowledge base and provide insights into new therapeutic strategies for managing AD.
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Affiliation(s)
- Jianchang Ren
- Institute of Sport and Health, Guangdong Provincial Kay Laboratory of Development and Education for Special Needs Child, Lingnan Normal University, Zhanjiang 524037, China
- Institute of Sport and Health, South China Normal University, Guangzhou 510631, China
| | - Haili Xiao
- Institute of Sport and Health, Lingnan Normal University, Zhanjiang 524037, China;
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Zhou Y, Xu B. New insights into anti-diabetes effects and molecular mechanisms of dietary saponins. Crit Rev Food Sci Nutr 2023; 63:12372-12397. [PMID: 35866515 DOI: 10.1080/10408398.2022.2101425] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Diabetes mellitus (DM) is a long-term metabolic disorder that manifests as chronic hyperglycemia and impaired insulin, bringing a heavy load on the global health care system. Considering the inevitable side effects of conventional anti-diabetic drugs, saponins-rich natural products exert promising therapeutic properties to serve as safer and more cost-effective alternatives for DM management. Herein, this review systematically summarized the research progress on the anti-diabetic properties of dietary saponins and their underlying molecular mechanisms in the past 20 years. Dietary saponins possessed the multidirectional anti-diabetic capabilities by concurrent regulation of various signaling pathways, such as IRS-1/PI3K/Akt, AMPK, Nrf2/ARE, NF-κB-NLRP3, SREBP-1c, and PPARγ, in liver, pancreas, gut, and skeletal muscle. However, the industrialization and commercialization of dietary saponin-based drugs are confronted with a significant challenge due to the low bioavailability and lack of the standardization. Hence, in-depth evaluations in pharmacological profile, function-structure interaction, drug-signal pathway interrelation are essential for developing dietary saponins-based anti-diabetic treatments in the future.
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Affiliation(s)
- Yifan Zhou
- Food Science and Technology Program, BNU-HKBU United International College, Zhuhai, Guangdong, China
- Department of Food Science and Technology, National University of Singapore, Singapore, Singapore
| | - Baojun Xu
- Food Science and Technology Program, BNU-HKBU United International College, Zhuhai, Guangdong, China
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Simulated Microgravity Alters P-Glycoprotein Efflux Function and Expression via the Wnt/β-Catenin Signaling Pathway in Rat Intestine and Brain. Int J Mol Sci 2023; 24:ijms24065438. [PMID: 36982513 PMCID: PMC10049079 DOI: 10.3390/ijms24065438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/03/2023] [Accepted: 03/08/2023] [Indexed: 03/18/2023] Open
Abstract
The drug efflux transporter permeability glycoprotein (P-gp) plays an important role in oral drug absorption and distribution. Under microgravity (MG), the changes in P-gp efflux function may alter the efficacy of oral drugs or lead to unexpected effects. Oral drugs are currently used to protect and treat multisystem physiological damage caused by MG; whether P-gp efflux function changes under MG remains unclear. This study aimed to investigate the alteration of P-gp efflux function, expression, and potential signaling pathway in rats and cells under different simulated MG (SMG) duration. The altered P-gp efflux function was verified by the in vivo intestinal perfusion and the brain distribution of P-gp substrate drugs. Results showed that the efflux function of P-gp was inhibited in the 7 and 21 day SMG-treated rat intestine and brain and 72 h SMG-treated human colon adenocarcinoma cells and human cerebral microvascular endothelial cells. P-gp protein and gene expression levels were continually down-regulated in rat intestine and up-regulated in rat brain by SMG. P-gp expression was regulated by the Wnt/β-catenin signaling pathway under SMG, verified by a pathway-specific agonist and inhibitor. The elevated intestinal absorption and brain distribution of acetaminophen levels also confirmed the inhibited P-gp efflux function in rat intestine and brain under SMG. This study revealed that SMG alters the efflux function of P-gp and regulates the Wnt/β-catenin signaling pathway in the intestine and the brain. These findings may be helpful in guiding the use of P-gp substrate drugs during spaceflight.
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Saheb M, Khodadadegan MA, Sahab Negah S, Saburi E, Hajali V. Effect of a combined program of running exercise and environmental enrichment on memory function and neurogenesis markers in amyloid-beta-induced Alzheimer-like model. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2023; 26:1400-1408. [PMID: 37970437 PMCID: PMC10634047 DOI: 10.22038/ijbms.2023.70269.15277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 05/31/2023] [Indexed: 11/17/2023]
Abstract
Objectives It is urgent to develop non-pharmacological interventions or multifactor combination approaches to combat Alzheimer's disease (AD). The effect of exercise (EX) combined with environmental enrichment (EE) on behavioral phenotypes and neurogenesis markers in an Alzheimer-like rat model was investigated. Materials and Methods The groups consisted of AD, sham-operated, AD+EX, AD+EE, and AD+EX+EE. AD was produced by injection of amyloid-beta (1-42, 6 µg) intrahippocampally, and a daily treadmill for 3 consecutive weeks was used for EX animals. EE was a large cage (50× 50× 50 cm) containing differently shaped objects. Spatial learning and memory were evaluated in the Morris water maze (MWM), and a shuttle box was used to evaluate inhibitory avoidance memory. RT-PCR was performed to assess the expression of early neurogenesis markers, DCX, and Sox2 within the hippocampus. Results Pretreatment with exercise and EE, both individually and in combination, could provide protection from memory impairments in AD rats. Combined treatment led to a significantly more pronounced improvement in memory deficits of AD rats than either paradigm alone. Combination therapy with exercise and EE could also reverse the passive avoidance memory impairment and hippocampal DCX expression of AD rats to the control levels. Conclusion These data suggest that exercise in combination with cognitive engagement can provide a non-pharmacological and multidomain policy that may prevent or delay AD symptoms.
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Affiliation(s)
- Mahsa Saheb
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Sajad Sahab Negah
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ehsan Saburi
- Medical Genetics and Molecular Medicine Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Hajali
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Ryu YC, Kim YR, Park J, Choi S, Kim GU, Kim E, Hwang Y, Kim H, Bak SS, Lee JE, Sung YK, Han G, Lee SH, Choi KY. Wnt/β-catenin signaling activator restores hair regeneration suppressed by diabetes mellitus. BMB Rep 2022; 55:559-564. [PMID: 36016500 PMCID: PMC9712708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus is one of the most prevalent diseases in modern society. Many complicationssuch as hepatic cirrhosis, neuropathy, cardiac infarction, and so on are associated with diabetes. Although a relationship between diabetes and hair loss has been recently reported, the treatment of diabetic hair loss by Wnt/β-catenin activators has not been achieved yet. In this study, we found that the depilation-induced anagen phase was delayed in both db/db mice and high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice. In diabetic mice, both hair regrowth and wound-induced hair follicle neogenesis (WIHN) were reduced because of suppression of Wnt/β-catenin signaling and decreased proliferation of hair follicle cells. We identified that KY19382, a small molecule that activates Wnt/β-catenin signaling, restored the capabilities of regrowth and WIHN in diabetic mice. The Wnt/β-catenin signaling activator also increased the length of the human hair follicle which was decreased under high glucose culture conditions. Overall, the diabetic condition reduced both hair regrowth and regeneration with suppression of the Wnt/β-catenin signaling pathway. Consequently, the usage of Wnt/β-catenin signaling activators could be a potential strategy to treat diabetes-induced alopecia patients. [BMB Reports 2022; 55(11): 559-564].
