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Cohen A, Levine SZ, Vainstein G, Beeri MS, Weinstein G. New-generation antidiabetic medications and dementia risk in older adults with type 2 diabetes: A retrospective cohort study. J Prev Alzheimers Dis 2025:100199. [PMID: 40345929 DOI: 10.1016/j.tjpad.2025.100199] [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: 01/28/2025] [Revised: 04/24/2025] [Accepted: 04/30/2025] [Indexed: 05/11/2025]
Abstract
BACKGROUND New-generation antidiabetic medications may have therapeutic potential for dementia, beyond their glycemic effects. However, information from observational studies exploring the association between new-generation antidiabetic use and dementia risk is limited. OBJECTIVES To examine the association between new-generation antidiabetic medication use and dementia risk. DESIGN Retrospective cohort study using electronic health records of a large non-profit health maintenance organization. PARTICIPANTS 84,798 dementia-free individuals aged ≥65y with type 2 diabetes. MEASUREMENTS Antidiabetic medication exposure was based on purchased prescriptions and was used as a time-varying variable. Exposure periods were defined as periods in which either dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), or glucagon-like peptide-1 analogs (GLP-1a) or their combinations were used, otherwise unexposed. Dementia classification was based on the International Classification of Diseases, Ninth Revision codes or antidementia medication prescriptions. Cox regression models were fitted to quantify the association between antidiabetic medication use and incident dementia. Models were adjusted for 13 potential sources of confounding using inverse-probability weighting. RESULTS Among 84,798 individuals with a mean diabetes onset age of 66.4 ± 7.5 years, the median follow-up for dementia risk was 8.7 years (Q1-Q3: 5.4-12.8). Dementia was diagnosed in 11,642 (13.7%) individuals. New-generation medication use was associated with reduced dementia risk (HR = 0.69; 95% CI, 0.66-0.73) and by drug classes (DPP-4i, HR 0.67 [95% CI 0.63-0.71]; SGLT-2i, 0.63 [95% CI 0.56-0.70], GLP-1a, 0.61 [95% CI 0.54-0.69]. CONCLUSIONS The results of this large-scale study suggest that new-generation antidiabetic medication use may be associated with lower dementia risk in older adults with T2D.
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Affiliation(s)
- Avi Cohen
- School of Public Health, University of Haifa, Haifa 3498838, Israel.
| | - Stephen Z Levine
- School of Public Health, University of Haifa, Haifa 3498838, Israel
| | - Gabriel Vainstein
- Kahn-Sagol-Maccabi Research and Innovation Institute, Tel-Aviv 6800001, Israel
| | - Michal Schnaider Beeri
- The Kreiger Klein Alzheimer's Research Center, Brain Health Institute, Rutgers Health, New Brunswick 08901, NJ, USA
| | - Galit Weinstein
- School of Public Health, University of Haifa, Haifa 3498838, Israel
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2
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Na D, Zhang Z, Meng M, Li M, Gao J, Kong J, Zhang G, Guo Y. Energy Metabolism and Brain Aging: Strategies to Delay Neuronal Degeneration. Cell Mol Neurobiol 2025; 45:38. [PMID: 40259102 PMCID: PMC12011708 DOI: 10.1007/s10571-025-01555-z] [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: 01/12/2025] [Accepted: 04/09/2025] [Indexed: 04/23/2025]
Abstract
Aging is characterized by a gradual decline in physiological functions, with brain aging being a major risk factor for numerous neurodegenerative diseases. Given the brain's high energy demands, maintaining an adequate ATP supply is crucial for its proper function. However, with advancing age, mitochondria dysfunction and a deteriorating energy metabolism lead to reduced overall energy production and impaired mitochondrial quality control (MQC). As a result, promoting healthy aging has become a key focus in contemporary research. This review examines the relationship between energy metabolism and brain aging, highlighting the connection between MQC and energy metabolism, and proposes strategies to delay brain aging by targeting energy metabolism.
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Affiliation(s)
- Donghui Na
- Department of Forensic Medicine, Hebei North University, Zhangjiakou, Hebei, China
| | - Zechen Zhang
- Mudi Meng Honors College, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Meng Meng
- Department of Forensic Medicine, Hebei North University, Zhangjiakou, Hebei, China
| | - Meiyu Li
- Department of Forensic Medicine, Hebei North University, Zhangjiakou, Hebei, China
- Department of Pathology, Hebei North University, Zhangjiakou, Hebei, China
| | - Junyan Gao
- Department of Forensic Medicine, Hebei North University, Zhangjiakou, Hebei, China
| | - Jiming Kong
- Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada.
| | - Guohui Zhang
- Department of Forensic Medicine, Hebei North University, Zhangjiakou, Hebei, China.
| | - Ying Guo
- Department of Forensic Medicine, Hebei North University, Zhangjiakou, Hebei, China.
- Department of Pathology, Hebei North University, Zhangjiakou, Hebei, China.
- Hebei Key Laboratory of Neuropharmacology, Hebei North University, Zhangjiakou, Hebei, China.
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Kruczkowska W, Gałęziewska J, Buczek P, Płuciennik E, Kciuk M, Śliwińska A. Overview of Metformin and Neurodegeneration: A Comprehensive Review. Pharmaceuticals (Basel) 2025; 18:486. [PMID: 40283923 PMCID: PMC12030719 DOI: 10.3390/ph18040486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/13/2025] [Accepted: 03/26/2025] [Indexed: 04/29/2025] Open
Abstract
This comprehensive review examines the therapeutic potential of metformin, a well-established diabetes medication, in treating neurodegenerative disorders. Originally used as a first-line treatment for type 2 diabetes, recent studies have begun investigating metformin's effects beyond metabolic disorders, particularly its neuroprotective capabilities against conditions like Parkinson's disease, Alzheimer's disease, Huntington's disease, and multiple sclerosis. Key findings demonstrate that metformin's neuroprotective effects operate through multiple pathways: AMPK activation enhancing cellular energy metabolism and autophagy; upregulation of antioxidant defenses; suppression of inflammation; inhibition of protein aggregation; and improvement of mitochondrial function. These mechanisms collectively address common pathological features in neurodegeneration and neuroinflammation, including oxidative stress, protein accumulation, and mitochondrial dysfunction. Clinical and preclinical evidence supporting metformin's association with improved cognitive performance, reduced risk of dementia, and modulation of pathological hallmarks of neurodegenerative diseases is critically evaluated. While metformin shows promise as a therapeutic agent, this review emphasizes the need for further investigation to fully understand its mechanisms and optimal therapeutic applications in neurodegenerative diseases.
