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Yavari M, Kalupahana NS, Harris BN, Ramalingam L, Zu Y, Kahathuduwa CN, Moustaid-Moussa N. Mechanisms Linking Obesity, Insulin Resistance, and Alzheimer's Disease: Effects of Polyphenols and Omega-3 Polyunsaturated Fatty Acids. Nutrients 2025; 17:1203. [PMID: 40218960 PMCID: PMC11990358 DOI: 10.3390/nu17071203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/23/2025] [Accepted: 03/24/2025] [Indexed: 04/14/2025] Open
Abstract
Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive cognitive decline, memory loss, and behavioral changes. It poses a significant global health challenge. AD is associated with the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in the brain, along with chronic inflammation, dysfunctional neurons, and synapse loss. While the prevalence of AD continues to rise, the current FDA-approved drugs offer only limited effectiveness. Emerging evidence suggests that obesity, insulin resistance (IR), and type 2 diabetes mellitus (T2DM) are also implicated in AD pathogenesis, with epidemiological studies and animal models confirming the impact of IR on Aβ accumulation, and high-fat diets also exacerbating Aβ accumulation. Since neuroinflammation activated by Aβ involves the nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway, the inhibition of NF-κB and NLRP3 inflammasome activation are potential therapeutic strategies in AD. Bioactive compounds, including polyphenols (resveratrol, epigallocatechin-3-gallate, curcumin, and quercetin), and omega-3 polyunsaturated fatty acids, show promising results in animal studies and clinical trials for reducing Aβ levels, improving cognition and modulating the signaling pathways implicated in AD. This review explores the interplay between obesity, IR, inflammation, and AD pathology, emphasizing the potential of dietary compounds and their role in reducing inflammation, oxidative stress, and cognitive decline, as viable strategies for AD prevention and treatment. By integrating epidemiological findings, observational studies, and clinical trials, this review aims to provide a comprehensive understating of how metabolic dysfunctions and bioactive compounds influence AD progression.
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Affiliation(s)
- Mahsa Yavari
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA; (M.Y.); (L.R.); (Y.Z.)
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University, Lubbock, TX 79409, USA; (B.N.H.); (C.N.K.)
| | - Nishan Sudheera Kalupahana
- Department of Nutrition and Health, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates;
| | - Breanna N. Harris
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University, Lubbock, TX 79409, USA; (B.N.H.); (C.N.K.)
- Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA
- Institute for One Health Innovation, Offices of Research & Innovation, Texas Tech University, Texas Tech Health Sciences Center, Lubbock, TX 79409, USA
| | - Latha Ramalingam
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA; (M.Y.); (L.R.); (Y.Z.)
| | - Yujiao Zu
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA; (M.Y.); (L.R.); (Y.Z.)
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University, Lubbock, TX 79409, USA; (B.N.H.); (C.N.K.)
| | - Chanaka Nadeeshan Kahathuduwa
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University, Lubbock, TX 79409, USA; (B.N.H.); (C.N.K.)
- Department of Neurology, Texas Tech University Health Sciences Center, El Paso, TX 79409, USA
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA; (M.Y.); (L.R.); (Y.Z.)
- Obesity Research Institute, Office of Research & Innovation, Texas Tech University, Lubbock, TX 79409, USA; (B.N.H.); (C.N.K.)
- Institute for One Health Innovation, Offices of Research & Innovation, Texas Tech University, Texas Tech Health Sciences Center, Lubbock, TX 79409, USA
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Miao J, Zhang Y, Su C, Zheng Q, Guo J. Insulin-Like Growth Factor Signaling in Alzheimer's Disease: Pathophysiology and Therapeutic Strategies. Mol Neurobiol 2025; 62:3195-3225. [PMID: 39240280 PMCID: PMC11790777 DOI: 10.1007/s12035-024-04457-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 08/27/2024] [Indexed: 09/07/2024]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia among the elderly population, posing a significant public health challenge due to limited therapeutic options that merely delay cognitive decline. AD is associated with impaired energy metabolism and reduced neurotrophic signaling. The insulin-like growth factor (IGF) signaling pathway, crucial for central nervous system (CNS) development, metabolism, repair, cognition, and emotion regulation, includes IGF-1, IGF-2, IGF-1R, IGF-2R, insulin receptor (IR), and six insulin-like growth factor binding proteins (IGFBPs). Research has identified abnormalities in IGF signaling in individuals with AD and AD models. Dysregulated expression of IGFs, receptors, IGFBPs, and disruptions in downstream phosphoinositide 3-kinase-protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) pathways collectively increase AD susceptibility. Studies suggest modulating the IGF pathway may ameliorate AD pathology and cognitive decline. This review explores the CNS pathophysiology of IGF signaling in AD progression and assesses the potential of targeting the IGF system as a novel therapeutic strategy. Further research is essential to elucidate how aberrant IGF signaling contributes to AD development, understand underlying molecular mechanisms, and evaluate the safety and efficacy of IGF-based treatments.
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Affiliation(s)
- Jie Miao
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Yanli Zhang
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
- Department of Neurology, Sixth Hospital of Shanxi Medical University (General Hospital of Tisco), Taiyuan, 030001, Shanxi, China
| | - Chen Su
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Qiandan Zheng
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China
| | - Junhong Guo
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
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Campagna R, Cecati M, Vignini A. The Multifaceted Role of the Polyphenol Curcumin: A Focus on Type 2 Diabetes Mellitus. Curr Diabetes Rev 2025; 21:e15733998313402. [PMID: 39620334 DOI: 10.2174/0115733998313402240726080637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 06/18/2024] [Accepted: 06/26/2024] [Indexed: 04/23/2025]
Abstract
Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by chronic hyperglycemia, which often co-exists with other metabolic impairments. This condition can damage various tissues and organs, resulting in the development of severe complications, both microvascular, such as retinopathy, nephropathy, and neuropathy, and macrovascular, responsible for an increased risk of cardiovascular diseases. Curcumin is the main bioactive molecule found in the rhizomes of turmeric. Many studies have reported curcumin to exhibit antioxidant, anti-inflammatory, anti-infectious, and anti-cancer properties; thus, there is an increasing interest in exploiting these properties in order to prevent the rise or the progression of T2DM, as well as its possible associated conditions. In this review, we have presented the current state-ofart regarding the clinical trials that have involved curcumin administration and analyzed the possible mechanisms by which curcumin might exert the beneficial effects observed in literature.
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Affiliation(s)
- Roberto Campagna
- Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
| | - Monia Cecati
- Scientific Direction, Advanced Technology Center for Aging Research, IRCCS INRCA, Ancona, Italy
| | - Arianna Vignini
- Department of Clinical Sciences, Polytechnic University of Marche, Ancona, Italy
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Xu M, Li T, Liu X, Islam B, Xiang Y, Zou X, Wang J. Mechanism and Clinical Application Prospects of Mitochondrial DNA Single Nucleotide Polymorphism in Neurodegenerative Diseases. Neurochem Res 2024; 50:61. [PMID: 39673588 DOI: 10.1007/s11064-024-04311-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 11/12/2024] [Accepted: 12/03/2024] [Indexed: 12/16/2024]
Abstract
Mitochondrial dysfunction is well recognized as a critical component of the complicated pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. This review investigates the influence of mitochondrial DNA single nucleotide polymorphisms on mitochondrial function, as well as their role in the onset and progression of these neurodegenerative diseases. Furthermore, the contemporary approaches to mitochondrial regulation in these disorders are discussed. Our objective is to uncover early diagnostic targets and formulate precision medicine strategies for neurodegenerative diseases, thereby offering new paths for preventing and treating these conditions.
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Affiliation(s)
- Mengying Xu
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Tianjiao Li
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Xuan Liu
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Binish Islam
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Yuyue Xiang
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Xiyan Zou
- Xiangya School of Public Health, Central South University, Changsha, 410078, China
| | - Jianwu Wang
- Xiangya School of Public Health, Central South University, Changsha, 410078, China.
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Xie Y, Li X, Shi Q, Le L, Wang C, Xu H, Wu G, Du X, Chen Z. The synergistic effect of curcumin and mitoquinol mesylate on cognitive impairment and the neuropathology of Alzheimer's disease. Brain Res 2024; 1837:148959. [PMID: 38670478 DOI: 10.1016/j.brainres.2024.148959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 04/01/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024]
Abstract
Given the complexity and heterogeneity of Alzheimer's disease (AD) pathology, targeted monotherapy drugs may not be effective. Therefore, synergistic combination therapy of curcumin and Mito Q was proposed and evaluated in a triple-transgenic AD model mice (3 × Tg-AD mice). The cognitive ability was assessed using behavioral tests and typical pathological changes were observed through Western blotting and histological analysis. The results demonstrated a significant enhancement in cognitive ability along with the mitigation of typical AD pathological features such as Aβ aggregation, tau phosphorylation, and synaptic damage. Notably, the combination therapy demonstrated superior efficacy over individual drugs alone. These findings provide valuable insights for optimizing the development of AD drugs.