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Affiliation(s)
- Yeong Chan Ryu
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - You-rin Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jiyeon Park
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Sehee Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Geon-Uk Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Eunhwan Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Yumi Hwang
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Heejene Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Soon Sun Bak
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Jin Eun Lee
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Young Kwan Sung
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Gyoonhee Han
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Soung-Hoon Lee
- CK Regeon Inc., Engineering Research Park, Seoul 03722, Korea,Corresponding authors. Kang-Yell Choi, Tel: +82-2-2123-7438; Fax: +82-2-2123-8284; E-mail: ; Soung-Hoon Lee, Tel: +82-2-2123-7438; Fax: +82-2-2123-8284; E-mail: sexyondal@ gmail.com
| | - Kang-Yell Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea,CK Regeon Inc., Engineering Research Park, Seoul 03722, Korea,Corresponding authors. Kang-Yell Choi, Tel: +82-2-2123-7438; Fax: +82-2-2123-8284; E-mail: ; Soung-Hoon Lee, Tel: +82-2-2123-7438; Fax: +82-2-2123-8284; E-mail: sexyondal@ gmail.com
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Ryu YC, Kim YR, Park J, Choi S, Kim GU, Kim E, Hwang Y, Kim H, Bak SS, Lee JE, Sung YK, Han G, Lee SH, Choi KY. Wnt/β-catenin signaling activator restores hair regeneration suppressed by diabetes mellitus. BMB Rep 2022; 55:559-564. [PMID: 36016500 PMCID: PMC9712708 DOI: 10.5483/bmbrep.2022.55.11.081] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 05/31/2022] [Accepted: 08/02/2022] [Indexed: 08/30/2023] Open
Abstract
Diabetes mellitus is one of the most prevalent diseases in modern society. Many complicationssuch as hepatic cirrhosis, neuropathy, cardiac infarction, and so on are associated with diabetes. Although a relationship between diabetes and hair loss has been recently reported, the treatment of diabetic hair loss by Wnt/β-catenin activators has not been achieved yet. In this study, we found that the depilation-induced anagen phase was delayed in both db/db mice and high-fat diet (HFD) and streptozotocin (STZ)-induced diabetic mice. In diabetic mice, both hair regrowth and wound-induced hair follicle neogenesis (WIHN) were reduced because of suppression of Wnt/β-catenin signaling and decreased proliferation of hair follicle cells. We identified that KY19382, a small molecule that activates Wnt/β-catenin signaling, restored the capabilities of regrowth and WIHN in diabetic mice. The Wnt/β-catenin signaling activator also increased the length of the human hair follicle which was decreased under high glucose culture conditions. Overall, the diabetic condition reduced both hair regrowth and regeneration with suppression of the Wnt/β-catenin signaling pathway. Consequently, the usage of Wnt/β-catenin signaling activators could be a potential strategy to treat diabetes-induced alopecia patients. [BMB Reports 2022; 55(11): 559-564].
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Affiliation(s)
- Yeong Chan Ryu
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - You-rin Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Jiyeon Park
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Sehee Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Geon-Uk Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Eunhwan Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Yumi Hwang
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Heejene Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Soon Sun Bak
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Jin Eun Lee
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Young Kwan Sung
- Department of Immunology, School of Medicine, Kyungpook National University, Daegu 41944, Korea
| | - Gyoonhee Han
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
| | - Soung-Hoon Lee
- CK Regeon Inc., Engineering Research Park, Seoul 03722, Korea
| | - Kang-Yell Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea
- CK Regeon Inc., Engineering Research Park, Seoul 03722, Korea
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Zhou XP, Zhang LM, Chen GQ, Wang SW, He JF, Li Z, Zhang BS. Meta analysis of aerobic exercise improving intelligence and cognitive function in patients with Alzheimer's disease. Medicine (Baltimore) 2022; 101:e31177. [PMID: 36281092 PMCID: PMC9592430 DOI: 10.1097/md.0000000000031177] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Alzheimer's disease (AD) is a neurodegenerative disease. This study aims to explore the intervention and treatment effects of aerobic exercise and different exercise modes on AD through meta-analysis. METHODS Using the set inclusion and exclusion criteria, retrieve the China national knowledge infrastructure (CNKI), Wanfang Data Knowledge Service Platform, China Science and Technology Journal Database, Cochrane Library, and PubMed were searched from January 1, 2012, to December 31, 2021. Cochrane risk bias assessment tool was used to evaluate the quality of the included articles, and ReMan5.4.1 was used for forest plot analysis of mini-mental state exam (MMSE) score indicators included in the included articles. RESULTS Twelve randomized controlled trials and 795 samples were included. Meta analysis of all articles: I2 = 91%, P ≤ .00001, (MD = 2.95, 95%CI [2.49, 3.40], P ≤ .00001). Meta analysis of 5 fit aerobics groups: I2 = 4%, P = .38, (MD = 1.53, 95%CI [0.72, 2.33], P = .0002); meta-analysis of three spinning groups: I2 = 3%, P = .36, (MD = 1.79, 95%CI [0.29, 3.29], P = .02). CONCLUSION Aerobic exercise can effectively improve intellectual and cognitive impairment in AD patients, and for different forms of aerobic exercise, the therapeutic effect of spinning aerobic exercise is better than that of fit aerobics.
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Affiliation(s)
- Xin-Pei Zhou
- College of basic medicine, Dali University, Dali, Yunnan, China
| | - Li-Mei Zhang
- College of basic medicine, Dali University, Dali, Yunnan, China
| | - Guo-Qiang Chen
- College of clinical medicine, Dali University, Dali, Yunnan, China
| | - Shen-Wu Wang
- College of clinical medicine, Dali University, Dali, Yunnan, China
| | - Jin-Fen He
- College of clinical medicine, Dali University, Dali, Yunnan, China
| | - Zhuang Li
- College of clinical medicine, Dali University, Dali, Yunnan, China
| | - Ben-Si Zhang
- College of basic medicine, Dali University, Dali, Yunnan, China
- *Correspondence: Bensi Zhang, College of basic medicine, Dali University, 671000 Dali, Yunnan, China (e-mail: )
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Liu H, Wei T, Huang Q, Liu W, Yang Y, Jin Y, Wu D, Yuan K, Zhang P. The roles, mechanism, and mobilization strategy of endogenous neural stem cells in brain injury. Front Aging Neurosci 2022; 14:924262. [PMID: 36062152 PMCID: PMC9428262 DOI: 10.3389/fnagi.2022.924262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Brain injury poses a heavy disease burden in the world, resulting in chronic deficits. Therapies for brain injuries have been focused on pharmacologic, small molecule, endocrine and cell-based therapies. Endogenous neural stem cells (eNSCs) are a group of stem cells which can be activated in vivo by damage, neurotrophic factors, physical factor stimulation, and physical exercise. The activated eNSCs can proliferate, migrate and differentiate into neuron, oligodendrocyte and astrocyte, and play an important role in brain injury repair and neural plasticity. The roles of eNSCs in the repair of brain injury include but are not limited to ameliorating cognitive function, improving learning and memory function, and promoting functional gait behaviors. The activation and mobilization of eNSCs is important to the repair of injured brain. In this review we describe the current knowledge of the common character of brain injury, the roles and mechanism of eNSCs in brain injury. And then we discuss the current mobilization strategy of eNSCs following brain injury. We hope that a comprehensive awareness of the roles and mobilization strategy of eNSCs in the repair of cerebral ischemia may help to find some new therapeutic targets and strategy for treatment of stroke.