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Affiliation(s)
- Weronika Kruczkowska
- Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; (W.K.); (J.G.); (P.B.); (E.P.)
| | - Julia Gałęziewska
- Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; (W.K.); (J.G.); (P.B.); (E.P.)
| | - Paulina Buczek
- Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; (W.K.); (J.G.); (P.B.); (E.P.)
| | - Elżbieta Płuciennik
- Department of Functional Genomics, Faculty of Medicine, Medical University of Lodz, Żeligowskiego 7/9, 90-752 Lodz, Poland; (W.K.); (J.G.); (P.B.); (E.P.)
| | - Mateusz Kciuk
- Department of Molecular Biotechnology and Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland;
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland
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Kadı A, Öner S, Yuca H, Arslan ME, Atila A, İncekara Ü, Karakaya S. Integrative Study of Plantago lanceolata L.: Phytochemical Properties and Therapeutic Effects on Cancer, Diabetes, and Alzheimer's Disease. Nat Prod Res 2025:1-11. [PMID: 39992729 DOI: 10.1080/14786419.2025.2469311] [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: 10/22/2024] [Revised: 01/27/2025] [Accepted: 02/10/2025] [Indexed: 02/26/2025]
Abstract
Alzheimer's disease is linked with diabetes and cancer, emphasising the need for effective treatments. Plantago lanceolata, recognised as safe by various pharmacopeias, was investigated in this study for therapeutic potential. We examined the effects of its leaf extracts and sub-extracts (methanol, hexane, dichloromethane, ethyl acetate, butanol, aqueous) on AChE, BChE, α-amylase, α-glucosidase enzymes, as well as their impact on HDF-a and U87-MG cancer cells. The phytochemical characterisation was performed using ICP-MS and LC-MS/MS. Cytotoxic effects were evaluated on HDF-a and U87-MG cell lines, along with assessments for nuclear abnormalities. Na and K were detected in extracts, with isoleucine and cyanidin-3-O-glucoside being the most concentrated compounds. Extracts at concentrations exceeding 25 µg/mL significantly increased cytotoxicity in HDF-a cell lines compared to the control group, without inducing nuclear abnormalities. Methanol extract demonstrated moderate inhibition against AChE and BChE at concentrations of 100 µg/mL and 500 µg/mL, respectively. These findings suggest that extracts exhibit potential therapeutic effects.
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Affiliation(s)
- Abdulrahim Kadı
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Türkiye
| | - Sena Öner
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Türkiye
| | - Hafize Yuca
- Department of Pharmacognosy, Faculty of Pharmacy, Atatürk University, Erzurum, Türkiye
| | - Mehmet Enes Arslan
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Türkiye
| | - Alptuğ Atila
- Department of Analytical Chemistry, Faculty of Pharmacy, Atatürk University, Erzurum, Türkiye
| | - Ümit İncekara
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Türkiye
| | - Songül Karakaya
- Department of Pharmaceutical Botany, Faculty of Pharmacy, Atatürk University, Erzurum, Türkiye
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Blotenberg I, Wittström F, Michalowsky B, Platen M, Wucherer D, Teipel S, Hoffmann W, Thyrian JR. Modifiable risk factors and symptom progression in dementia over up to 8 years-Results of the DelpHi-MV trial. ALZHEIMER'S & DEMENTIA (AMSTERDAM, NETHERLANDS) 2025; 17:e70050. [PMID: 39811699 PMCID: PMC11730075 DOI: 10.1002/dad2.70050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/21/2024] [Accepted: 11/22/2024] [Indexed: 01/16/2025]
Abstract
INTRODUCTION This study investigated the association between modifiable factors and symptom progression in dementia over up to 8 years. METHODS Multilevel growth curve models assessed the role of modifiable risk factors (low education, hearing impairment and its treatment, depression, physical inactivity, diabetes and its treatment, smoking, hypertension and its treatment, obesity, alcohol consumption, social isolation, and visual impairment) on cognitive and functional trajectories in 353 people with dementia. RESULTS Higher education was associated with higher initial cognitive status but faster decline. Antidiabetic medication was associated with slower cognitive decline, whereas depression and visual impairment were linked to low baseline functioning and faster cognitive decline. DISCUSSION Several modifiable risk factors influenced symptom progression. Education initially had a protective effect, whereas depressive symptoms were linked to worse symptom progression. Treatment of comorbidities (diabetes, visual impairment) could have a positive impact on dementia symptoms. Modifiable risk factors are promising targets for tertiary prevention. Highlights Modifiable risk factors were associated with symptom progression in dementia over up to 8 years.More education was associated with higher initial cognitive status but faster decline.Depressive symptoms were linked to less favorable symptom progression.Treatment of comorbidities (diabetes, visual impairment) may positively impact the course of symptoms.Modifiable risk factors are promising targets for tertiary prevention.