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Affiliation(s)
- Yongli Xie
- College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory for Plant Epigenetics, Shenzhen University, Shenzhen 518055, China
| | - Xuexia Li
- College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory for Plant Epigenetics, Shenzhen University, Shenzhen 518055, China; Tianjin Institute for Food Safety Inspection Technology, Tianjin 300308, China; Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Qingqing Shi
- Department of Psychiatry, Xijing Hospital, Air Force Medical University, Xi'an 710032, Shanxi, China
| | - Linfeng Le
- College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory for Plant Epigenetics, Shenzhen University, Shenzhen 518055, China
| | - Chao Wang
- Shenzhen Center for Disease Control and Prevention, Shenzhen 518055, China
| | - Hao Xu
- College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory for Plant Epigenetics, Shenzhen University, Shenzhen 518055, China
| | - Guoli Wu
- College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory for Plant Epigenetics, Shenzhen University, Shenzhen 518055, China
| | - Xiubo Du
- College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory for Plant Epigenetics, Shenzhen University, Shenzhen 518055, China; Shenzhen Bay Laboratory, Shenzhen 518055, China
| | - Zetao Chen
- College of Life Sciences and Oceanography, Guangdong Provincial Key Laboratory for Plant Epigenetics, Shenzhen University, Shenzhen 518055, China; Shenzhen Bao'an Traditional Chinese Medicine Hospital Group, Shenzhen 518133, China.
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Perluigi M, Di Domenico F, Butterfield DA. Oxidative damage in neurodegeneration: roles in the pathogenesis and progression of Alzheimer disease. Physiol Rev 2024; 104:103-197. [PMID: 37843394 PMCID: PMC11281823 DOI: 10.1152/physrev.00030.2022] [Citation(s) in RCA: 70] [Impact Index Per Article: 70.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 03/30/2023] [Accepted: 05/24/2023] [Indexed: 10/17/2023] Open
Abstract
Alzheimer disease (AD) is associated with multiple etiologies and pathological mechanisms, among which oxidative stress (OS) appears as a major determinant. Intriguingly, OS arises in various pathways regulating brain functions, and it seems to link different hypotheses and mechanisms of AD neuropathology with high fidelity. The brain is particularly vulnerable to oxidative damage, mainly because of its unique lipid composition, resulting in an amplified cascade of redox reactions that target several cellular components/functions ultimately leading to neurodegeneration. The present review highlights the "OS hypothesis of AD," including amyloid beta-peptide-associated mechanisms, the role of lipid and protein oxidation unraveled by redox proteomics, and the antioxidant strategies that have been investigated to modulate the progression of AD. Collected studies from our groups and others have contributed to unraveling the close relationships between perturbation of redox homeostasis in the brain and AD neuropathology by elucidating redox-regulated events potentially involved in both the pathogenesis and progression of AD. However, the complexity of AD pathological mechanisms requires an in-depth understanding of several major intracellular pathways affecting redox homeostasis and relevant for brain functions. This understanding is crucial to developing pharmacological strategies targeting OS-mediated toxicity that may potentially contribute to slow AD progression as well as improve the quality of life of persons with this severe dementing disorder.
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Affiliation(s)
- Marzia Perluigi
- Department of Biochemical Sciences "A. Rossi Fanelli," Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - Fabio Di Domenico
- Department of Biochemical Sciences "A. Rossi Fanelli," Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy
| | - D Allan Butterfield
- Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, United States
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Kooshki L, Zarneshan SN, Fakhri S, Moradi SZ, Echeverria J. The pivotal role of JAK/STAT and IRS/PI3K signaling pathways in neurodegenerative diseases: Mechanistic approaches to polyphenols and alkaloids. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 112:154686. [PMID: 36804755 DOI: 10.1016/j.phymed.2023.154686] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 01/10/2023] [Accepted: 01/28/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Neurodegenerative diseases (NDDs) are characterized by progressive neuronal dysfunctionality which results in disability and human life-threatening events. In recent decades, NDDs are on the rise. Besides, conventional drugs have not shown potential effectiveness to attenuate the complications of NDDs. So, exploring novel therapeutic agents is an urgent need to combat such disorders. Accordingly, growing evidence indicates that polyphenols and alkaloids are promising natural candidates, possessing several beneficial pharmacological effects against diseases. Considering the complex pathophysiological mechanisms behind NDDs, Janus kinase (JAK), insulin receptor substrate (IRS), phosphoinositide 3-kinase (PI3K), and signal transducer and activator of transcription (STAT) seem to play critical roles during neurodegeneration/neuroregeneration. In this line, modulation of the JAK/STAT and IRS/PI3K signaling pathways and their interconnected mediators by polyphenols/alkaloids could play pivotal roles in combating NDDs, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), stroke, aging, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), depression and other neurological disorders. PURPOSE Thus, the present study aimed to investigate the neuroprotective roles of polyphenols/alkaloids as multi-target natural products against NDDs which are critically passing through the modulation of the JAK/STAT and IRS/PI3K signaling pathways. STUDY DESIGN AND METHODS A systematic and comprehensive review was performed to highlight the modulatory roles of polyphenols and alkaloids on the JAK/STAT and IRS/PI3K signaling pathways in NDDs, according to the PRISMA guideline, using scholarly electronic databases, including Scopus, PubMed, ScienceDirect, and associated reference lists. RESULTS In the present study 141 articles were included from a total of 1267 results. The results showed that phenolic compounds such as curcumin, epigallocatechin-3-gallate, and quercetin, and alkaloids such as berberine could be introduced as new strategies in combating NDDs through JAK/STAT and IRS/PI3K signaling pathways. This is the first systematic review that reveals the correlation between the JAK/STAT and IRS/PI3K axis which is targeted by phytochemicals in NDDs. Hence, this review highlighted promising insights into the neuroprotective potential of polyphenols and alkaloids through the JAK/STAT and IRS/PI3K signaling pathway and interconnected mediators toward neuroprotection. CONCLUSION Amongst natural products, phenolic compounds and alkaloids are multi-targeting agents with the most antioxidants and anti-inflammatory effects possessing the potential of combating NDDs with high efficacy and lower toxicity. However, additional reports are needed to prove the efficacy and possible side effects of natural products.
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Affiliation(s)
- Leila Kooshki
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | | | - Sajad Fakhri
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran.
| | - Seyed Zachariah Moradi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran; Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran
| | - Javier Echeverria
- Departamento de Ciencias del Ambiente, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.
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Prajjwal P, Asharaf S, Makhanasa D, Yamparala A, Tariq H, Aleti S, Gadam S, Vora N. Association of Alzheimer's dementia with oral bacteria, vitamin B12, folate, homocysteine levels, and insulin resistance along with its pathophysiology, genetics, imaging, and biomarkers. Dis Mon 2023; 69:101546. [PMID: 36931946 DOI: 10.1016/j.disamonth.2023.101546] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023]
Abstract
Alzheimer's disease is a prevalent form of dementia, particularly among the elderly population. It is characterized by progressive cognitive decline and neurodegeneration. Despite numerous studies, the exact cause of Alzheimer's disease remains uncertain, and various theories have been proposed, including Aβ amyloid deposition in the brain and tau protein hyper-phosphorylation. This review article explores the potential pathogenesis of Alzheimer's disease, focusing on the effects of derangements in the levels of vitamin B12, folate, and homocysteine, as well as the impact of oral bacteria causing periodontitis and insulin resistance, and their relationship to Alzheimer's. Studies have shown that high levels of homocysteine and low levels of vitamin B12 and folate, are associated with an increased risk of developing Alzheimer's disease. The article also explores the link between Alzheimer's disease and oral bacteria, specifically dental infections and periodontitis, which contribute to the inflammatory processes in the nervous system of Alzheimer's patients. There could be derangement in the insulin signaling further causing disruption in glucose metabolism within the brain, suggesting that Alzheimer's disease may represent a form of type 2 diabetes mellitus associated with the brain, commonly known as type 3 diabetes. Neuroimaging techniques, including MRI, PET, and tau PET, can identify the predictive characteristics of Alzheimer's disease, with amyloid PET being the most useful in ruling out the disease. The article concludes by stressing the importance of understanding genetic and neuroimaging factors in the diagnosing and treating Alzheimer's disease.