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Affiliation(s)
- Haijing Liu
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Tao Wei
- Library, Kunming Medical University, Kunming, China
- School of Continuing Education, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Qin Huang
- Department of Teaching Affairs and Administration, Kunming Medical University, Kunming, China
| | - Wei Liu
- School of Public Health, Kunming Medical University, Kunming, China
| | - Yaopeng Yang
- Department of Pulmonary and Critical Care Medicine, The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, China
| | - Yaju Jin
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Danli Wu
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Kai Yuan
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Pengyue Zhang
- Key Laboratory of Acupuncture and Massage for Treatment of Encephalopathy, College of Acupuncture, Tuina and Rehabilitation, Yunnan University of Traditional Chinese Medicine, Kunming, China
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11
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Zhao Y, Yu J, Ping F, Xu L, Li W, Zhang H, Li Y. Insulin and liraglutide attenuate brain pathology in diabetic mice by enhancing the Wnt/β‑catenin signaling pathway. Exp Ther Med 2022; 24:439. [PMID: 35720633 PMCID: PMC9185805 DOI: 10.3892/etm.2022.11366] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/05/2022] [Indexed: 11/06/2022] Open
Abstract
Insulin and liraglutide have been demonstrated to control blood glucose and exert neuroprotective effects. However, the impact of liraglutide or insulin alone or in combination on brain pathology in type 1 diabetes mellitus (T1DM) and their underlying mechanisms are unclear. In the present study, diabetes mellitus (DM) was induced via intraperitoneal injection of streptozotocin in mice and subsequently mice were treated with insulin, liraglutide, a combination of the two drugs or saline. Changes in body weight and blood glucose were assessed weekly. The pathological changes in the brain tissue and the apoptosis of neurons were assessed using H&E staining and TUNEL staining. The mRNA and protein expression levels of apoptosis-related proteins were detected using reverse transcription-quantitative PCR (RT-qPCR) and western blotting, respectively. Moreover, Ki67 protein expression was analyzed using immunohistochemistry and the mRNA and protein expression levels of Wnt/β-catenin signaling pathway-related proteins were examined using RT-qPCR and western blotting, respectively. The results of the present study suggested that DM mice developed hyperglycemia and weight loss and also exhibited significantly increased neural cell apoptosis and significantly reduced numbers of Ki67-positive cells. Liraglutide significantly decreased blood glucose levels in DM mice, whereas both insulin and the combination of the two drugs failed to control blood glucose well. Insulin, liraglutide and their combination also failed to control body weight well, but significantly attenuated brain pathological changes and activation of the pro-apoptotic proteins Caspase-3 and Bax, which may have resulted in the significant increase in the expression levels of Wnt/β-catenin signaling pathway-associated molecules such as Wnt3a and S9-pGSK-3β. Liraglutide also promoted the protein expression of the neurogenesis marker of Ki67 and the antiapoptotic factor Bcl-2. These results suggested that insulin and liraglutide may improve brain damage via upregulation of the Wnt/β-catenin signaling pathway and could be of therapeutic relevance for improvement of cognitive impairment in patients with DM.
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Affiliation(s)
- Yuan Zhao
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Jie Yu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Fan Ping
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Lingling Xu
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Wei Li
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Huabing Zhang
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
| | - Yuxiu Li
- Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China
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12
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El-Safty H, Ismail A, Abdelsalam RM, El-Sahar AE, Saad MA. Dapagliflozin diminishes memory and cognition impairment in Streptozotocin induced diabetes through its effect on Wnt/β-Catenin and CREB pathway. Brain Res Bull 2022; 181:109-120. [PMID: 35093471 DOI: 10.1016/j.brainresbull.2022.01.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 12/22/2022]
Abstract
Diabetic neuropathy is a chronic condition that affects a significant number of individuals with diabetes. Streptozotocin injection intraperitoneally to rodents produces pancreatic islet β-cell destruction causing hyperglycemia, which affect the brain leading to memory and cognition impairment. Dapagliflozin may be able to reverse beta-cell injury and alleviate this impairment. This effect may be via neuroprotective effect or possible involvement of the antioxidant, and anti-apoptotic properties. Forty rats were divided into four groups as follows: The normal control group, STZ-induced diabetes group, STZ-induced diabetic rats followed by treatment with oral dapagliflozin group and normal rats treated with oral dapagliflozin. Behavioral tests (Object location memory task and Morris water maze) were performed. Serum biomarkers (blood glucose and insulin) were measured and then the homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. In the hippocampus the followings were determined; calmodulin, ca-calmodulin kinase Ⅳ (CaMKIV), protein kinase A (PKA) and cAMP-responsive element-binding protein to determine the transcription factor CREB and its signaling pathway also Wnt signaling pathway and related parameters (WnT, B-catenin, lymphoid enhancer binding factor LEF, glycogen synthase kinase 3β). Moreover, nuclear receptor-related protein-1, acetylcholine and its hydrolyzing enzyme acetylcholine esterase, oxidative stress parameter malondialdehyde (MDA) and apoptotic parameter caspase-3 were determined. STZ was able to cause destruction to pancreatic β-cells which was reflected on glucose levels causing diabetes. Diabetic neuropathy was clear in the rats performing the behavioral tests. Memory and cognition parameters in the hippocampus were negatively affected. Oxidative stress and apoptotic parameter were elevated while the electrical activity was declined. Dapagliflozin was able to reverse the previously mentioned parameters and behavior. Thus, to say dapagliflozin significantly showed neuroprotective action along with antioxidant, and anti-apoptotic properties.
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Affiliation(s)
- Hala El-Safty
- National Institute of Diabetes and Endocrinology, Cairo, Egypt.
| | - Ashraf Ismail
- Research and Training Center, National Institute of Diabetes and Endocrinology, Cairo, Egypt
| | - Rania M Abdelsalam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; School of Pharmacy, Newgiza University, Cairo, Egypt
| | - Ayman E El-Sahar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Muhammed A Saad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; School of Pharmacy, Newgiza University, Cairo, Egypt
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13
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Narvaes RF, Furini CRG. Role of Wnt signaling in synaptic plasticity and memory. Neurobiol Learn Mem 2021; 187:107558. [PMID: 34808336 DOI: 10.1016/j.nlm.2021.107558] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 10/15/2021] [Accepted: 11/15/2021] [Indexed: 12/24/2022]
Abstract
Ever since their discoveries, the Wnt pathways have been consistently associated with key features of cellular development, including metabolism, structure and cell fate. The three known pathways (the canonical Wnt/β-catenin and the two non-canonical Wnt/Ca++ and Wnt/JNK/PCP pathways) participate in complex networks of interaction with a wide range of regulators of cell function, such as GSK-3β, AKT, PKC and mTOR, among others. These proteins are known to be involved in the formation and maintenance of memory. Currently, studies with Wnt and memory have shown that the canonical and non-canonical pathways play key roles in different processes associated with memory. So, in this review we briefly summarize the different roles that Wnt signaling can play in neurons and in memory, as well as in Alzheimer's disease, focusing towards animal studies. We start with the molecular characterization of the family and its receptors, as well as the most commonly used drugs for pharmacological manipulations. Next, we describe its role in synaptic plasticity and memory, and how the regulations of these pathways affect crucial features of neuronal function. Furthermore, we succinctly present the current knowledge on how the Wnt pathways are implicated in Alzheimer's disease, and how studies are seeing them as a potential candidate for effective treatments. Lastly, we point toward challenges of Wnt research, and how knowledge on these pathways can lead towards a better understanding of neurobiological and pathological processes.
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Affiliation(s)
- Rodrigo F Narvaes
- Laboratory of Cognition and Memory Neurobiology, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - 3rd floor, 90610-000 Porto Alegre, RS, Brazil.
| | - Cristiane R G Furini
- Laboratory of Cognition and Memory Neurobiology, Brain Institute, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Av. Ipiranga, 6690 - 3rd floor, 90610-000 Porto Alegre, RS, Brazil.
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14
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Nie X, Wei X, Ma H, Fan L, Chen WD. The complex role of Wnt ligands in type 2 diabetes mellitus and related complications. J Cell Mol Med 2021; 25:6479-6495. [PMID: 34042263 PMCID: PMC8278111 DOI: 10.1111/jcmm.16663] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 05/02/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the major chronic diseases, whose prevalence is increasing dramatically worldwide and can lead to a range of serious complications. Wnt ligands (Wnts) and their activating Wnt signalling pathways are closely involved in the regulation of various processes that are important for the occurrence and progression of T2DM and related complications. However, our understanding of their roles in these diseases is quite rudimentary due to the numerous family members of Wnts and conflicting effects via activating the canonical and/or non-canonical Wnt signalling pathways. In this review, we summarize the current findings on the expression pattern and exact role of each human Wnt in T2DM and related complications, including Wnt1, Wnt2, Wnt2b, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt7b, Wnt8a, Wnt8b, Wnt9a, Wnt9b, Wnt10a, Wnt10b, Wnt11 and Wnt16. Moreover, the role of main antagonists (sFRPs and WIF-1) and coreceptor (LRP6) of Wnts in T2DM and related complications and main challenges in designing Wnt-based therapeutic approaches for these diseases are discussed. We hope a deep understanding of the mechanistic links between Wnt signalling pathways and diabetic-related diseases will ultimately result in a better management of these diseases.