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Affiliation(s)
- Iris Blotenberg
- Health Care ResearchDeutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)GreifswaldMecklenburg‐VorpommernGermany
| | - Felix Wittström
- Centre for PharmacoepidemiologyKarolinska Institutet, SolnaStockholms IänSweden
| | - Bernhard Michalowsky
- Health Care ResearchDeutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)GreifswaldMecklenburg‐VorpommernGermany
| | - Moritz Platen
- Health Care ResearchDeutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)GreifswaldMecklenburg‐VorpommernGermany
| | - Diana Wucherer
- Health Care ResearchDeutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)GreifswaldMecklenburg‐VorpommernGermany
| | - Stefan Teipel
- Clinical ResearchDeutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)RostockMecklenburg‐VorpommernGermany
- Department of Psychosomatic MedicineUniversity Hospital RostockRostockMecklenburg‐VorpommernGermany
| | - Wolfgang Hoffmann
- Health Care ResearchDeutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)GreifswaldMecklenburg‐VorpommernGermany
- Institute for Community Medicine, University Medicine GreifswaldGreifswaldMecklenburg‐VorpommernGermany
| | - Jochen René Thyrian
- Health Care ResearchDeutsches Zentrum für Neurodegenerative Erkrankungen (DZNE)GreifswaldMecklenburg‐VorpommernGermany
- Institute for Community Medicine, University Medicine GreifswaldGreifswaldMecklenburg‐VorpommernGermany
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Chakraborty S, Vishwas S, Harish V, Gupta G, Paudel KR, Dhanasekaran M, Goh BH, Zacconi F, de Jesus Andreoli Pinto T, Kumbhar P, Disouza J, Dua K, Singh SK. Exploring nanoparticular platform in delivery of repurposed drug for Alzheimer's disease: current approaches and future perspectives. Expert Opin Drug Deliv 2024; 21:1771-1792. [PMID: 39397403 DOI: 10.1080/17425247.2024.2414768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/07/2024] [Indexed: 10/15/2024]
Abstract
INTRODUCTION Alzheimer's disease (AD) stands as significant challenge in realm of neurodegenerative disorder. It is characterized by gradual decline in cognitive function and memory loss. It has already expanded its prevalence to 55 million people worldwide and is expected to rise significantly. Unfortunately, there exists a limited therapeutic option that would mitigate its progression. Repurposing existing drugs and employing nanoparticle as delivery agent presents a potential solution to address the intricate pathology of AD. AREAS COVERED In this review, we delve into utilization of nanoparticular platforms to enhance the delivery of repurposed drugs for treatment of AD. Firstly, the review begins with the elucidation of intricate pathology underpinning AD, subsequently followed by rationale behind drug repurposing in AD. Covered are explorations of nanoparticle-based repurposing of drugs in AD, highlighting their clinical implication. Further, the associated challenges and probable future perspective are delineated. EXPERT OPINION The article has highlighted that extensive research has been carried out on the delivery of repurposed nanomedicines against AD. However, there is a need for advanced and long-term research including clinical trials required to shed light upon their safety and toxicity profile. Furthermore, their scalability in pharmaceutical set-up should also be validated.
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Affiliation(s)
- Snigdha Chakraborty
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
- Overseas R & D Centre, Overseas HealthCare Pvt. Ltd, Phillaur, Punjab, India
| | - Sukriti Vishwas
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Vancha Harish
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Gaurav Gupta
- Centre for Research Impact & Outcome, Chitkara College of Pharmacy, Chitkara University, Punjab, India
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Keshav Raj Paudel
- Centre of Inflammation, Centenary Institute and University of Technology Sydney, Faculty of Science, School of Life Sciences, Sydney, NSW, Australia
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University Auburn, Alabama, USA
| | - Bey Hing Goh
- Sunway Biofunctional Molecules Discovery Centre (SBMDC), School of Medical and Life Sciences, Sunway University, Darul Ehsan, Selangor, Malaysia
| | - Flavia Zacconi
- Facultad de Química y de Farmacia, Pontificia Universidad Cat´ olica de Chile, Santiago, Chile
- Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Cat´olica de Chile, Santiago, Chile
| | | | - Popat Kumbhar
- Department of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Kolhapur, Maharashtra, India
| | - John Disouza
- Department of Pharmaceutics, Tatyasaheb Kore College of Pharmacy, Kolhapur, Maharashtra, India
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, Australia
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, Australia
- School of Medical and Life Sciences, Sunway University, Sunway City, Malaysia
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Sighencea MG, Popescu RȘ, Trifu SC. From Fundamentals to Innovation in Alzheimer's Disease: Molecular Findings and Revolutionary Therapies. Int J Mol Sci 2024; 25:12311. [PMID: 39596378 PMCID: PMC11594972 DOI: 10.3390/ijms252212311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Revised: 11/11/2024] [Accepted: 11/14/2024] [Indexed: 11/28/2024] Open
Abstract
Alzheimer's disease (AD) is a global health concern and the leading cause of dementia in the elderly. The prevalence of this neurodegenerative condition is projected to increase concomitantly with increased life expectancy, resulting in a significant economic burden. With very few FDA-approved disease-modifying drugs available for AD, there is an urgent need to develop new compounds capable of impeding the progression of the disease. Given the unclear etiopathogenesis of AD, this review emphasizes the underlying mechanisms of this condition. It explores not only well-studied aspects, such as the accumulation of Aβ plaques and neurofibrillary tangles, but also novel areas, including glymphatic and lymphatic pathways, microbiota and the gut-brain axis, serotoninergic and autophagy alterations, vascular dysfunction, the metal hypothesis, the olfactory pathway, and oral health. Furthermore, the potential molecular targets arising from all these mechanisms have been reviewed, along with novel promising approaches such as nanoparticle-based therapy, neural stem cell transplantation, vaccines, and CRISPR-Cas9-mediated genome editing techniques. Taking into account the overlap of these various mechanisms, individual and combination therapies emerge as the future direction in the AD strategy.