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Affiliation(s)
| | - Shahnaz Asharaf
- Internal Medicine, Travancore Medical College, Kollam, Kerala, India
| | | | | | - Halla Tariq
- Internal Medicine, Multan Medical and Dental College, Multan, Pakistan
| | - Soumya Aleti
- Internal Medicine, Berkshire Medical Center, Pittsfield, MA, USA
| | - Srikanth Gadam
- Internal Medicine, Postdoctoral Research Fellow, Mayo Clinic, USA
| | - Neel Vora
- Internal Medicine, B. J. Medical College, Ahmedabad, India
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De la Cruz-Concepción B, Flores-Cortez YA, Barragán-Bonilla MI, Mendoza-Bello JM, Espinoza-Rojo M. Insulin: A connection between pancreatic β cells and the hypothalamus. World J Diabetes 2023; 14:76-91. [PMID: 36926659 PMCID: PMC10011898 DOI: 10.4239/wjd.v14.i2.76] [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: 10/06/2022] [Revised: 12/13/2022] [Accepted: 01/17/2023] [Indexed: 02/14/2023] Open
Abstract
Insulin is a hormone secreted by pancreatic β cells. The concentration of glucose in circulation is proportional to the secretion of insulin by these cells. In target cells, insulin binds to its receptors and activates phosphatidylinositol-3-kinase/protein kinase B, inducing different mechanisms depending on the cell type. In the liver it activates the synthesis of glycogen, in adipose tissue and muscle it allows the capture of glucose, and in the hypothalamus, it regulates thermogenesis and appetite. Defects in insulin function [insulin resistance (IR)] are related to the development of neurodegenerative diseases in obese people. Furthermore, in obesity and diabetes, its role as an anorexigenic hormone in the hypothalamus is diminished during IR. Therefore, hyperphagia prevails, which aggravates hyper-glycemia and IR further, becoming a vicious circle in which the patient cannot regulate their need to eat. Uncontrolled calorie intake induces an increase in reactive oxygen species, overcoming cellular antioxidant defenses (oxidative stress). Reactive oxygen species activate stress-sensitive kinases, such as c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, that induce phos-phorylation in serine residues in the insulin receptor, which blocks the insulin signaling pathway, continuing the mechanism of IR. The brain and pancreas are organs mainly affected by oxidative stress. The use of drugs that regulate food intake and improve glucose metabolism is the conventional therapy to improve the quality of life of these patients. Currently, the use of antioxidants that regulate oxidative stress has given good results because they reduce oxidative stress and inflammatory processes, and they also have fewer side effects than synthetic drugs.
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Affiliation(s)
- Brenda De la Cruz-Concepción
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Yaccil Adilene Flores-Cortez
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Martha Isela Barragán-Bonilla
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Juan Miguel Mendoza-Bello
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Monica Espinoza-Rojo
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
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Wang Y, Hu H, Liu X, Guo X. Hypoglycemic medicines in the treatment of Alzheimer's disease: Pathophysiological links between AD and glucose metabolism. Front Pharmacol 2023; 14:1138499. [PMID: 36909158 PMCID: PMC9995522 DOI: 10.3389/fphar.2023.1138499] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/13/2023] [Indexed: 02/25/2023] Open
Abstract
Alzheimer's Disease (AD) is a global chronic disease in adults with beta-amyloid (Aβ) deposits and hyperphosphorylated tau protein as the pathologic characteristics. Although the exact etiology of AD is still not fully elucidated, aberrant metabolism including insulin signaling and mitochondria dysfunction plays an important role in the development of AD. Binding to insulin receptor substrates, insulin can transport through the blood-brain barrier (BBB), thus mediating insulin signaling pathways to regulate physiological functions. Impaired insulin signaling pathways, including PI3K/Akt/GSK3β and MAPK pathways, could cause damage to the brain in the pathogenesis of AD. Mitochondrial dysfunction and overexpression of TXNIP could also be causative links between AD and DM. Some antidiabetic medicines may have benefits in the treatment of AD. Metformin can be beneficial for cognition improvement in AD patients, although results from clinical trials were inconsistent. Exendin-4 may affect AD in animal models but there is a lack of clinical trials. Liraglutide and dulaglutide could also benefit AD patients in adequate clinical studies but not semaglutide. Dipeptidyl peptidase IV inhibitors (DPP4is) such as saxagliptin, vildagliptin, linagliptin, and sitagliptin could boost cognitive function in animal models. And SGLT2 inhibitors such as empagliflozin and dapagliflozin were also considerably protective against new-onset dementia in T2DM patients. Insulin therapy is a promising therapy but some studies indicated that it may increase the risk of AD. Herbal medicines are helpful for cognitive function and neuroprotection in the brain. For example, polyphenols, alkaloids, glycosides, and flavonoids have protective benefits in cognition function and glucose metabolism. Focusing on glucose metabolism, we summarized the pharmacological mechanism of hypoglycemic drugs and herbal medicines. New treatment approaches including antidiabetic synthesized drugs and herbal medicines would be provided to patients with AD. More clinical trials are needed to produce definite evidence for the effectiveness of hypoglycemic medications.
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Affiliation(s)
- Yixuan Wang
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Hao Hu
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Xinyu Liu
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
| | - Xiangyu Guo
- Dongfang Hospital of Beijing University of Chinese Medicine, Beijing, China
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Dacrema M, Ali A, Ullah H, Khan A, Di Minno A, Xiao J, Martins AMC, Daglia M. Spice-Derived Bioactive Compounds Confer Colorectal Cancer Prevention via Modulation of Gut Microbiota. Cancers (Basel) 2022; 14:5682. [PMID: 36428774 PMCID: PMC9688386 DOI: 10.3390/cancers14225682] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 11/16/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
Colorectal cancer (CRC) is the second most frequent cause of cancer-related mortality among all types of malignancies. Sedentary lifestyles, obesity, smoking, red and processed meat, low-fiber diets, inflammatory bowel disease, and gut dysbiosis are the most important risk factors associated with CRC pathogenesis. Alterations in gut microbiota are positively correlated with colorectal carcinogenesis, as these can dysregulate the immune response, alter the gut's metabolic profile, modify the molecular processes in colonocytes, and initiate mutagenesis. Changes in the daily diet, and the addition of plant-based nutraceuticals, have the ability to modulate the composition and functionality of the gut microbiota, maintaining gut homeostasis and regulating host immune and inflammatory responses. Spices are one of the fundamental components of the human diet that are used for their bioactive properties (i.e., antimicrobial, antioxidant, and anti-inflammatory effects) and these exert beneficial effects on health, improving digestion and showing anti-inflammatory, immunomodulatory, and glucose- and cholesterol-lowering activities, as well as possessing properties that affect cognition and mood. The anti-inflammatory and immunomodulatory properties of spices could be useful in the prevention of various types of cancers that affect the digestive system. This review is designed to summarize the reciprocal interactions between dietary spices and the gut microbiota, and highlight the impact of dietary spices and their bioactive compounds on colorectal carcinogenesis by targeting the gut microbiota.
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Affiliation(s)
- Marco Dacrema
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy
| | - Arif Ali
- Postgraduate Program in Pharmacology, Federal University of Ceará, Fortaleza 60430372, Brazil
| | - Hammad Ullah
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy
| | - Ayesha Khan
- Department of Medicine, Combined Military Hospital Nowshera, Nowshera 24110, Pakistan
| | - Alessandro Di Minno
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy
- CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145 Naples, Italy
| | - Jianbo Xiao
- Department of Analytical and Food Chemistry, Faculty of Sciences, Universidade de Vigo, 32004 Ourense, Spain
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
| | - Alice Maria Costa Martins
- Department of Clinical and Toxicological Analysis, Federal University of Ceará, Fortaleza 60430372, Brazil
| | - Maria Daglia
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
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12
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Dou Y, Zhao D. Targeting Emerging Pathogenic Mechanisms by Natural Molecules as Potential Therapeutics for Neurodegenerative Diseases. Pharmaceutics 2022; 14:2287. [PMID: 36365106 PMCID: PMC9695024 DOI: 10.3390/pharmaceutics14112287] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/18/2022] [Accepted: 10/24/2022] [Indexed: 10/07/2024] Open
Abstract
Natural molecules with favorable safety profile and broad pharmacological activities have shown great promise in the treatment of various neurodegenerative diseases (NDDs). Current studies applying natural molecules against NDDs mainly focus on well-recognized conventional pathogenesis, such as toxic protein aggregation, oxidative stress, and neuroinflammation. However, accumulating evidence reveals that some underlying pathogenic mechanisms are involved earlier and more deeply in the occurrence and development of NDDs, such as ferroptosis, energy metabolism disorders, autophagy-lysosomal dysfunction, endoplasmic reticulum stress, and gut dysbiosis. Therefore, determining whether natural molecules can play therapeutic roles in these emerging pathogenic mechanisms will help clarify the actual targets of natural molecules and their future clinical translation. Furthermore, how to overcome the inability of most poorly water-soluble natural molecules to cross the blood-brain barrier is also critical for effective NDD treatment. This review summarizes emerging pathogenic mechanisms targeted by natural molecules for NDD treatment, proposes nanocarrier-based drug delivery and intranasal administration to enhance the intracerebral bioavailability of natural molecules, and summarizes the current state of clinical research on natural product-based therapeutics.