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Affiliation(s)
- Xiaobo Nie
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Xiaoyun Wei
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Han Ma
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Lili Fan
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Sciences, People's Hospital of Hebi, Henan University, Kaifeng, China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
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15
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Yıldırım AB. The effect of exercise on the total number of BrdU + cell counts in rats' hippocampal dentate gyrus: A meta-analysis study. Brain Res 2021; 1766:147512. [PMID: 33961895 DOI: 10.1016/j.brainres.2021.147512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/26/2021] [Accepted: 04/30/2021] [Indexed: 11/17/2022]
Affiliation(s)
- Ayşegül Burçin Yıldırım
- Gaziantep Islam, Science and Technology University, Faculty of Medicine, Histology-Embriyology Department, Turkey
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16
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Patel D, Zhang X, Farrell JJ, Chung J, Stein TD, Lunetta KL, Farrer LA. Cell-type-specific expression quantitative trait loci associated with Alzheimer disease in blood and brain tissue. Transl Psychiatry 2021; 11:250. [PMID: 33907181 PMCID: PMC8079392 DOI: 10.1038/s41398-021-01373-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/24/2021] [Accepted: 04/08/2021] [Indexed: 02/02/2023] Open
Abstract
Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1 Mb of genes was evaluated using linear regression models for unrelated subjects and linear-mixed models for related subjects. Cell-type-specific eQTL (ct-eQTL) models included an interaction term for the expression of "proxy" genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell types is supported by the observation that a large portion of GWS ct-eQTLs map within 1 Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type-specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type-specific analysis.
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Affiliation(s)
- Devanshi Patel
- Bioinformatics Graduate Program, Boston University, Boston, MA, USA
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
| | - Xiaoling Zhang
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - John J Farrell
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
| | - Jaeyoon Chung
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA
| | - Thor D Stein
- Department of Pathology & Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA
- VA Boston Healthcare System, Boston, MA, USA
- Department of Veterans Affairs Medical Center, Bedford, MA, USA
| | - Kathryn L Lunetta
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Lindsay A Farrer
- Bioinformatics Graduate Program, Boston University, Boston, MA, USA.
- Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, USA.
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
- Departments of Neurology and Ophthalmology, Boston University School of Medicine, Boston, MA, USA.
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.
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17
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alinejad H, abbassi daloii A, farzanegi P, abdi A. Response of Cardiac Tissue β-catenin and GSK-3β to Aerobic Training and Hyaluronic Acid in Knee OA Model Rats. MEDICAL LABORATORY JOURNAL 2021. [DOI: 10.29252/mlj.15.1.45] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
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18
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From Obesity to Hippocampal Neurodegeneration: Pathogenesis and Non-Pharmacological Interventions. Int J Mol Sci 2020; 22:ijms22010201. [PMID: 33379163 PMCID: PMC7796248 DOI: 10.3390/ijms22010201] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/21/2020] [Accepted: 12/23/2020] [Indexed: 12/16/2022] Open
Abstract
High-caloric diet and physical inactivity predispose individuals to obesity and diabetes, which are risk factors of hippocampal neurodegeneration and cognitive deficits. Along with the adipose-hippocampus crosstalk, chronically inflamed adipose tissue secretes inflammatory cytokine could trigger neuroinflammatory responses in the hippocampus, and in turn, impairs hippocampal neuroplasticity under obese and diabetic conditions. Hence, caloric restriction and physical exercise are critical non-pharmacological interventions to halt the pathogenesis from obesity to hippocampal neurodegeneration. In response to physical exercise, peripheral organs, including the adipose tissue, skeletal muscles, and liver, can secret numerous exerkines, which bring beneficial effects to metabolic and brain health. In this review, we summarized how chronic inflammation in adipose tissue could trigger neuroinflammation and hippocampal impairment, which potentially contribute to cognitive deficits in obese and diabetic conditions. We also discussed the potential mechanisms underlying the neurotrophic and neuroprotective effects of caloric restriction and physical exercise by counteracting neuroinflammation, plasticity deficits, and cognitive impairments. This review provides timely insights into how chronic metabolic disorders, like obesity, could impair brain health and cognitive functions in later life.
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19
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Sakr HI, Amen MA, Rashed LA, Khowailed AA, Sayed HA, Motawee ME, Sakr H, Khalifa MM. Comparing prophylactic effect of exercise and metformin on cognitive brain functions in rats with type 3 diabetes mellitus. Arch Med Sci 2020; 20:618-631. [PMID: 38757028 PMCID: PMC11094824 DOI: 10.5114/aoms.2020.99023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 03/26/2020] [Indexed: 05/18/2024] Open
Abstract
Introduction Type 2 diabetes mellitus (DM) and Alzheimer's disease (AD) are two major medical conditions that constitute a significant financial burden on most healthcare systems. Due to AD sharing "insulin resistance" mechanistic features with DM, some scientists have proposed "type 3 DM" terminology for it. This study aims to compare the prophylactic effect of exercise and metformin on cognitive brain functions in rats with type 3 DM. Material and methods Two groups of rats were included in the study: the control group (n = 15) and the streptozotocin-induced type 2 diabetic group (n = 45). The diabetic group was subdivided into three equal subgroups: a sedentary non-treated diabetic group, an exercised group, and a metformin-treated group. We estimated step-down avoidance task latency, serum glucose, insulin, free fatty acids (FFA), cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides (TG), brain Aβ-42 and glucose, histological changes by toluidine blue, and immunohistochemistry for brain Aβ-42 and tau-positive cells. Results Serum glucose, FFA, TG, cholesterol, LDL, brain Aβ-42, brain glucose, the number of hippocampal dark and degenerated cells, and brain Aβ-42 and tau-positive cells, were all significantly lower. In contrast, serum insulin and HDL, the number of hippocampal granular cells, and latency of the step-down avoidance task were significantly higher in exercised and metformin-treated groups compared to the diabetic group. There were significantly higher values of serum insulin and brain/plasma glucose ratio and number of brain tau-positive cells in the metformin-treated group than in the exercised group. Conclusions We can conclude that exercise can be as effective as metformin regarding prophylaxis against the deleterious effects of type 3 DM on cognitive brain functions.
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Affiliation(s)
- Hader Ibrahim Sakr
- Department of Medical Physiology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Mohamed A. Amen
- Department of Medical Physiology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Laila A. Rashed
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Akef A. Khowailed
- Department of Medical Physiology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hazem A. Sayed
- Department of Anatomy and Embryology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Moustafa E. Motawee
- Department of Histology and Cytology, Faculty of Medicine, Alazhar University, Cairo, Egypt
| | - Hany Sakr
- Department of Pathology and Laboratory Medicine, VAMC North East Ohio Healthcare System, Louis Stokes, Cleveland, Ohio, USA
| | - Mohamed Mansour Khalifa
- Department of Medical Physiology, Kasr Alainy Faculty of Medicine, Cairo University, Cairo, Egypt
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20
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Lee CB, Baek SS. Impact of exercise on hippocampal neurogenesis in hyperglycemic diabetes. J Exerc Rehabil 2020; 16:115-117. [PMID: 32509694 PMCID: PMC7248443 DOI: 10.12965/jer.2040210.105] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 03/25/2020] [Indexed: 11/28/2022] Open
Abstract
Hyperglycemic diabetes is a chronic metabolic disorder characterized by high level of plasma glucose. Numerous studies have shown that hy-perglycemic diabetes leads to brain dysfunction including cognitive im-pairment and emotional disorders. This study evaluated the impact of exercise on brain dysfunction, hippocampal neurogenesis, and cogni-tive impairment in hyperglycemic diabetes. The present study suggests that exercise improves hyperglycemic control and prevents decline of cognition through increasing hippocampal neurogenesis. Understanding the mechanism of exercise for hippocampal neurogenesis can lead to the development of therapeutic strategies for metabolic disorders.