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Affiliation(s)
| | - Ramona Ștefania Popescu
- Department of Infectious Diseases, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania;
| | - Simona Corina Trifu
- Department of Psychiatry, “Carol Davila” University of Medicine and Pharmacy Bucharest, 020021 Bucharest, Romania
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Yang C, Zhang H, Ma Z, Fan Y, Xu Y, Tan J, Tian J, Cao J, Zhang W, Huang G, Zhao L. Structural and functional alterations of the hippocampal subfields in T2DM with mild cognitive impairment and insulin resistance: A prospective study. J Diabetes 2024; 16:e70029. [PMID: 39537579 PMCID: PMC11560383 DOI: 10.1111/1753-0407.70029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 05/26/2024] [Accepted: 10/20/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance (IR) and is often accompanied by mild cognitive impairment (MCI). The detrimental effects of T2DM and IR on the hippocampus have been extensively demonstrated. Few studies have examined the effects of IR on structure and function of hippocampal subfields in T2DM-MCI patients. METHOD A total of 104 T2DM patients were recruited in this prospective study and divided into four groups (T2DM-MCI-higherIR, n = 17; T2DM-MCI-lowerIR, n = 32; T2DM-nonMCI-higherIR, n = 19; T2DM-nonMCI-lowerIR, n = 36). Structure and function MRI data were captured. Clinical variables and neuropsychological scores were determined for all participants. Hippocampal subfield volume and functional connectivity were compared among four groups. Partial correlation analysis was performed between imaging indicators, clinical variables, and neuropsychological scores in all patients. RESULTS T2DM-MCI-higher IR group had the smallest volumes of bilateral hippocampal tail, right subiculum-body, right GC-ML-DG-body, and right CA4-body. IR in right hippocampal tail, right subiculum-body, and right GC-ML-DG-body exerted main effect. Furthermore, elevated functional connectivity was found between right subiculum-body and bilateral dorsolateral prefrontal cortex and right anterior cingulate-medial prefrontal cortex. Hippocampal subfield volume positively correlates with total cholesterol and triglycerides and negatively correlates with fasting insulin. CONCLUSION The present study found that T2DM-MCI patients have structural and functional alterations in hippocampal subfields, and IR is a negative factor influencing the alteration of hippocampal subfields volume. These findings support the importance of IR in T2DM-MCI patients and might be potential neuroimaging biomarkers of cerebral impairment in T2DM-MCI patients.
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Affiliation(s)
- Chen Yang
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital)Gansu University of Chinese MedicineLanzhouChina
| | - Huiyan Zhang
- School of Clinical MedicineNingxia Medical UniversityYinchuanChina
| | - Zihan Ma
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital)Gansu University of Chinese MedicineLanzhouChina
| | - Yanjun Fan
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital)Gansu University of Chinese MedicineLanzhouChina
| | - Yanan Xu
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital)Gansu University of Chinese MedicineLanzhouChina
| | - Jian Tan
- The First Clinical Medical College of Gansu University of Chinese Medicine (Gansu Provincial Hospital)Gansu University of Chinese MedicineLanzhouChina
| | - Jing Tian
- Department of RadiologyGansu Provincial HospitalLanzhouChina
| | - Jiancang Cao
- Department of RadiologyGansu Provincial HospitalLanzhouChina
| | - Wenwen Zhang
- Department of RadiologyGansu Provincial HospitalLanzhouChina
| | - Gang Huang
- Department of RadiologyGansu Provincial HospitalLanzhouChina
| | - Lianping Zhao
- Department of RadiologyGansu Provincial HospitalLanzhouChina
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Mbah NE, Myers AL, Sajjakulnukit P, Chung C, Thompson JK, Hong HS, Giza H, Dang D, Nwosu ZC, Shan M, Sweha SR, Maydan DD, Chen B, Zhang L, Magnuson B, Zhu Z, Radyk M, Lavoie B, Yadav VN, Koo I, Patterson AD, Wahl DR, Franchi L, Agnihotri S, Koschmann CJ, Venneti S, Lyssiotis CA. Therapeutic targeting of differentiation-state dependent metabolic vulnerabilities in diffuse midline glioma. Nat Commun 2024; 15:8983. [PMID: 39419964 PMCID: PMC11487135 DOI: 10.1038/s41467-024-52973-4] [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: 03/01/2022] [Accepted: 09/27/2024] [Indexed: 10/19/2024] Open
Abstract
H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more sensitive to statins and OXPHOS inhibitors. Additionally, statins and OXPHOS inhibitors show efficacy and extend survival in preclinical orthotopic models established with stem-like H3K27M DMG cells. Together, this study demonstrates that cellular subtypes within DMGs harbor distinct metabolic vulnerabilities that can be uniquely and selectively targeted for therapeutic gain.
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Affiliation(s)
- Nneka E Mbah
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
| | - Amy L Myers
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
| | - Peter Sajjakulnukit
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA
- Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, USA
| | - Chan Chung
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA
- Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, USA
- Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, South Korea
| | | | - Hanna S Hong
- Graduate Program in Immunology, University of Michigan, Ann Arbor, USA
| | - Heather Giza
- Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, USA
| | - Derek Dang
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA
- Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, USA
- Graduate Program in Molecular & Cellular Pathology, University of Michigan, Ann Arbor, USA
| | - Zeribe C Nwosu
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
| | - Mengrou Shan
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
| | - Stefan R Sweha
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA
- Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, USA
- Neuroscience Graduate Program, University of Michigan, Ann Arbor, USA
| | - Daniella D Maydan
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
| | - Brandon Chen
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
- Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, USA
| | - Li Zhang
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
| | - Brian Magnuson
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, USA
| | - Zirui Zhu
- Graduate Program in Chemical Biology, University of Michigan, Ann Arbor, USA
| | - Megan Radyk
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
| | - Brooke Lavoie
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA
| | - Viveka Nand Yadav
- The Department of Pediatrics, Children's Mercy Research Institute (CMRI), Kansas, USA
| | - Imhoi Koo
- Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, USA
| | - Andrew D Patterson
- Department of Biochemistry and Molecular Biology and Department of Veterinary and Biomedical Sciences, the Pennsylvania State University, University Park, USA
| | - Daniel R Wahl
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, USA
| | - Luigi Franchi
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, USA
| | | | - Carl J Koschmann
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, USA
| | - Sriram Venneti
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA.