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Affiliation(s)
- Yan Dou
- Department of Radiology and Tianjin Key Laboratory of Functional Imaging, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Dongju Zhao
- School of Life Sciences, Tianjin University, Tianjin 300072, China
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13
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Deng C, Chen H, Meng Z, Meng S. Roles of traditional chinese medicine regulating neuroendocrinology on AD treatment. Front Endocrinol (Lausanne) 2022; 13:955618. [PMID: 36213283 PMCID: PMC9533021 DOI: 10.3389/fendo.2022.955618] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/01/2022] [Indexed: 11/20/2022] Open
Abstract
The incidence of sporadic Alzheimer's disease (AD) is increasing in recent years. Studies have shown that in addition to some genetic abnormalities, the majority of AD patients has a history of long-term exposure to risk factors. Neuroendocrine related risk factors have been proved to be strongly associated with AD. Long-term hormone disorder can have a direct detrimental effect on the brain by producing an AD-like pathology and result in cognitive decline by impairing neuronal metabolism, plasticity and survival. Traditional Chinese Medicine(TCM) may regulate the complex process of endocrine disorders, and improve metabolic abnormalities, as well as the resulting neuroinflammation and oxidative damage through a variety of pathways. TCM has unique therapeutic advantages in treating early intervention of AD-related neuroendocrine disorders and preventing cognitive decline. This paper reviewed the relationship between neuroendocrine and AD as well as the related TCM treatment and its mechanism. The advantages of TCM intervention on endocrine disorders and some pending problems was also discussed, and new insights for TCM treatment of dementia in the future was provided.
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Affiliation(s)
- Chujun Deng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Huize Chen
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Zeyu Meng
- The Second Clinical Medical College, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shengxi Meng
- Department of Traditional Chinese Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
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14
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Shabbir A, Rehman K, Akbar M, Hamid Akash MS. Neuroprotective potential of curcuminoids in modulating Alzheimer's Disease via multiple signaling pathways. Curr Med Chem 2022; 29:5560-5581. [PMID: 35674299 DOI: 10.2174/0929867329666220607161328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 02/12/2022] [Accepted: 03/15/2022] [Indexed: 11/22/2022]
Abstract
Alzheimer's disease (AD) is a progressive and frequent neurodegenerative disease of elderly people. In the 21st century, owing to the increasing prevalence of AD, there is a crucial need for finding better and effective pharmacotherapeutic approaches. This review article demonstrated the various sources and possible metabolic pathways of curcuminoids obtained from Curcuma longa herb, to prevent and treat AD but the information related to the metabolic fate of curcuminoids is deficient. Different in vitro and in vivo research studies demonstrating the mechanisms by which curcuminoids attenuated AD have been summarized. Administration of curcuminoids has been indicated to inhibit hyperphosphorylation of tau protein, deposition, and oligomerization of amyloid beta plaques in several AD models. Curcuminoids also chelate metals and form complexes, have antioxidant properties, mediates neuroinflammatory signaling pathways by modifying microglial cells activity, inhibit acetylcholinesterase activities and also modulates other associated signaling pathways including insulin signaling pathways and heme-oxygenase pathway. Briefly curcuminoids exhibit the capability to be more productive and efficacious compared to many recent treatments due to their antioxidant, delayed neuron degeneration and anti-inflammatory potential. Although their effectiveness as a curative agent is considered to be reduced due to their low bioavailability, If the issue of curcuminoids' low bioavailability is resolved then curcuminoid-based medications are hopefully on the horizon against AD.
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Affiliation(s)
- Anam Shabbir
- Department of Pharmaceutical Chemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, University of Agriculture, Faisalabad, Pakistan
| | - Moazzama Akbar
- Department of Pharmaceutical Chemistry, Government College University, Faisalabad, Pakistan
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15
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Coppola A, Zorzetto G, Piacentino F, Bettoni V, Pastore I, Marra P, Perani L, Esposito A, De Cobelli F, Carcano G, Fontana F, Fiorina P, Venturini M. Imaging in experimental models of diabetes. Acta Diabetol 2022; 59:147-161. [PMID: 34779949 DOI: 10.1007/s00592-021-01826-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 10/30/2021] [Indexed: 12/01/2022]
Abstract
Translational medicine, experimental medicine and experimental animal models, in particular mice and rats, represent a multidisciplinary field that has made it possible to achieve, in the last decades, important scientific progress. In this review, we have summarized the most frequently used imaging animal models, such as ultrasound (US), micro-CT, MRI and the optical imaging methods, and their main implications in diagnostic and therapeutic fields, with a particular focus on diabetes mellitus, a multifactorial disease extremely widespread among the general population.
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Affiliation(s)
- Andrea Coppola
- Diagnostic and Interventional Radiology Unit, ASST Settelaghi, Varese, Italy.
| | | | - Filippo Piacentino
- Diagnostic and Interventional Radiology Unit, ASST Settelaghi, Varese, Italy
- Insubria University, Varese, Italy
| | - Valeria Bettoni
- Diagnostic and Interventional Radiology Unit, ASST Settelaghi, Varese, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Paolo Marra
- Department of Diagnostic Radiology, Giovanni XXIII Hospital, Milano-Bicocca University, Bergamo, Italy
| | - Laura Perani
- Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy
| | - Antonio Esposito
- Experimental Imaging Center, San Raffaele Scientific Institute, Milan, Italy
- Radiology Unit, San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milan, Italy
| | - Francesco De Cobelli
- Radiology Unit, San Raffaele Scientific Institute, San Raffaele Vita-Salute University, Milan, Italy
| | - Giulio Carcano
- Insubria University, Varese, Italy
- General, Emergency, and Transplant Surgery Unit, ASST Settelaghi, Varese, Italy
| | - Federico Fontana
- Diagnostic and Interventional Radiology Unit, ASST Settelaghi, Varese, Italy
- Insubria University, Varese, Italy
| | - Paolo Fiorina
- International Center for T1D, Centro di Ricerca Pediatrica Romeo ed Enrica Invernizzi, Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università di Milano, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Endocrinology Division, ASST Fatebenefratelli Sacco, Milan, Italy
| | - Massimo Venturini
- Diagnostic and Interventional Radiology Unit, ASST Settelaghi, Varese, Italy
- Insubria University, Varese, Italy
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16
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Noor NA, Hosny EN, Khadrawy YA, Mourad IM, Othman AI, Aboul Ezz HS, Mohammed HS. Effect of curcumin nanoparticles on streptozotocin-induced male Wistar rat model of Alzheimer's disease. Metab Brain Dis 2022; 37:343-357. [PMID: 35048324 DOI: 10.1007/s11011-021-00897-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease that afflicts millions of people all over the world. Intracerebroventricular (ICV) injection of a sub-diabetogenic dose of streptozotocin (STZ) was established as an experimental animal model of AD. The present study was conducted to evaluate the efficacy of curcumin nanoparticles (CNs) against the behavioral, neurochemical and histopathological alterations induced by ICV-STZ. The animals were divided into: control animals, the animal model of AD that received a single bilateral ICV microinjection of STZ, and the animals protected by a daily oral administration of CNs for 6 days before the ICV-STZ injection. The animals of all groups were subjected to surgical operation on the 7th day of administration. Then the administration of distilled water or CNs was continued for 8 days. The ICV-STZ microinjection produced cognitive impairment as evident from the behavioral Morris water maze (MWM) test and induced oxidative stress in the cortex and hippocampus as indicated by the significant increases in lipid peroxidation and nitric oxide (NO) levels and the significant decrease in reduced glutathione (GSH) levels. It also produced a significant increase in acetylcholinesterase (AChE) and tumor necrosis-alpha (TNF-ɑ) and a significant decrease in Na+,K + -ATPase. In addition, a significant increase in amino acid neurotransmitters occurred in the hippocampus, whereas a significant decrease was obtained in the cortex of STZ-induced AD rats. CNs ameliorated the behavioral, immunohistochemical and most of the neurochemical alterations induced by STZ in the hippocampus and cortex. It may be concluded that CNs might be considered as a promising therapeutic agent for the treatment of AD.