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Affiliation(s)
| | - Seung-Soo Baek
- Corresponding author: Seung-Soo Baek, https://orcid.org/0000-0002-1340-2098, Department of Sport & Health Care, College of Art & Culture, Sangmyung University, 20 Hongjimun 2-gil, Jongno-gu, Seoul 03016, Korea, E-mail:
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21
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Rashid MH, Zahid MF, Zain S, Kabir A, Hassan SU. The Neuroprotective Effects of Exercise on Cognitive Decline: A Preventive Approach to Alzheimer Disease. Cureus 2020; 12:e6958. [PMID: 32190507 PMCID: PMC7067577 DOI: 10.7759/cureus.6958] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive disorder that causes brain cells to slowly degenerate and die. This leads to a continuous decline in thinking, behavioral and social skills that disrupts a person's ability to function independently. AD is the most common cause of dementia globally. Neuroinflammation caused by intracellular neurofibrillary tangles and extracellular amyloid deposits leads to atrophy of brain cells especially the hippocampus, which is associated with memory formation. This atrophy leads to dementia and cognitive decline. Among the many preventive factors being studied, exercise is thought to play a vital role in not only preventing the pre-clinical stage of AD but also slowing the clinical progression of AD. It is also deployed as a treatment option for late-stage AD along with pharmacological treatment options. Various studies and clinical trials in both human and animal models are of the opinion that exercise slows the onset and progression of cognitive decline in AD patients. Some studies suggest that this effect is due to a decrease in neurofibrillary tangles and amyloid deposits in brain parenchyma. Others suggest that exercise causes an increase in angiogenesis, neurogenesis, and synaptogenesis mainly due to an increase in blood flow, brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), hormones, and second messengers.
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Affiliation(s)
| | | | - Sarmad Zain
- Internal Medicine, Nishtar Hospital, Nishtar Medical University, Multan, PAK
| | - Ahmad Kabir
- Pathology, Bakhtawar Amin Medical and Dental College, Multan, PAK
| | - Sibt Ul Hassan
- Internal Medicine, Bakhtawar Amin Memorial Hospital, Multan, PAK
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22
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Gholamnezhad Z, Boskabady MH, Jahangiri Z. Exercise and Dementia. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1228:303-315. [PMID: 32342466 DOI: 10.1007/978-981-15-1792-1_20] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Several experimental and human studies documented the preventive and therapeutic effects of exercise on various diseases as well as the normal physiological function of different systems during aging. The findings of several basic animal studies and clinical investigations identified the advantageous effects of exercise as non-pharmaceutical intervention on dementia and Alzheimer's disease (AD). The main positive effects suggested for exercise are less cognitive and behavioral impairment or decline, development of health-associated conditions (stress, sleep), reduction of dementia risk factors including chronic non-communicable disease (diabetes, cardiovascular disease), increase in neurotrophins, enhancement of brain blood flow, angiogenesis, neurogenesis, synaptogenesis and synaptic plasticity in the brain memory-related region (e.g., hippocampus), and reduction of neuroinflammation and apoptosis. However, regarding the controversial evidence in literature, designing standard clinical and experimental studies to reveal the correlation between physical activity and dementia sign and symptom including biomarker alternation, brain supramolecular and molecular changes, and neuropsychological manifestation is necessary for preparation of effective guidelines and recommendations.
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Affiliation(s)
- Zahra Gholamnezhad
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mohammad Hossien Boskabady
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Jahangiri
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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23
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Li B, Liang F, Ding X, Yan Q, Zhao Y, Zhang X, Bai Y, Huang T, Xu B. Interval and continuous exercise overcome memory deficits related to β-Amyloid accumulation through modulating mitochondrial dynamics. Behav Brain Res 2019; 376:112171. [DOI: 10.1016/j.bbr.2019.112171] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Revised: 08/03/2019] [Accepted: 08/21/2019] [Indexed: 12/16/2022]
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24
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Voluntary exercise increases brain tissue oxygenation and spatially homogenizes oxygen delivery in a mouse model of Alzheimer's disease. Neurobiol Aging 2019; 88:11-23. [PMID: 31866158 DOI: 10.1016/j.neurobiolaging.2019.11.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 11/20/2019] [Accepted: 11/22/2019] [Indexed: 11/21/2022]
Abstract
Although vascular contributions to dementia and Alzheimer's disease (AD) are increasingly recognized, the potential brain oxygenation disruption associated with AD and whether preventive strategies to maintain tissue oxygenation are beneficial remain largely unknown. This study aimed to examine (1) whether brain oxygenation is compromised by the onset of AD and (2) how voluntary exercise modulates the influence of AD on brain oxygenation. In vivo 2-photon phosphorescence lifetime microscopy was used to investigate local changes of brain tissue oxygenation with the progression of AD and its modulation by exercise in the barrel cortex of awake transgenic AD mice. Our results show that cerebral tissue oxygen partial pressure (PO2) decreased with the onset of AD. Reduced PO2 was associated with the presence of small near-hypoxic areas, an increased oxygen extraction fraction, and reduced blood flow, observations that were all reverted by exercise. AD and age also increased the spatial heterogeneity of brain tissue oxygenation, which was normalized by exercise. Ex vivo staining also showed fewer amyloid-β (Aβ) deposits in the exercise group. Finally, we observed correlations between voluntary running distance and cerebral tissue oxygenation/blood flow, suggesting a dose-response relationship of exercise on the brain. Overall, this study suggests that compromised brain oxygenation is an indicator of the onset of AD, with the emergence of potential deleterious mechanisms associated with hypoxia. Furthermore, voluntary exercise enhanced the neurovascular oxygenation process, potentially offering a means to delay these changes.
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25
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Granno S, Nixon-Abell J, Berwick DC, Tosh J, Heaton G, Almudimeegh S, Nagda Z, Rain JC, Zanda M, Plagnol V, Tybulewicz VLJ, Cleverley K, Wiseman FK, Fisher EMC, Harvey K. Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus. Sci Rep 2019; 9:7322. [PMID: 31086297 PMCID: PMC6513850 DOI: 10.1038/s41598-019-43820-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 04/29/2019] [Indexed: 12/14/2022] Open
Abstract
Pathological mechanisms underlying Down syndrome (DS)/Trisomy 21, including dysregulation of essential signalling processes remain poorly understood. Combining bioinformatics with RNA and protein analysis, we identified downregulation of the Wnt/β-catenin pathway in the hippocampus of adult DS individuals with Alzheimer's disease and the 'Tc1' DS mouse model. Providing a potential underlying molecular pathway, we demonstrate that the chromosome 21 kinase DYRK1A regulates Wnt signalling via a novel bimodal mechanism. Under basal conditions, DYRK1A is a negative regulator of Wnt/β-catenin. Following pathway activation, however, DYRK1A exerts the opposite effect, increasing signalling activity. In summary, we identified downregulation of hippocampal Wnt/β-catenin signalling in DS, possibly mediated by a dose dependent effect of the chromosome 21-encoded kinase DYRK1A. Overall, we propose that dosage imbalance of the Hsa21 gene DYRK1A affects downstream Wnt target genes. Therefore, modulation of Wnt signalling may open unexplored avenues for DS and Alzheimer's disease treatment.