- Laboratory of Brain Tumor Metabolism and Epigenetics, Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, USA.
- Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
| | - Costas A Lyssiotis
- Chad Carr Pediatric Brain Tumor Center, University of Michigan, Ann Arbor, USA.
- Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, USA.
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, USA.
- Rogel Cancer Center, University of Michigan, Ann Arbor, USA.
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10
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Li C, Qian H, Feng L, Li M. Causal Association Between Type 2 Diabetes Mellitus and Alzheimer's Disease: A Two-Sample Mendelian Randomization Study. J Alzheimers Dis Rep 2024; 8:945-957. [PMID: 39114544 PMCID: PMC11305840 DOI: 10.3233/adr-240053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 05/17/2024] [Indexed: 08/10/2024] Open
Abstract
Background There is now increasing evidence that type 2 diabetes mellitus (T2DM) is associated with Alzheimer's disease (AD). However, it is unclear whether the two are causally related. Objective To reveal the causal association between T2DM and AD, we performed a bidirectional Mendelian randomization (MR) analysis. Methods Genetic instrumental variables were systematically screened, and inverse-variance weighting, MR-Egger regression, weighted median, simple mode, and weighted mode were applied to assess the pathogenic associations between the two diseases, and sensitivity analyses were used to further validate the robustness of the results. Results The results of forward MR analysis with T2DM as the exposure were [OR = 0.998, 95% CI (0.975∼1.021), p = 0.857], and the results of reverse MR analysis with AD as the exposure were [OR = 0.966, 95% CI (0.934∼0.999), p = 0.043]. The results showed no significant association between T2DM and AD at the gene level (p < 0.025). Sensitivity analyses were consistent with the results of the main analysis, confirming the robustness of the study. Conclusions T2DM and AD may not be genetically causally associated.
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Affiliation(s)
- Cong Li
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Haifeng Qian
- Department of Image Center, the Third Affiliated Clinical Hospital of the Changchun University of Chinese Medicine, Changchun, China
| | - Lina Feng
- Department of Neurology, the Second Affiliated Hospital of Shandong First Medical University, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, China
| | - Mingquan Li
- Neurology Department, the Third Affiliated Clinical Hospital of the Changchun University of Chinese Medicine, Changchun, China
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11
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Kothandan D, Singh DS, Yerrakula G, D B, N P, Santhana Sophia B V, A R, Ramya Vg S, S K, M J. Advanced Glycation End Products-Induced Alzheimer's Disease and Its Novel Therapeutic Approaches: A Comprehensive Review. Cureus 2024; 16:e61373. [PMID: 38947632 PMCID: PMC11214645 DOI: 10.7759/cureus.61373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2024] [Indexed: 07/02/2024] Open
Abstract
Advanced glycation end products (AGEs) accumulate in the brain, leading to neurodegenerative conditions such as Alzheimer's disease (AD). The pathophysiology of AD is influenced by receptors for AGEs and toll-like receptor 4 (TLR4). Protein glycation results in irreversible AGEs through a complicated series of reactions involving the formation of Schiff's base, the Amadori reaction, followed by the Maillard reaction, which causes abnormal brain glucose metabolism, oxidative stress, malfunctioning mitochondria, plaque deposition, and neuronal death. Amyloid plaque and other stimuli activate macrophages, which are crucial immune cells in AD development, triggering the production of inflammatory molecules and contributing to the disease's pathogenesis. The risk of AD is doubled by risk factors for atherosclerosis, dementia, advanced age, and type 2 diabetic mellitus (DM). As individuals age, the prevalence of neurological illnesses such as AD increases due to a decrease in glyoxalase levels and an increase in AGE accumulation. Insulin's role in proteostasis influences hallmarks of AD-like tau phosphorylation and amyloid β peptide clearance, affecting lipid metabolism, inflammation, vasoreactivity, and vascular function. The high-mobility group box 1 (HMGB1) protein, a key initiator and activator of a neuroinflammatory response, has been linked to the development of neurodegenerative diseases such as AD. The TLR4 inhibitor was found to improve memory and learning impairment and decrease Aβ build-up. Therapeutic research into anti-glycation agents, receptor for advanced glycation end products (RAGE) inhibitors, and AGE breakers offers hope for intervention strategies. Dietary and lifestyle modifications can also slow AD progression. Newer therapeutic approaches targeting AGE-related pathways are needed.