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Affiliation(s)
- Neveen A Noor
- Zoology department, Faculty of Science, Cairo University, Giza, Egypt
| | - Eman N Hosny
- Department of Medical Physiology, Medical Division, National Research Center, El-Behouth St., Giza, Egypt
| | - Yasser A Khadrawy
- Department of Medical Physiology, Medical Division, National Research Center, El-Behouth St., Giza, Egypt.
| | - Iman M Mourad
- Zoology department, Faculty of Science, Cairo University, Giza, Egypt
| | - Amel I Othman
- Zoology department, Faculty of Science, Cairo University, Giza, Egypt
| | - Heba S Aboul Ezz
- Zoology department, Faculty of Science, Cairo University, Giza, Egypt
| | - Haitham S Mohammed
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt
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17
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Saleh DO, Nasr M, Hassan A, El‐Awdan SA, Abdel Jaleel GA. Curcumin nanoemulsion ameliorates brain injury in diabetic rats. J Food Biochem 2022; 46:e14104. [DOI: 10.1111/jfbc.14104] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/14/2021] [Accepted: 01/13/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Dalia O. Saleh
- Department of Pharmacology Medical Research and Clinical Studies Institute, National Research Centre Giza Egypt
| | - Maha Nasr
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy Ain Shams University Cairo Egypt
| | - Azza Hassan
- Pathology Department, Faculty of Veterinary Medicine Cairo University Cairo Egypt
| | - Sally A. El‐Awdan
- Department of Pharmacology Medical Research and Clinical Studies Institute, National Research Centre Giza Egypt
| | - Gehad A. Abdel Jaleel
- Department of Pharmacology Medical Research and Clinical Studies Institute, National Research Centre Giza Egypt
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18
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Lai J, Tang Y, Yang F, Chen J, Huang FH, Yang J, Wang L, Qin D, Law BYK, Wu AG, Wu JM. Targeting autophagy in ethnomedicine against human diseases. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114516. [PMID: 34487846 DOI: 10.1016/j.jep.2021.114516] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/29/2021] [Accepted: 08/09/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In the past five years, ethnopharmacy-based drugs have been increasingly used in clinical practice. It has been reported that hundreds of ethnopharmacy-based drugs can modulate autophagy to regulate physiological and pathological processes, and ethnomedicines also have certain therapeutic effects on illnesses, revealing the important roles of these medicines in regulating autophagy and treating diseases. AIM OF THE STUDY This study reviews the regulatory effects of natural products on autophagy in recent years, and discusses their pharmacological effects and clinical applications in the process of diseases. It provides a preliminary literature basis and reference for the research of plant drugs in the regulation of autophagy. MATERIALS AND METHODS A comprehensive systematic review in the fields of relationship between autophagy and ethnomedicine in treating diseases from PubMed electronic database was performed. Information was obtained from documentary sources. RESULTS We recorded some illnesses associated with autophagy, then classified them into different categories reasonably. Based on the uses of these substances in different researches of diseases, a total of 80 active ingredients or compound preparations of natural drugs were searched. The autophagy mechanisms of these substances in the treatments of divers diseases have been summarized for the first time, we also looked forward to the clinical application of some of them. CONCLUSIONS Autophagy plays a key function in lots of illnesses, the regulation of autophagy has become one of the important means to prevent and treat these diseases. About 80 compounds and preparations involved in this review have been proved to have therapeutic effects on related diseases through the mechanism of autophagy. Experiments in vivo and in vitro showed that these compounds and preparations could treat these diseases by regulating autophagy. The typical natural products curcumin and tripterine have powerful roles in regulating autophagy and show good and diversified curative effects.
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Affiliation(s)
- Jia Lai
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Yong Tang
- Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, 646000, China; State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
| | - Fei Yang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Jianping Chen
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, China
| | - Fei-Hong Huang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, 646000, China
| | - Jing Yang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, 646000, China
| | - Long Wang
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, 646000, China
| | - Dalian Qin
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
| | - Betty Yuen-Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China.
| | - An-Guo Wu
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, 646000, China.
| | - Jian-Ming Wu
- School of Pharmacy, Southwest Medical University, Luzhou, 646000, China; Education Ministry Key Laboratory of Medical Electrophysiology, Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Southwest Medical University, Luzhou, 646000, China.
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19
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Hao M, Chu Y, Lei J, Yao Z, Wang P, Chen Z, Wang K, Sang X, Han X, Wang L, Cao G. Pharmacological Mechanisms and Clinical Applications of Curcumin: Update. Aging Dis 2022; 14:716-749. [PMID: 37191432 DOI: 10.14336/ad.2022.1101] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 11/01/2022] [Indexed: 11/19/2022] Open
Abstract
Curcumin, a well-known hydrophobic polyphenol extracted from the rhizomes of turmeric (Curcuma longa L.), has attracted great interest in the last ten years due to its multiple pharmacological activities. A growing body of evidence has manifested that curcumin has extensive pharmacological activities including anti-inflammatory, anti-oxygenation, lipid regulation, antiviral, and anticancer with hypotoxicity and minor adverse reactions. However, the disadvantages of low bioavailability, short half-life in plasma, low drug concentration in blood, and poor oral absorption severely limited the clinical application of curcumin. Pharmaceutical researchers have carried out plenty of dosage form transformations to improve the druggability of curcumin and have achieved remarkable results. Therefore, the objective of this review summarizes the pharmacological research progress, problems in clinical application and the improvement methods of curcumin's druggability. By reviewing the latest research progress of curcumin, we believe that curcumin has a broad clinical application prospect for its wide range of pharmacological activities with few side effects. The deficiencies of lower bioavailability of curcumin could be improved by dosage form transformation. However, curcumin in the clinical application still requires further study regarding the underlying mechanism and clinical trial verification.
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20
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Zhao N, Xu B. The beneficial effect of exercise against Alzheimer's disease may result from improved brain glucose metabolism. Neurosci Lett 2021; 763:136182. [PMID: 34418507 DOI: 10.1016/j.neulet.2021.136182] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 08/14/2021] [Accepted: 08/16/2021] [Indexed: 02/07/2023]
Abstract
The potential of physical exercise as an intervention for Alzheimer's disease (AD) has been extensively reported. In fact, a number of studies have highlighted improvements in β-amyloid (Aβ) peptide and hyperphosphorylated tau (p-tau) as critical mechanisms in exercise-induced beneficial neurological outcomes. However, no therapeutic management have been proven to be effective in humans. Recent evidence has shown that AD may be a metabolic disease related to glucose metabolic dysfunction in the brain. In this regard, some of the mechanisms responsible for the beneficial effects of physical exercise in the pathology of AD appear to be related to alterations in glucose metabolism. Therefore, we propose that the neuroprotective effect of physical exercise against AD through synergetic improvement in brain glucose metabolism and its pathophysiology. The novel perspective presented here partly explains the failure of Aβ/tau-based therapeutic approaches and provides evidence for brain glucose metabolism as a potential therapeutic target in AD.
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Affiliation(s)
- Na Zhao
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China; College of Physical Education and Health, East China Normal University, Shanghai, China
| | - Bo Xu
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China; College of Physical Education and Health, East China Normal University, Shanghai, China.
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21
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Ge X, Zuo Y, Xie J, Li X, Li Y, Thirupathi A, Yu P, Gao G, Zhou C, Chang Y, Shi Z. A new mechanism of POCD caused by sevoflurane in mice: cognitive impairment induced by cross-dysfunction of iron and glucose metabolism. Aging (Albany NY) 2021; 13:22375-22389. [PMID: 34547719 PMCID: PMC8507282 DOI: 10.18632/aging.203544] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 07/13/2021] [Indexed: 12/16/2022]
Abstract
Sevoflurane (Sev) is a commonly used anesthetic in hospitals that can cause neurotoxicity. Postoperative cognitive dysfunction (POCD) is a common clinical problem induced by some anesthetics. However, the exact mechanism of neurotoxicity induced by Sev is unclear. Here we studied a new mechanism of POCD induced by Sev. We treated 15-month-old mice with 2% Sev for 6 hours, and we had found that Sev causes POCD. Using isobaric tags for relative and absolute quantitation (iTRAQ), we found that the transporter and the metabolism of carbohydrates and inorganic ions were involved in the cognitive impairment induced by Sev. Using synchrotron radiation micro-X-ray fluorescence (μ-XRF), we showed that Sev caused the iron overload in the brain of 15-month-old mice. Subsequently, excessive iron led to oxidative stress and impaired mitochondrial function that further led to glucose metabolism disorder and reduced ATP production by regulating the expression of key enzyme genes or proteins including G6Pase, Pck1, and Cs. Meanwhile, Sev also inhibited the oxygen consumption rate and glucose absorption by downregulating the expression of glucose transporter 1 in cerebral vascular endothelial cells. The cross-dysfunction of iron and glucose metabolism caused the apoptosis in the cortex and hippocampus through Bcl2/Bax pathway. In conclusion, the data here showed a new mechanism that Sev caused apoptosis by cross-dysregulation of iron and glucose metabolism and induced energy stress in mice. Maintaining iron and glucose metabolism homeostasis may play an important role in cognitive impairment induced by Sev.