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Affiliation(s)
- Simone Granno
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
- Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
| | - Jonathon Nixon-Abell
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
- Cell Biology Section, Neurogenetics Branch, National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, USA
| | - Daniel C Berwick
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
- School of Health, Life and Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK6 7AA, UK
| | - Justin Tosh
- Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
| | - George Heaton
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Sultan Almudimeegh
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Zenisha Nagda
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK
| | - Jean-Christophe Rain
- Hybrigenics Services - Fondation Jérôme Lejeune, 3-5 Impasse Reille, 75014, Paris, France
| | - Manuela Zanda
- UCL Genetics Institute, Darwin Building, Gower Street, London, WC1E 6BT, UK
| | - Vincent Plagnol
- UCL Genetics Institute, Darwin Building, Gower Street, London, WC1E 6BT, UK
| | - Victor L J Tybulewicz
- The Francis Crick Institute, 1 Midland Rd, Kings Cross, London, NW1 1AT, UK
- Department of Medicine, Imperial College, London, W12 0NN, UK
- London Down Syndrome Consortium (LonDownS), London, UK
| | - Karen Cleverley
- Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
| | - Frances K Wiseman
- Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
- London Down Syndrome Consortium (LonDownS), London, UK
| | - Elizabeth M C Fisher
- Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK
- London Down Syndrome Consortium (LonDownS), London, UK
| | - Kirsten Harvey
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London, WC1N 1AX, UK.
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Lee JM, Kim TW, Park SS, Kim CJ, Shin MS, Lee SJ, Kim SH, Baek SS. Wnt signaling pathway is implicated in the alleviating effect of treadmill exercise on maternal separation-induced depression. J Exerc Rehabil 2019; 15:200-205. [PMID: 31111001 PMCID: PMC6509450 DOI: 10.12965/jer.1938148.074] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 03/21/2019] [Indexed: 01/31/2023] Open
Abstract
Maternal separation in the developmental stage has a negative influence on brain development and causes depression. The extracellular ligand, Wnt, and its receptors play an important role in axis formation and neural development. Exercise inhibits apoptosis, increases cell proliferation, and exerts antidepressive effect. In this study, the effect of treadmill exercise on the maternal separation-induced depression was investigated in the aspect of Wnt signaling pathway. The maternal separation started on the postnatal day 14. The rat pups in the exercise groups were forced to run on a treadmill for 30 min once a day from postnatal day 21 to postnatal day 34. The rat pups in the maternal separation and fluoxetine-treated group were intraperitoneally injected with 5-mg/kg fluoxetine once a day from postnatal day 21 to postnatal day 34. Forced swimming test was performed to evaluate the depression level. Western blotting was performed for the expressions of Wnt signaling ligands, Wnt2 and Wnt3a, and Wnt signaling inhibitors, Dkk1, and sFRP3. Maternal separation showed depressive behaviors in the forced swimming test. Treadmill exercise alleviated depressive behaviors in the maternal separation rat pups. Expressions of Wnt2 and Wnt3a were decreased by maternal separation. Treadmill exercise alleviated maternal separation-induced reduction of Wnt2 and Wnt3a expressions. Expressions of Dkk1 and sFRP3 in the hippocampus were increased by maternal separation. Treadmill exercise alleviated maternal separation-induced reduction of Dkk1 and sFRP3 expressions. Our study demonstrated that treadmill exercise activates Wnt signaling pathway, and then exerted antidepressive effect.
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Affiliation(s)
- Jae-Min Lee
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Tae-Woon Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Sang-Seo Park
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Chang-Ju Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea
| | - Mal-Soon Shin
- School of Global Sport Studies, Korea University, Sejong, Korea
| | - Sam-Jun Lee
- Department of Physical Education, College of Health, Welfare, and Education, Tong Myong University, Busan, Korea
| | - Sang-Hoon Kim
- Department of Physiology, College of Medicine, Kyung Hee University, Seoul, Korea.,Department of Sport & Health Care, College of Art & Culture, Sangmyung University, Seoul, Korea
| | - Seung-Soo Baek
- Department of Sport & Health Care, College of Art & Culture, Sangmyung University, Seoul, Korea
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Hu S, Yang L, Wu C, Liu TY. Regulation of Wnt signaling by physical exercise in the cell biological processes of the locomotor system. Physiol Int 2019; 106:1-20. [PMID: 30917670 DOI: 10.1556/2060.106.2019.07] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In the past decade, researches on Wnt signaling in cell biology have made remarkable progress regarding our understanding of embryonic development, bone formation, muscle injury and repair, neurogenesis, and tumorigenesis. The study also showed that physical activity can reverse age-dependent decline in skeletal muscle, preventing osteoporosis, regenerative neurogenesis, hippocampal function, cognitive ability, and neuromuscular junction formation, and the age-dependent recession is highly correlated with Wnt signaling pathways. However, how the biological processes in cell and physical activity during/following exercise affect the Wnt signaling path of the locomotor system is largely unknown. In this study, we first briefly introduce the important features of the cellular biological processes of exercise in the locomotor system. Then, we discuss Wnt signaling and review the very few studies that have examined Wnt signaling pathways in cellular biological processes of the locomotor system during physical exercise.
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Affiliation(s)
- S Hu
- 1 College of Physical Education and Sports Science, HengYang Normal University , Hengyang, Hunan, China
| | - L Yang
- 2 Department of Neuroscience and Regenerative Medicine, Augusta University , Augusta, GA, USA
| | - C Wu
- 3 Laboratory of Laser Sports Medicine, College of Physical Education and Sports Science, South China Normal University , Guangzhou, China
| | - Tc-Y Liu
- 3 Laboratory of Laser Sports Medicine, College of Physical Education and Sports Science, South China Normal University , Guangzhou, China
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Jahangiri Z, Gholamnezhad Z, Hosseini M. Neuroprotective effects of exercise in rodent models of memory deficit and Alzheimer's. Metab Brain Dis 2019; 34:21-37. [PMID: 30443769 DOI: 10.1007/s11011-018-0343-y] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Accepted: 11/08/2018] [Indexed: 01/08/2023]
Abstract
Alzheimer's disease (AD) is a fastest growing neurodegenerative condition with no standard treatment. There are growing evidence about the beneficial effects of exercise in brain health promotion and slowing the cognitive decline. The aim of this study was to review the protective mechanisms of treadmill exercise in different models of rodent memory deficits. Online literature database, including PubMed-Medline, Scopus, Google scholar were searched from 2003 till 2017. Original article with English language were chosen according to following key words in the title: (exercise OR physical activity) AND (memory OR learning). Ninety studies were finally included in the qualitative synthesis. The results of these studies showed the protective effects of exercise on AD induced neurodegerative and neuroinflammatory process. Neuroperotective effects of exercise on the hippocampus seem to be increasing in immediate-early gene c-Fos expression in dentate gyrus; enhancing the Wnt3 expression and inhibiting glycogen synthase kinase-3β expression; increasing the 5-bro-mo-2'-deoxyridine-positive and doublecortin-positive cells (dentate gyrus); increasing the level of astrocytes glial fibrillary acidic protein and decrease in S100B protein, increasing in blood brain barrier integrity; prevention of oxidative stress injury, inducing morphological changes in astrocytes in the stratum radiatum of cornu ammonis 1(CA1) area; increase in cell proliferation and suppress apoptosis in dentate gyrus; increase in brain-derived neurotrophic factor and tropomyosin receptor kinase B expressions; enhancing the glycogen levels and normalizing the monocarboxylate transporter 2 expression.
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Affiliation(s)
- Zahra Jahangiri
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Gholamnezhad
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran.