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Affiliation(s)
- Dhivya Kothandan
- Department of Pharmacy Practice, C.L. Baid Metha College of Pharmacy, Chennai, IND
| | - Daniel S Singh
- Department of Pharmacy Practice, C.L. Baid Metha College of Pharmacy, Chennai, IND
| | - Goutham Yerrakula
- School of Pharmacy, Faculty of Health Sciences, JSS Academy of Higher Education and Research, Vacoas, MUS
| | - Backkiyashree D
- Department of Pharmacy Practice, C.L. Baid Metha College of Pharmacy, Chennai, IND
| | - Pratibha N
- Department of Pharmacy Practice, C.L. Baid Metha College of Pharmacy, Chennai, IND
| | | | - Ramya A
- Department of Pharmacy Practice, C.L. Baid Metha College of Pharmacy, Chennai, IND
| | - Sapthami Ramya Vg
- Department of Pharmacy Practice, C.L. Baid Metha College of Pharmacy, Chennai, IND
| | - Keshavini S
- Department of Pharmacy Practice, C.L. Baid Metha College of Pharmacy, Chennai, IND
| | - Jagadheeshwari M
- Department of Pharmacy Practice, C.L. Baid Metha College of Pharmacy, Chennai, IND
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12
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Zhang Y, Wu C, Jiang W, Cao Y, Chen D. VGLUT2 and APP family: unraveling the neurobiochemical mechanisms of neurostimulation therapy to STZ-induced diabetes and neuropathy. Front Endocrinol (Lausanne) 2024; 15:1336854. [PMID: 38370359 PMCID: PMC10869491 DOI: 10.3389/fendo.2024.1336854] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Accepted: 01/17/2024] [Indexed: 02/20/2024] Open
Abstract
Diabetic Peripheral Neuropathy (DPN) poses an escalating threat to public health, profoundly impacting well-being and quality of life. Despite its rising prevalence, the pathogenesis of DPN remains enigmatic, and existing clinical interventions fall short of achieving meaningful reversals of the condition. Notably, neurostimulation techniques have shown promising efficacy in alleviating DPN symptoms, underscoring the imperative to elucidate the neurobiochemical mechanisms underlying DPN. This study employs an integrated multi-omics approach to explore DPN and its response to neurostimulation therapy. Our investigation unveiled a distinctive pattern of vesicular glutamate transporter 2 (VGLUT2) expression in DPN, rigorously confirmed through qPCR and Western blot analyses in DPN C57 mouse model induced by intraperitoneal Streptozotocin (STZ) injection. Additionally, combining microarray and qPCR methodologies, we revealed and substantiated variations in the expression of the Amyloid Precursor Protein (APP) family in STZ-induced DPN mice. Analyzing the transcriptomic dataset generated from neurostimulation therapy for DPN, we intricately explored the differential expression patterns of VGLUT2 and APPs. Through correlation analysis, protein-protein interaction predictions, and functional enrichment analyses, we predicted the key biological processes involving VGLUT2 and the APP family in the pathogenesis of DPN and during neurostimulation therapy. This comprehensive study not only advances our understanding of the pathogenesis of DPN but also provides a theoretical foundation for innovative strategies in neurostimulation therapy for DPN. The integration of multi-omics data facilitates a holistic view of the molecular intricacies of DPN, paving the way for more targeted and effective therapeutic interventions.
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Affiliation(s)
- Yitong Zhang
- School of Medical Technology, Beijing Institute of Technology, Beijing, China
| | - Chenxuan Wu
- School of Life Science, Beijing Institute of Technology, Beijing, China
| | - Wenqi Jiang
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan Cao
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Dongtai Chen
- State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
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13
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Barbera M, Lehtisalo J, Perera D, Aspö M, Cross M, De Jager Loots CA, Falaschetti E, Friel N, Luchsinger JA, Gavelin HM, Peltonen M, Price G, Neely AS, Thunborg C, Tuomilehto J, Mangialasche F, Middleton L, Ngandu T, Solomon A, Kivipelto M. A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol. Alzheimers Res Ther 2024; 16:23. [PMID: 38297399 PMCID: PMC10829308 DOI: 10.1186/s13195-023-01355-x] [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: 07/12/2023] [Accepted: 11/17/2023] [Indexed: 02/02/2024]
Abstract
BACKGROUND Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60-79 years) at increased risk of dementia. METHODS MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. CONCLUSION MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field. TRIAL REGISTRATION ClinicalTrials.gov (NCT05109169).
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Affiliation(s)
- Mariagnese Barbera
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
- The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, LondonLondon, W6 8RP, UK.
| | - Jenni Lehtisalo
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland
- Population Health Unit, Finnish Institute for Health and Welfare, Mannerheimintie 166, P.O. Box 30, Helsinki, Finland
| | - Dinithi Perera
- The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, LondonLondon, W6 8RP, UK
- FINGERS Brain Health Institute, C/O Stockholms Sjukhem, Box 122 30, SE-102 26, Stockholm, Sweden
| | - Malin Aspö
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska Vägen 37A, 171 64, Solna, Sweden
- Theme Inflammation and Aging, Medical Unit Aging, Karolinska University Hospital, Karolinska Vägen 37A, 171 76, Solna, Sweden
| | - Mary Cross
- Imperial Clinical Trials Unit, School of Public Health, Faculty of Medicine, Imperial College London, Imperial College London, Stadium House, 68 Wood Lane, London, W12 7RH, UK
| | - Celeste A De Jager Loots
- The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, LondonLondon, W6 8RP, UK
| | - Emanuela Falaschetti
- Imperial Clinical Trials Unit, School of Public Health, Faculty of Medicine, Imperial College London, Imperial College London, Stadium House, 68 Wood Lane, London, W12 7RH, UK
| | - Naomi Friel
- The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, LondonLondon, W6 8RP, UK
| | - José A Luchsinger
- Departments of Medicine and Epidemiology, Columbia University Irving Medical Center, 622 W 168Th St, New York, NY, USA
| | | | - Markku Peltonen
- Population Health Unit, Finnish Institute for Health and Welfare, Mannerheimintie 166, P.O. Box 30, Helsinki, Finland
- FINGERS Brain Health Institute, C/O Stockholms Sjukhem, Box 122 30, SE-102 26, Stockholm, Sweden
| | - Geraint Price
- The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, LondonLondon, W6 8RP, UK
| | - Anna Stigsdotter Neely
- Department of Social and Psychological Studies, Karlstad University, 651 88, Karlstad, Sweden
- Department of Health, Education and Technology, Luleå University of Technology, 971 87, Luleå, Sweden
| | - Charlotta Thunborg
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska Vägen 37A, 171 64, Solna, Sweden
- Theme Inflammation and Aging, Medical Unit Aging, Karolinska University Hospital, Karolinska Vägen 37A, 171 76, Solna, Sweden
| | - Jaakko Tuomilehto
- Population Health Unit, Finnish Institute for Health and Welfare, Mannerheimintie 166, P.O. Box 30, Helsinki, Finland
- Department of Public Health, University of Helsinki, PO BOX 20, 00014, Helsinki, Finland
- Diabetes Research Group, King Abdulaziz University, 21589, Jeddah, Saudi Arabia
| | - Francesca Mangialasche
- FINGERS Brain Health Institute, C/O Stockholms Sjukhem, Box 122 30, SE-102 26, Stockholm, Sweden
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska Vägen 37A, 171 64, Solna, Sweden
- Theme Inflammation and Aging, Medical Unit Aging, Karolinska University Hospital, Karolinska Vägen 37A, 171 76, Solna, Sweden
| | - Lefkos Middleton
- The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, LondonLondon, W6 8RP, UK
- Directorate of Public Health, Imperial College NHS Healthcare Trust Hospitals, Praed Street, London, W2 1NY, UK
| | - Tiia Ngandu
- Population Health Unit, Finnish Institute for Health and Welfare, Mannerheimintie 166, P.O. Box 30, Helsinki, Finland
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska Vägen 37A, 171 64, Solna, Sweden
| | - Alina Solomon
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland.