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Affiliation(s)
- Xing Ge
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
| | - Yong Zuo
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
| | - Jinhong Xie
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
| | - Xincheng Li
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
| | - Yan Li
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
| | - Anand Thirupathi
- Faculty of Sports Science, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Peng Yu
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
| | - Guofen Gao
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
| | - Changhao Zhou
- The First Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei Province, China
| | - Yanzhong Chang
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
| | - Zhenhua Shi
- Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China
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22
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Insulin and Insulin Resistance in Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22189987. [PMID: 34576151 PMCID: PMC8472298 DOI: 10.3390/ijms22189987] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/09/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023] Open
Abstract
Insulin plays a range of roles as an anabolic hormone in peripheral tissues. It regulates glucose metabolism, stimulates glucose transport into cells and suppresses hepatic glucose production. Insulin influences cell growth, differentiation and protein synthesis, and inhibits catabolic processes such as glycolysis, lipolysis and proteolysis. Insulin and insulin-like growth factor-1 receptors are expressed on all cell types in the central nervous system. Widespread distribution in the brain confirms that insulin signaling plays important and diverse roles in this organ. Insulin is known to regulate glucose metabolism, support cognition, enhance the outgrowth of neurons, modulate the release and uptake of catecholamine, and regulate the expression and localization of gamma-aminobutyric acid (GABA). Insulin is also able to freely cross the blood–brain barrier from the circulation. In addition, changes in insulin signaling, caused inter alia insulin resistance, may accelerate brain aging, and affect plasticity and possibly neurodegeneration. There are two significant insulin signal transduction pathways: the PBK/AKT pathway which is responsible for metabolic effects, and the MAPK pathway which influences cell growth, survival and gene expression. The aim of this study is to describe the role played by insulin in the CNS, in both healthy people and those with pathologies such as insulin resistance and Alzheimer’s disease.
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23
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Brain Glucose Transporters: Role in Pathogenesis and Potential Targets for the Treatment of Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22158142. [PMID: 34360906 PMCID: PMC8348194 DOI: 10.3390/ijms22158142] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 07/06/2021] [Accepted: 07/28/2021] [Indexed: 12/16/2022] Open
Abstract
The most common cause of dementia, especially in elderly people, is Alzheimer’s disease (AD), with aging as its main risk factor. AD is a multifactorial neurodegenerative disease. There are several factors increasing the risk of AD development. One of the main features of Alzheimer’s disease is impairment of brain energy. Hypometabolism caused by decreased glucose uptake is observed in specific areas of the AD-affected brain. Therefore, glucose hypometabolism and energy deficit are hallmarks of AD. There are several hypotheses that explain the role of glucose hypometabolism in AD, but data available on this subject are poor. Reduced transport of glucose into neurons may be related to decreased expression of glucose transporters in neurons and glia. On the other hand, glucose transporters may play a role as potential targets for the treatment of AD. Compounds such as antidiabetic drugs, agonists of SGLT1, insulin, siRNA and liposomes are suggested as therapeutics. Nevertheless, the suggested targets of therapy need further investigations.
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Wu L, Zheng Q, Guo YY, Zhang KN, Luo J, Xiao S, Li WJ, Yang M. Effect of Zhenxin Xingshui Yizhi Fang on Aβ 25-35 induced expression of related transporters in HBMEC cell model. JOURNAL OF ETHNOPHARMACOLOGY 2020; 260:112783. [PMID: 32240783 DOI: 10.1016/j.jep.2020.112783] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 03/20/2020] [Accepted: 03/20/2020] [Indexed: 06/11/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Aβ (β-amyloid) deposition and abnormal transport were suggested to be risk factors for Alzheimer's disease (AD). Zhenxin Xingshui Yizhi Fang (XSF), an ancient prescription in traditional Chinese medicine, was first recorded in Qianjin Yifang for treating palpitation, hypnosia, amnesia. It is reported that XSF could improve mice learning memory ability, reduce the deposition of senile plaques in hippocampus of rat brain. In this study, the neuroprotective effect of XSF against Aβ25-35-induced apoptosis in cultured human brain microvascular endothelial cells (HBMEC) and its potential mechanism were investigated. MATERIALS AND METHODS HBMEC cells were treated with Aβ25-35 to established neurotoxic cell model. After that, the cells were treated with 125, 250, 500 μg/mL XSF to observe the protective effect. The viability of HBMEC cells were evaluated by MTT assay, the Aβ25-35-induced apoptosis was characterized by Hoechst-33258 and the activity of cysteinyl aspartate specific proteinase-3. The expression level of Aβ1-42 in cells induced by Aβ25-35 was measured by human Aβ1-42 kit. Protein and mRNA expression levels of advanced glycation end products (RAGE), low density lipoprotein receptor-related protein 1 (LRP1), glucose transporter 1 and 3 (GLUT1 and GLUT3) were assayed by capillary electrophoresis immunoassay and quantitative real-time polymerase chain reaction analyses. RESULTS In Aβ25-35 induced neurotoxic cells, the percentage of apoptotic cells, the concentration of Aβ1-42 and CASPASE-3 activity, protein and mRNA expression levels of RAGE increased significantly, but that of LRP1, GLUT1 and GLUT3 significantly decreased. XSF could inhibit the apoptotic of cells, reduced the concentration of Aβ1-42 and CASPASE-3 expression, downregulate RAGE and upregulate LRP1, GLUT1 and GLUT3 expression. CONCLUSION The results suggest that XSF can reduce the cytotoxicity of HBMEC induced by Aβ25-35, inhibit apoptosis, and regulate the transport of Aβ on BBB and energy metabolism disorder in HBMEC.
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Affiliation(s)
- Ling Wu
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China
| | - Qin Zheng
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China.
| | - Yuan-Yuan Guo
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China
| | - Ke-Nan Zhang
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China
| | - Jun Luo
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China
| | - Shuai Xiao
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China
| | - Wen-Jing Li
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China
| | - Ming Yang
- Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, State Key Lab of Innovation Drug and Efficient Energy-Saving Pharmaceutical Equipment, Jiangxi University of Traditional Chinese Medicine, Nanchang, Jiangxi, 330004, China
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Peng Y, Gao P, Shi L, Chen L, Liu J, Long J. Central and Peripheral Metabolic Defects Contribute to the Pathogenesis of Alzheimer's Disease: Targeting Mitochondria for Diagnosis and Prevention. Antioxid Redox Signal 2020; 32:1188-1236. [PMID: 32050773 PMCID: PMC7196371 DOI: 10.1089/ars.2019.7763] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 02/09/2020] [Accepted: 02/10/2020] [Indexed: 12/20/2022]
Abstract
Significance: Epidemiological studies indicate that metabolic disorders are associated with an increased risk for Alzheimer's disease (AD). Metabolic remodeling occurs in the central nervous system (CNS) and periphery, even in the early stages of AD. Mitochondrial dysfunction has been widely accepted as a molecular mechanism underlying metabolic disorders. Therefore, focusing on early metabolic changes, especially from the perspective of mitochondria, could be of interest for early AD diagnosis and intervention. Recent Advances: We and others have identified that the levels of several metabolites are fluctuated in the periphery before their accumulation in the CNS, which plays an important role in the pathogenesis of AD. Mitochondrial remodeling is likely one of the earliest signs of AD, linking nutritional imbalance to cognitive deficits. Notably, by improving mitochondrial function, mitochondrial nutrients efficiently rescue cellular metabolic dysfunction in the CNS and periphery in individuals with AD. Critical Issues: Peripheral metabolic disorders should be intensively explored and evaluated for the early diagnosis of AD. The circulating metabolites derived from mitochondrial remodeling represent novel potential diagnostic biomarkers for AD that are more readily detected than CNS-oriented biomarkers. Moreover, mitochondrial nutrients provide a promising approach to preventing and delaying AD progression. Future Directions: Abnormal mitochondrial metabolism in the CNS and periphery is involved in AD pathogenesis. More clinical studies provide evidence for the suitability and reliability of circulating metabolites and cytokines for the early diagnosis of AD. Targeting mitochondria to rewire cellular metabolism is a promising approach to preventing AD and ameliorating AD-related metabolic disorders.