- Department of Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mahmoud Hosseini
- Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, 9177948564, Iran
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Sun Q, Wei LL, Zhang M, Li TX, Yang C, Deng SP, Zeng QC. Rapamycin inhibits activation of AMPK-mTOR signaling pathway-induced Alzheimer's disease lesion in hippocampus of rats with type 2 diabetes mellitus. Int J Neurosci 2018; 129:179-188. [PMID: 29962282 DOI: 10.1080/00207454.2018.1491571] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is strongly correlated with Alzheimer's disease (AD). Rapamycin has important uses in oncology, cardiology and transplantation medicine. This study aims to investigate effects of rapamycin on AD in hippocampus of T2DM rat by AMPK/mTOR signaling pathway. METHODS Morris water maze test was applied to evaluate the learning and memory abilities. The fasting plasma glucose (FBG), glycosylated haemoglobin, total cholesterol, triglyceride and serum insulin level were measured. RT-qPCR and Western blot analysis were performed to test expression of AMPK and mTOR. Immunohistochemistry was used to detect the Aβ deposition and immunoblotting to test the total tau, p-tau and Aβ precursor APP expressions. RESULTS After treated with rapamycin, T2DM rats and rats with T2DM and AD showed increased learning-memory ability, and decreased levels of FBG, glycosylated hemoglobin, total cholesterol, triglyceride and serum insulin, decreased expression of APP and p-tau, increased AMPK mRNA expression and p-AMPK and decreased Aβ deposition, mTOR mRNA expression and p-mTOR. CONCLUSION The study demonstrated that rapamycin reduces the risk of AD in T2DM rats and inhibits activation of AMPK-mTOR signaling pathway, thereby improving AD lesion in hippocampus of T2DM rats.
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Affiliation(s)
- Qin Sun
- a Department of Geratology, Center of Diabetes Mellitus, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine , University of Electronic Science and Technology of China , Chengdu , Sichuan Province , PR China
| | - Ling-Ling Wei
- b Department of Organ Transplantation , Center of Diabetes Mellitus, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China , Chengdu, Sichuan Province , PR China
| | - Min Zhang
- c Department of Geratology , Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital , Chengdu , PR China
| | - Ting-Xin Li
- d Department of General Medicine , Health Management Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital , Chengdu , PR China
| | - Chun Yang
- e Department of Gastrointestinal Surgery , Center of Diabetes Mellitus, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu , Chengdu , PR China
| | - Shao-Ping Deng
- b Department of Organ Transplantation , Center of Diabetes Mellitus, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China , Chengdu, Sichuan Province , PR China
| | - Qing-Cui Zeng
- c Department of Geratology , Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital , Chengdu , PR China
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Li H, Tang Z, Chu P, Song Y, Yang Y, Sun B, Niu M, Qaed E, Shopit A, Han G, Ma X, Peng J, Hu M, Tang Z. Neuroprotective effect of phosphocreatine on oxidative stress and mitochondrial dysfunction induced apoptosis in vitro and in vivo: Involvement of dual PI3K/Akt and Nrf2/HO-1 pathways. Free Radic Biol Med 2018; 120:228-238. [PMID: 29559323 DOI: 10.1016/j.freeradbiomed.2018.03.014] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 03/03/2018] [Accepted: 03/09/2018] [Indexed: 12/15/2022]
Abstract
Methylglyoxal (MGO), an active metabolite of glucose, is observed in high levels in the tissues and blood of diabetic patients. Phosphocreatine (PCr), a high-energy phosphate compound, exhibits a range of pharmacological actions but little is well known of its neuroprotective action. The aim of the present study was to investigate the neuroprotective effects and the possible mechanisms of PCr. Diabetes is closely associated with neurodegenerative diseases, leading not only to the peripheral nervous system (PNS) and but also to central nervous system (CNS) damage. Therefore, we established two rat models of diabetes in vivo induced by MGO and streptozocin (STZ) respectively, while utilized differentiated PC-12 cells in vitro. Treatment of PC-12 cells with PCr markedly attenuated MGO-induced change of viability, apoptosis, accompanied by decreased levels of caspase-3, casapse-9 and Bcl-2/Bax protein ratio. Determination of cellular respiratory function was performed with intact PC-12 cells and homogenized hippocampal neuron tissue of rat. Reactive oxygen species (ROS) generation was assessed by membrane permeable fluorescent probe DCFH-DA. The expressions of Akt, Nrf2 and HO-1 were examined by Western blot. PCr pretreatment significantly reduced oxidative stress-induced high LDH, MDA level, and ROS production of PC-12 cells. PCr pretreatment also significantly decreased mitochondrial dysfunction in vitro and in vivo. In addition, PCr pretreatment increased the expression of p-Akt, Nrf2 and HO-1, and reduced the apoptosis. Moreover, the expression of Cleaved caspase3 was partially increased and the p-Akt, Nrf2 and HO-1 was partially reduced by a PI3K inhibitor (LY294002). While, compared with LY294002 groups, pre-treatment with PCr at the concentrations of 20 mM significantly reduced the expression of Cleaved caspase3 and increased the expression of p-Akt, Nrf2 and HO-1. Molecular docking assay showed that PCr possessed powerful affinity towards to Akt with lower binding energy. In conclusion, the neuroprotective effects of PCr in vitro and in vivo rely on normalizing mitochondrial function and reducing oxidative stress via Akt mediated Nrf2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the treatment of diabetes-associated neurodegenerative diseases.
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Affiliation(s)
- Hailong Li
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Zhongyuan Tang
- Department of Orthodontics, School of Stomatology, Jilin University, 1500 Qinghua Road, Changchun 130021, PR China
| | - Peng Chu
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Yanlin Song
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Ying Yang
- Dalian Medical University, Affiliated Hosp 2, Neurological Intensive Care Un it, Dalian 116027, PR China
| | - Bin Sun
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Mengyue Niu
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Eskandar Qaed
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Abdullah Shopit
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Guozhu Han
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Xiaodong Ma
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Jinyong Peng
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China
| | - Min Hu
- Department of Orthodontics, School of Stomatology, Jilin University, 1500 Qinghua Road, Changchun 130021, PR China.
| | - Zeyao Tang
- Department of Pharmacology, Dalian Medical University, Dalian, Liaoning 116044, PR China.
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Jang Y, Kwon I, Song W, Cosio-Lima LM, Lee Y. Endurance Exercise Mediates Neuroprotection Against MPTP-mediated Parkinson’s Disease via Enhanced Neurogenesis, Antioxidant Capacity, and Autophagy. Neuroscience 2018; 379:292-301. [DOI: 10.1016/j.neuroscience.2018.03.015] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 02/27/2018] [Accepted: 03/12/2018] [Indexed: 12/13/2022]
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Abstract
Alzheimer's disease (AD) is a debilitating disease influencing a multitude of outcomes, including memory function. Recent work suggests that memory may be influenced by exercise ('memorcise'), even among those with AD. The present narrative review details (1) the underlying mechanisms of AD; (2) whether exercise has a protective effect in preventing AD; (3) the mechanisms through which exercise may help to prevent AD; (4) the mechanisms through which exercise may help attenuate the progression of AD severity among those with existing AD; (5) the effects and mechanisms through which exercise is associated with memory among those with existing AD; and (6) exercise recommendations for those with existing AD. Such an understanding will aid clinicians in their ability to use exercise as a potential behavioral strategy to help prevent and treat AD.