- The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, LondonLondon, W6 8RP, UK.
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska Vägen 37A, 171 64, Solna, Sweden.
| | - Miia Kivipelto
- The Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, Charing Cross Hospital, St Dunstan's Road, LondonLondon, W6 8RP, UK
- Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Karolinska Vägen 37A, 171 64, Solna, Sweden
- Theme Inflammation and Aging, Medical Unit Aging, Karolinska University Hospital, Karolinska Vägen 37A, 171 76, Solna, Sweden
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Yliopistonranta 1C, 70211, Kuopio, Finland
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14
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Solingapuram Sai KK, Erichsen JM, Gollapelli KK, Krizan I, Miller M, Bansode A, Jorgensen MJ, Register T, Cazzola C, Gandhi R, Suman J, Craft S. First Biodistribution Study of [68Ga]Ga-NOTA-Insulin Following Intranasal Administration in Adult Vervet Monkeys. J Alzheimers Dis 2024; 101:309-320. [PMID: 39213084 DOI: 10.3233/jad-240484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Background Intranasal insulin (INI) is being explored as a treatment for Alzheimer's disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes. Objective To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system. Methods To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans. Results We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq. Conclusions The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans.
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Affiliation(s)
| | - Jennifer M Erichsen
- Department of Internal Medicine, Division of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | | | - Ivan Krizan
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Mack Miller
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Avinash Bansode
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Mathew J Jorgensen
- Department of Pathology, Division of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Thomas Register
- Department of Pathology, Division of Comparative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | | | | | | | - Suzanne Craft
- Department of Internal Medicine, Division of Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
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15
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Yuan X, Yan F, Gao L, Ma Q, Wang J. Hypericin as a potential drug for treating Alzheimer's disease and type 2 diabetes with a view to drug repositioning. CNS Neurosci Ther 2023; 29:3307-3321. [PMID: 37183545 PMCID: PMC10580347 DOI: 10.1111/cns.14260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 04/25/2023] [Accepted: 04/29/2023] [Indexed: 05/16/2023] Open
Abstract
AIMS Alzheimer's disease (AD) and type 2 diabetes (T2D) are two of the most common diseases in elderly population and they have a high rate of comorbidity. Study has revealed that T2D is a major risk factor of AD, and thus exploring therapeutic approaches that can target both diseases has drawn much interest in recent years. In this study, we tried to explore drugs that could be potentially used to prevent or treat both AD and T2D via a drug repositioning approach. METHODS We first searched the known drugs that may be effective to T2D treatment based on the network distance between the T2D-associated genes and drugs deposited in the DrugBank database. Then, via molecular docking, we further screened these drugs by examining their interaction with islet amyloid polypeptide (IAPP) and Aβ42 peptide, the key components involved in the pathogenesis of T2D or AD. Finally, the binding between the selected drug candidates and the target proteins was verified by molecular dynamics (MD) simulation; and the potential function of the drug candidates and the corresponding targets were analyzed. RESULTS From multiple resources, 734 T2D-associated genes were collected, and a list of 1109 drug candidates for T2D was obtained. We found that hypericin had the lowest binding energy and the most stable interaction with either IAPP or Aβ42 peptide. In addition, we also found that the target genes regulated by hypericin were differentially expressed in the tissues related to the two diseases. CONCLUSION Our results show that hypericin may be able to bind with IAPP and Aβ42 stably and prevent their accumulation, and thus could be a promising drug candidate for treating the comorbidity of AD and T2D.
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Affiliation(s)
- Xin Yuan
- School of Biomedical EngineeringTianjin Medical UniversityTianjinChina
| | - Fei Yan
- School of Biomedical EngineeringTianjin Medical UniversityTianjinChina
| | - Li‐Hui Gao
- School of Biomedical EngineeringTianjin Medical UniversityTianjinChina
| | - Qian‐Hui Ma
- School of Biomedical EngineeringTianjin Medical UniversityTianjinChina
| | - Ju Wang
- School of Biomedical EngineeringTianjin Medical UniversityTianjinChina
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16
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Nelson ML, Pfeifer JA, Hickey JP, Collins AE, Kalisch BE. Exploring Rosiglitazone's Potential to Treat Alzheimer's Disease through the Modulation of Brain-Derived Neurotrophic Factor. BIOLOGY 2023; 12:1042. [PMID: 37508471 PMCID: PMC10376118 DOI: 10.3390/biology12071042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/24/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that debilitates over 55 million individuals worldwide. Currently, treatments manage and alleviate its symptoms; however, there is still a need to find a therapy that prevents or halts disease progression. Since AD has been labeled as "type 3 diabetes" due to its similarity in pathological hallmarks, molecular pathways, and comorbidity with type 2 diabetes mellitus (T2DM), there is growing interest in using anti-diabetic drugs for its treatment. Rosiglitazone (RSG) is a peroxisome proliferator-activated receptor-gamma agonist that reduces hyperglycemia and hyperinsulinemia and improves insulin signaling. In cellular and rodent models of T2DM-associated cognitive decline and AD, RSG has been reported to improve cognitive impairment and reverse AD-like pathology; however, results from human clinical trials remain consistently unsuccessful. RSG has also been reported to modulate the expression of brain-derived neurotrophic factor (BDNF), a protein that regulates neuroplasticity and energy homeostasis and is implicated in both AD and T2DM. The present review investigates RSG's limitations and potential therapeutic benefits in pre-clinical models of AD through its modulation of BDNF expression.