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Affiliation(s)
- Yunhua Peng
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Peipei Gao
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Le Shi
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Lei Chen
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiankang Liu
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
| | - Jiangang Long
- Center for Mitochondrial Biology & Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Frontier Institute of Science and Technology, Xi'an Jiaotong University, Xi'an, China
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Exercise and Curcumin in Combination Improves Cognitive Function and Attenuates ER Stress in Diabetic Rats. Nutrients 2020; 12:nu12051309. [PMID: 32375323 PMCID: PMC7284733 DOI: 10.3390/nu12051309] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/27/2020] [Accepted: 04/30/2020] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with chronic low-grade inflammation that is mainly associated with lifestyles. Exercise and healthy diet are known to be beneficial for adults with T2DM in terms of maintaining blood glucose control and overall health. We investigated whether a combination of exercise and curcumin supplementation ameliorates diabetes-related cognitive distress by regulating inflammatory response and endoplasmic reticulum (ER) stress. This study was performed using male Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a spontaneous diabetes Type 2 model) and Long-Evans Tokushima Otsuka (LETO) rats (LETO controls) by providing them with exercise alone or exercise and curcumin in combination. OLETF rats were fed either a diet of chow (as OLETF controls) or a diet of chow containing curcumin (5 g/kg diet) for five weeks. OLETF rats exercised with curcumin supplementation exhibited weight loss and improved glucose homeostasis and lipid profiles as compared with OLETF controls or exercised OLETF rats. Next, we examined cognitive functions using a Morris water maze test. Exercise plus curcumin improved escape latency and memory retention compared to OLETF controls. Furthermore, OLETF rats exercised and fed curcumin had lower IL6, TNFα, and IL10 levels (indicators of inflammatory response) and lower levels of ER stress markers (BiP and CHOP) in the intestine than OLETF controls. These observations suggest exercise plus curcumin may offer a means of treating diabetes-related cognitive dysfunction.
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27
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Popa-Wagner A, Dumitrascu DI, Capitanescu B, Petcu EB, Surugiu R, Fang WH, Dumbrava DA. Dietary habits, lifestyle factors and neurodegenerative diseases. Neural Regen Res 2020; 15:394-400. [PMID: 31571647 PMCID: PMC6921346 DOI: 10.4103/1673-5374.266045] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 06/20/2019] [Indexed: 12/12/2022] Open
Abstract
Worldwide stroke is increasing in parallel with modernization, changes in lifestyle, and the growing elderly population. Our review is focused on the link between diet, as part of 'modern lifestyle', and health in the context of genetic predisposition of individuals to 'unhealthy' metabolic pathway activity. It is concluded that lifestyle including high sugar diets, alcohol and tobacco addiction or high fat diets as well as ageing, brain injury, oxidative stress and neuroinflammation, negatively influence the onset, severity and duration of neurodegenerative diseases. Fortunately, there are several healthy dietary components such as polyunsaturated fatty acids and the anti-oxidants curcumin, resveratrol, blueberry polyphenols, sulphoraphane, salvionic acid as well as caloric restriction and physical activity, which may counteract ageing and associated neurodegenerative diseases via increased autophagy or increased neurogenesis in the adult brain.
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Affiliation(s)
- Aurel Popa-Wagner
- Griffith University School of Medicine, Gold Coast Campus, QLD, Australia
| | | | - Bogdan Capitanescu
- Department of Human Anatomy, Faculty of Medicine, University of Medicine and Pharmacy, Craiova, Romania
| | - Eugen Bogdan Petcu
- Griffith University School of Medicine, Gold Coast Campus, QLD, Australia
| | - Roxana Surugiu
- Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy, Craiova, Romania
| | - Wen-Hui Fang
- School of Healthcare Science, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, UK
| | - Danut-Adrian Dumbrava
- Center of Clinical and Experimental Medicine, University of Medicine and Pharmacy, Craiova, Romania
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28
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A high throughput drug screening paradigm using transgenic Caenorhabditis elegans model of Alzheimer’s disease. TRANSLATIONAL MEDICINE OF AGING 2020. [DOI: 10.1016/j.tma.2019.12.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Mana L, Feng H, Dong Y, Wang Y, Shi J, Tian J, Wang P. Effect of Chinese herbal compound GAPT on the early brain glucose metabolism of APP/PS1 transgenic mice. Int J Immunopathol Pharmacol 2019; 33:2058738419841482. [PMID: 30957587 PMCID: PMC6454641 DOI: 10.1177/2058738419841482] [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] [Indexed: 01/07/2023] Open
Abstract
A number of studies have shown that early-stage Alzheimer’s disease (AD) is
associated with abnormal brain glucose metabolism before cognitive decline,
which may be the key pathological change of asymptomatic AD. The pathogenesis of
AD in traditional Chinese medicine is kidney deficiency and turbid phlegm. Based
on this, GAPT (a mixture of herbal extracts) was made to invigorate kidney Yang
and eliminate phlegm. Previous studies have shown that GAPT can improve and
delay the memory decline, but the specific therapeutic target of AD in an early
stage has not been studied. The aim of this study was to investigate the effect
of GAPT on glucose metabolism in the early stage of AD. Eighty-eight 3-month-old
male APP/PS1 transgenic mice were randomly divided into model group; donepezil
group; and low, middle and high GAPT dosage groups. Twelve 3-month-old C57BL/6J
mice were used as a control group. The Morris water maze test and the Step-Down
Passive-Avoidance test were used to evaluate learning and memory ability.
Cerebral extraction and the accumulation of glucose were scanned with a
micro-positron-emission tomography (PET) imaging system. Immunohistochemistry,
western blot analysis and polymerase chain reaction (PCR) were used to detect
the expression of the PI3K/AKT-mTOR signalling pathway–related proteins and
messenger RNAs (mRNAs) in hippocampus of APP/PS1 transgenic mice after 3 months
of drug administration. GAPT can shorten the escape latency and error numbers
compared to the model group. In micro-PET imaging analysis, GAPT can increase
the glucose uptake average rate in the frontal lobe, temporal lobe, parietal
lobe and hippocampus. The immunohistochemistry, western blot analysis and PCR
results indicated that GAPT can increase the expression of PI3K, AKT, GLUT1 and
GLUT3 in the hippocampus of APP/PS1 transgenic mice. In summary, GAPT can
improve brain glucose metabolism damage in APP/PS1 transgenic mice, mainly by
increasing brain glucose uptake, increasing glucose transport and improving the
insulin signalling pathway.
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Affiliation(s)
- Lulu Mana
- 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.,2 Key Laboratory of Pharmacology of Dongzhimen Hospital (BUCM), State Administration of Traditional Chinese Medicine, Beijing, China
| | - Huili Feng
- 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.,3 The First Hospital Affiliated to Henan University of Traditional Chinese Medicine, Zhengzhou, China
| | - Yunfang Dong
- 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.,4 Zhongkang International Health Physical Examination Center, Qingdao Ruiyuan Hospital of Traditional Chinese Medicine, Qingdao, China
| | - Yahan Wang
- 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.,2 Key Laboratory of Pharmacology of Dongzhimen Hospital (BUCM), State Administration of Traditional Chinese Medicine, Beijing, China
| | - Jing Shi
- 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.,5 Beijing University of Chinese Medicine, BUCM Neurology Center, Dongzhimen Hospital, Beijing, China
| | - Jinzhou Tian
- 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.,5 Beijing University of Chinese Medicine, BUCM Neurology Center, Dongzhimen Hospital, Beijing, China
| | - Pengwen Wang
- 1 Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine (BUCM), Beijing, China.,2 Key Laboratory of Pharmacology of Dongzhimen Hospital (BUCM), State Administration of Traditional Chinese Medicine, Beijing, China
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Zholos AV, Moroz OF, Storozhuk MV. Curcuminoids and Novel Opportunities for the Treatment of Alzheimer's Disease: Which Molecules are Actually Effective? Curr Mol Pharmacol 2019; 12:12-26. [PMID: 30318014 DOI: 10.2174/1874467211666181012150847] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 09/30/2018] [Accepted: 10/08/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Millions of people worldwide are suffering from Alzheimer's disease (AD), and there are only symptomatic treatments available for this disease. Thus, there is a great need to identify drugs capable of arresting or reversing AD. Constituents of the spice turmeric, in particular, curcuminoids, seem to be very promising, as evident from in vitro experiments and tests using animal models of AD. However, most of the clinical trials did not reveal any beneficial effects of curcuminoids in the treatment of AD. These controversies, including conflicting results of clinical trials, are thought to be related to bioavailability of curcuminoids, which is low unless it is enhanced by developing a special formulation. However, there is growing evidence suggesting that other reasons may be of even greater importance, but these avenues are less explored. OBJECTIVE Review relevant literature, and analyze potential reasons for the controversial results. METHODOLOGY Recent in vitro and preclinical studies; clinical trials (without a limiting period) were searched in PubMed and Google Scholar. RESULTS While recent in vitro and preclinical studies confirm the therapeutic potential of curcuminoids in the treatment of AD and cognitive dysfunctions, results of corresponding clinical trials remain rather controversial. CONCLUSION The controversial results obtained in the clinical trials may be in part due to particularities of the curcuminoid formulations other than bioavailability. Namely, it seems likely that the various formulations differ in terms of their minor turmeric constituent(s). We hypothesize that these distinctions may be of key importance for efficacy of the particular formulation in clinical trials. A testable approach addressing this hypothesis is suggested.