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Affiliation(s)
- Paul D Loprinzi
- a Physical Activity Epidemiology Laboratory, Exercise Psychology Laboratory, Department of Health, Exercise Science and Recreation Management , The University of Mississippi , University , MS , USA
| | - Emily Frith
- a Physical Activity Epidemiology Laboratory, Exercise Psychology Laboratory, Department of Health, Exercise Science and Recreation Management , The University of Mississippi , University , MS , USA
| | - Pamela Ponce
- a Physical Activity Epidemiology Laboratory, Exercise Psychology Laboratory, Department of Health, Exercise Science and Recreation Management , The University of Mississippi , University , MS , USA
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Kim JH, Kim DY. Aquarobic exercises improve the serum blood irisin and brain-derived neurotrophic factor levels in elderly women. Exp Gerontol 2018; 104:60-65. [DOI: 10.1016/j.exger.2018.01.024] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 01/23/2018] [Accepted: 01/25/2018] [Indexed: 12/13/2022]
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Azimi M, Gharakhanlou R, Naghdi N, Khodadadi D, Heysieattalab S. Moderate treadmill exercise ameliorates amyloid-β-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway. Peptides 2018; 102:78-88. [PMID: 29309801 DOI: 10.1016/j.peptides.2017.12.027] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/27/2017] [Accepted: 12/29/2017] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder associated with loss of memory and cognitive abilities. Previous evidence suggested that exercise ameliorates learning and memory deficits by increasing brain derived neurotrophic factor (BDNF) and activating downstream pathways in AD animal models. However, upstream pathways related to increase BDNF induced by exercise in AD animal models are not well known. We investigated the effects of moderate treadmill exercise on Aβ-induced learning and memory impairment as well as the upstream pathway responsible for increasing hippocampal BDNF in an animal model of AD. Animals were divided into five groups: Intact, Sham, Aβ1-42, Sham-exercise (Sham-exe) and Aβ1-42-exercise (Aβ-exe). Aβ was microinjected into the CA1 area of the hippocampus and then animals in the exercise groups were subjected to moderate treadmill exercise (for 4 weeks with 5 sessions per week) 7 days after microinjection. In the present study the Morris water maze (MWM) test was used to assess spatial learning and memory. Hippocampal mRNA levels of BDNF, peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), fibronectin type III domain-containing 5 (FNDC5) as well as protein levels of AMPK-activated protein kinase (AMPK), PGC-1α, BDNF, phosphorylation of AMPK were measured. Our results showed that intra-hippocampal injection of Aβ1-42 impaired spatial learning and memory which was accompanied by reduced AMPK activity (p-AMPK/total-AMPK ratio) and suppression of the PGC-1α/FNDC5/BDNF pathway in the hippocampus of rats. In contrast, moderate treadmill exercise ameliorated the Aβ1-42-induced spatial learning and memory deficit, which was accompanied by restored AMPK activity and PGC-1α/FNDC5/BDNF levels. Our results suggest that the increased AMPK activity and up-regulation of the PGC-1α/FNDC5/BDNF pathway by exercise are likely involved in mediating the beneficial effects of exercise on Aβ-induced learning and memory impairment.
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Affiliation(s)
- Mohammad Azimi
- Department of Physical Education and Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran
| | - Reza Gharakhanlou
- Department of Physical Education and Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran.
| | - Nasser Naghdi
- Department of Physiology and Pharmacology, Pasteur Institute of Iran, 13164, Tehran, Iran
| | - Davar Khodadadi
- Department of Physical Education and Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, Iran
| | - Soomaayeh Heysieattalab
- Cognitive Neuroscience Division, Faculty of Education and Psychology, University of Tabriz, Tabriz, Iran
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Lee HJ, Baek SS. Role of exercise on molecular mechanisms in the regulation of antidepressant effects. J Exerc Rehabil 2017; 13:617-620. [PMID: 29326891 PMCID: PMC5747194 DOI: 10.12965/jer.1735188.594] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 12/18/2017] [Indexed: 12/15/2022] Open
Abstract
Regular exercise reduces depressive-like behavior activation. In this study, we look for exact roles of exercise on molecular and neuronal mechanisms for antidepressant action by studying the hippocampal neuroplasticity and proliferation. Increased hippocampal neurogenesis with exercise has potential significance for depression. Exercise promotes brain health in the molecular levels in the hippocampus and also affects behavior in a similar way to chronic antidepressant treatment. Wingless (Wnt) and frizzled signaling system plays an important role in cell proliferation, growth, and differentiation during development. Our results demonstrate complicated, differential effects of antidepressants on Wnt signaling system, and assume a role for selected signaling molecules in the neurogenic activity of antidepressant care. Our review suggests that exercise may preserve brain function by increasing neurogenesis through activating Wnt signaling pathway in the psychiatric disorders, such as depression.
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Affiliation(s)
- Hyo-Jun Lee
- Department of Sport & Health Science, College of Natural Science, Sangmyung University, Seoul, Korea
| | - Seung-Soo Baek
- Department of Sport & Health Science, College of Natural Science, Sangmyung University, Seoul, Korea
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Diabetes-Induced Dysfunction of Mitochondria and Stem Cells in Skeletal Muscle and the Nervous System. Int J Mol Sci 2017; 18:ijms18102147. [PMID: 29036909 PMCID: PMC5666829 DOI: 10.3390/ijms18102147] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 10/11/2017] [Indexed: 12/21/2022] Open
Abstract
Diabetes mellitus is one of the most common metabolic diseases spread all over the world, which results in hyperglycemia caused by the breakdown of insulin secretion or insulin action or both. Diabetes has been reported to disrupt the functions and dynamics of mitochondria, which play a fundamental role in regulating metabolic pathways and are crucial to maintain appropriate energy balance. Similar to mitochondria, the functions and the abilities of stem cells are attenuated under diabetic condition in several tissues. In recent years, several studies have suggested that the regulation of mitochondria functions and dynamics is critical for the precise differentiation of stem cells. Importantly, physical exercise is very useful for preventing the diabetic alteration by improving the functions of both mitochondria and stem cells. In the present review, we provide an overview of the diabetic alterations of mitochondria and stem cells and the preventive effects of physical exercise on diabetes, focused on skeletal muscle and the nervous system. We propose physical exercise as a countermeasure for the dysfunction of mitochondria and stem cells in several target tissues under diabetes complication and to improve the physiological function of patients with diabetes, resulting in their quality of life being maintained.
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Polydeoxyribonucleotide Ameliorates Lipopolysaccharide-Induced Lung Injury by Inhibiting Apoptotic Cell Death in Rats. Int J Mol Sci 2017; 18:ijms18091847. [PMID: 28837114 PMCID: PMC5618496 DOI: 10.3390/ijms18091847] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 08/21/2017] [Accepted: 08/21/2017] [Indexed: 12/27/2022] Open
Abstract
Lung injury is characterized by diffuse lung inflammation, alveolar-capillary destruction, and alveolar flooding, resulting in respiratory failure. Polydexyribonucleotide (PDRN) has an anti-inflammatory effect, decreasing inflammatory cytokines, and suppressing apoptosis. Thus, we investigated its efficacy in the treatment of lung injury, which was induced in rats using lipopolysaccharide (LPS). Rats were randomly divided into three groups according to sacrifice time, and each group split into control, lung injury-induced, and lung injury-induced + PDRN-treated groups. Rats were sacrificed 24 h and 72 h after PDRN administration, according to each group. Lung injury was induced by intratracheal instillation of LPS (5 mg/kg) in 0.2 mL saline. Rats in PDRN-treated groups received a single intraperitoneal injection of 0.3 mL distilled water including PDRN (8 mg/kg), 1 h after lung injury induction. Percentages of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive, cleaved caspase-3-, -8-, and -9-positive cells, the ratio of Bcl-2-associated X protein (Bax) to B-cell lymphoma 2 (Bcl-2), and expressions of inflammatory cytokines (tumor necrosis factor-α, interleukin-6) were decreased by PDRN treatment in the LPS-induced lung injury rats. Therefore, treatment with PDRN reduced lung injury score. This anti-apoptotic effect of PDRN can be ascribed to the enhancing effect of PDRN on adenosine A2A receptor expression. Based on these results, PDRN might be considered as a new therapeutic agent for the treatment of lung injury.
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Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer's disease. Biochem Biophys Res Commun 2017; 485:6-15. [DOI: 10.1016/j.bbrc.2017.01.069] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 01/15/2017] [Indexed: 11/23/2022]
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39
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de Senna PN, Bagatini PB, Galland F, Bobermin L, do Nascimento PS, Nardin P, Tramontina AC, Gonçalves CA, Achaval M, Xavier LL. Physical exercise reverses spatial memory deficit and induces hippocampal astrocyte plasticity in diabetic rats. Brain Res 2017; 1655:242-251. [PMID: 27984020 DOI: 10.1016/j.brainres.2016.10.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 10/11/2016] [Accepted: 10/26/2016] [Indexed: 12/26/2022]
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