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Affiliation(s)
- Alexander V Zholos
- A.A. Bogomoletz Institute of Physiology, National Academy of Science of Ukraine, 4 Bogomoletz Street, Kiev 01024, Ukraine.,Taras Shevchenko National University of Kyiv, Educational and Scientific Centre "Institute of Biology and Medicine", 2 Academician Glushkov Avenue, Kiev 03022, Ukraine
| | - Olesia F Moroz
- Taras Shevchenko National University of Kyiv, Educational and Scientific Centre "Institute of Biology and Medicine", 2 Academician Glushkov Avenue, Kiev 03022, Ukraine
| | - Maksim V Storozhuk
- A.A. Bogomoletz Institute of Physiology, National Academy of Science of Ukraine, 4 Bogomoletz Street, Kiev 01024, Ukraine
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Farkhondeh T, Samarghandian S, Pourbagher-Shahri AM, Sedaghat M. The impact of curcumin and its modified formulations on Alzheimer's disease. J Cell Physiol 2019; 234:16953-16965. [PMID: 30847942 DOI: 10.1002/jcp.28411] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Revised: 02/02/2019] [Accepted: 02/14/2019] [Indexed: 12/17/2022]
Abstract
Alzheimer's disease (AD) is a major health problem worldwide, with no effective treatment approach. Curcumin is the main ingredient of turmeric traditionally used in Asian medicine. Several experimental studies have indicated the protective effect of curcumin and its novel formulations in AD. Curcumin has antioxidant, anti-inflammatory and neurotrophic activities, proposing a strong potential to prevent neurodegenerative diseases. However, there are no sufficient clinical trials to confirm curcumin use in AD patients. Low bioavailability following oral administration of curcumin limits its usage in human. The present study was designed to gather the effects of curcumin and its modified formulations in human and experimental models of AD.
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Affiliation(s)
- Tahereh Farkhondeh
- Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | | | - Mahshid Sedaghat
- Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
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32
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Utility of curcumin for the treatment of diabetes mellitus: Evidence from preclinical and clinical studies. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2018. [DOI: 10.1016/j.jnim.2018.05.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Kim Y, Clifton P. Curcumin, Cardiometabolic Health and Dementia. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2018; 15:ijerph15102093. [PMID: 30250013 PMCID: PMC6210685 DOI: 10.3390/ijerph15102093] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Revised: 09/15/2018] [Accepted: 09/20/2018] [Indexed: 02/07/2023]
Abstract
Current research indicates curcumin [diferuloylmethane; a polyphenolic compound isolated from the rhizomes of the dietary spice turmeric (Curcuma longa)] exerts a beneficial effect on health which may be partly attributable to its anti-oxidative and anti-inflammatory properties. The aim of this review is to examine potential mechanisms of the actions of curcumin in both animal and human studies. Curcumin modulates relevant molecular target pathways to improve glucose and lipid metabolism, suppress inflammation, stimulate antioxidant enzymes, facilitate insulin signalling and reduce gut permeability. Curcumin also inhibits Aβ and tau accumulation in animal models and enhances mitochondria and synaptic function. In conclusion, in high-dose animal studies and in vitro, curcumin exerts a potential beneficial effect on cardiometabolic disease. However, human studies are relatively unconvincing. More intervention studies should be conducted with the new curcumin formulation with improved oral bioavailability.
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Affiliation(s)
- Yoona Kim
- Department of Food and Nutrition/Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea.
| | - Peter Clifton
- School of Pharmacy and Medical Sciences, University of South Australia, General Post Office Box 2471, Adelaide, SA 5001, Australia.
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35
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Penke B, Bogár F, Crul T, Sántha M, Tóth ME, Vígh L. Heat Shock Proteins and Autophagy Pathways in Neuroprotection: from Molecular Bases to Pharmacological Interventions. Int J Mol Sci 2018; 19:E325. [PMID: 29361800 PMCID: PMC5796267 DOI: 10.3390/ijms19010325] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/15/2018] [Accepted: 01/18/2018] [Indexed: 02/07/2023] Open
Abstract
Neurodegenerative diseases (NDDs) such as Alzheimer's disease, Parkinson's disease and Huntington's disease (HD), amyotrophic lateral sclerosis, and prion diseases are all characterized by the accumulation of protein aggregates (amyloids) into inclusions and/or plaques. The ubiquitous presence of amyloids in NDDs suggests the involvement of disturbed protein homeostasis (proteostasis) in the underlying pathomechanisms. This review summarizes specific mechanisms that maintain proteostasis, including molecular chaperons, the ubiquitin-proteasome system (UPS), endoplasmic reticulum associated degradation (ERAD), and different autophagic pathways (chaperon mediated-, micro-, and macro-autophagy). The role of heat shock proteins (Hsps) in cellular quality control and degradation of pathogenic proteins is reviewed. Finally, putative therapeutic strategies for efficient removal of cytotoxic proteins from neurons and design of new therapeutic targets against the progression of NDDs are discussed.
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Affiliation(s)
- Botond Penke
- Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Dóm Square 8, Hungary.
| | - Ferenc Bogár
- Department of Medical Chemistry, University of Szeged, H-6720 Szeged, Dóm Square 8, Hungary.
- MTA-SZTE Biomimetic Systems Research Group, University of Szeged, H-6720 Szeged, Dóm Square 8, Hungary.
| | - Tim Crul
- Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Temesvári krt. 62, Hungary.
| | - Miklós Sántha
- Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Temesvári krt. 62, Hungary.
| | - Melinda E Tóth
- Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Temesvári krt. 62, Hungary.
| | - László Vígh
- Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, H-6726 Szeged, Temesvári krt. 62, Hungary.
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Reddy PH, Manczak M, Yin X, Grady MC, Mitchell A, Tonk S, Kuruva CS, Bhatti JS, Kandimalla R, Vijayan M, Kumar S, Wang R, Adi Pradeepkiran J, Ogunmokun G, Thamarai K, Quesada K, Boles A, Reddy AP. Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer's Disease. J Alzheimers Dis 2018; 61:843-866. [PMID: 29332042 PMCID: PMC5796761 DOI: 10.3233/jad-170512] [Citation(s) in RCA: 234] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The purpose of our article is to assess the current understanding of Indian spice, curcumin, against amyloid-β (Aβ)-induced toxicity in Alzheimer's disease (AD) pathogenesis. Natural products, such as ginger, curcumin, and gingko biloba have been used as diets and dietary supplements to treat human diseases, including cancer, cardiovascular, respiratory, infectious, diabetes, obesity, metabolic syndromes, and neurological disorders. Products derived from plants are known to have protective effects, including anti-inflammatory, antioxidant, anti-arthritis, pro-healing, and boosting memory cognitive functions. In the last decade, several groups have designed and synthesized curcumin and its derivatives and extensively tested using cell and mouse models of AD. Recent research on Aβ and curcumin has revealed that curcumin prevents Aβ aggregation and crosses the blood-brain barrier, reach brain cells, and protect neurons from various toxic insults of aging and Aβ in humans. Recent research has also reported that curcumin ameliorates cognitive decline and improves synaptic functions in mouse models of AD. Further, recent groups have initiated studies on elderly individuals and patients with AD and the outcome of these studies is currently being assessed. This article highlights the beneficial effects of curcumin on AD. This article also critically assesses the current limitations of curcumin's bioavailability and urgent need for new formulations to increase its brain levels to treat patients with AD.
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Affiliation(s)
- P. Hemachandra Reddy
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Department of Neurology, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Speech, Language and Hearing Sciences, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Department of Public Health, Graduate School of Biomedical Studies, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 6630 S. Quaker Ste. E, MS 7495, Lubbock, Texas 79413
| | - Maria Manczak
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Xiangling Yin
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Mary Catherine Grady
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Andrew Mitchell
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Sahil Tonk
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Chandra Sekhar Kuruva
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Jasvinder Singh Bhatti
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Department of Biotechnology and Bioinformatics, Sri Guru Gobind Singh College, Sector 26 Chandigarh, India 160019
| | - Ramesh Kandimalla
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Department of Neurology, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Murali Vijayan
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Subodh Kumar
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Rui Wang
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Jangampalli Adi Pradeepkiran
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Gilbert Ogunmokun
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
- Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Kavya Thamarai
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Kandi Quesada
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
| | - Annette Boles
- Garrison Institute on Aging, Texas Tech University Health Sciences Center, 6630 S. Quaker Ste. E, MS 7495, Lubbock, Texas 79413
| | - Arubala P Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4 Street, MS 9424, Lubbock, Texas 79430
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