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Affiliation(s)
- Mackayla L Nelson
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Julia A Pfeifer
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Jordan P Hickey
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Andrila E Collins
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - Bettina E Kalisch
- Department of Biomedical Sciences and Collaborative Specialization in Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada
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17
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Wang W, Zhang L, Cao W, Xia K, Huo J, Huang T, Fan D. Systematic Screening of Associations between Medication Use and Risk of Neurodegenerative Diseases Using a Mendelian Randomization Approach. Biomedicines 2023; 11:1930. [PMID: 37509570 PMCID: PMC10377701 DOI: 10.3390/biomedicines11071930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/01/2023] [Accepted: 07/05/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Systematically assessing the causal associations between medications and neurodegenerative diseases is significant in identifying disease etiology and novel therapies. Here, we investigated the putative causal associations between 23 existing medication categories and major neurodegenerative diseases (NDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). METHODS A two-sample mendelian randomization (MR) approach was conducted. Estimates were calculated using the inverse-variance weighted (IVW) method as the main model. A sensitivity analysis and a pleiotropy analysis were performed to identify potential violations. RESULTS Genetically predisposition to antihypertensives (OR = 0.809, 95% CI = 0.668-0.981, p = 0.031), thyroid preparations (OR = 0.948, 95% CI = 0.909-0.988, p = 0.011), and immunosuppressants (OR = 0.879, 95% CI = 0.789-0.979, p = 0.018) was associated with a decreased risk of AD. Genetic proxies for thyroid preparations (OR = 0.934, 95% CI = 0.884-0.988, p = 0.017), immunosuppressants (OR = 0.825, 95% CI = 0.699-0.973, p = 0.022), and glucocorticoids (OR = 0.862, 95% CI = 0.756-0.983, p = 0.027) were causally associated with a decreased risk of PD. Genetically determined antithrombotic agents (OR = 1.234, 95% CI = 1.042-1.461, p = 0.015), HMG CoA reductase inhibitors (OR = 1.085, 95% CI = 1.025-1.148, p = 0.005), and salicylic acid and derivatives (OR = 1.294, 95% CI = 1.078-1.553, p = 0.006) were associated with an increased risk of ALS. CONCLUSIONS We presented a systematic view concerning the causal associations between medications and NDs, which will promote the etiology discovery, drug repositioning and patient management for NDs.
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Affiliation(s)
- Wenjing Wang
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing 100191, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing 100191, China
| | - Linjing Zhang
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing 100191, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing 100191, China
| | - Wen Cao
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing 100191, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing 100191, China
| | - Kailin Xia
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing 100191, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing 100191, China
| | - Junyan Huo
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing 100191, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing 100191, China
| | - Tao Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
- Key Laboratory of Molecular Cardiovascular Sciences, Peking University, Ministry of Education, Beijing 100191, China
| | - Dongsheng Fan
- Department of Neurology, Peking University Third Hospital, Beijing 100191, China
- Beijing Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing 100191, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing 100191, China
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Song M, Fan X. Systemic Metabolism and Mitochondria in the Mechanism of Alzheimer's Disease: Finding Potential Therapeutic Targets. Int J Mol Sci 2023; 24:ijms24098398. [PMID: 37176104 PMCID: PMC10179273 DOI: 10.3390/ijms24098398] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/30/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Elderly people over the age of 65 are those most likely to experience Alzheimer's disease (AD), and aging and AD are associated with apparent metabolic alterations. Currently, there is no curative medication against AD and only several drugs have been approved by the FDA, but these drugs can only improve the symptoms of AD. Many preclinical and clinical trials have explored the impact of adjusting the whole-body and intracellular metabolism on the pathogenesis of AD. The most recent evidence suggests that mitochondria initiate an integrated stress response to environmental stress, which is beneficial for healthy aging and neuroprotection. There is also an increasing awareness of the differential risk and potential targeting strategies related to the metabolic level and microbiome. As the main participants in intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been regarded as potential therapeutic targets for AD. This review summarizes and highlights these advances.
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Affiliation(s)
- Meiying Song
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Xiang Fan
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
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19
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Ha J, Choi DW, Kim KJ, Kim KY, Nam CM, Kim E. Pioglitazone Use and Reduced Risk of Dementia in Patients With Diabetes Mellitus With a History of Ischemic Stroke. Neurology 2023; 100:e1799-e1811. [PMID: 36792375 PMCID: PMC10136019 DOI: 10.1212/wnl.0000000000207069] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 01/03/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Previous studies have reported the protective effect of pioglitazone on dementia in patients with type 2 diabetes mellitus (DM). Recent studies have shown that pioglitazone also lowers the risk of primary and recurrent stroke. Understanding the characteristics of patients particularly associated with the benefits of pioglitazone would facilitate its personalized use by specifying subpopulations during routine clinical care. The aim of this study was to examine the effects of pioglitazone use on dementia in consideration of stroke occurrence. METHODS Using nationwide longitudinal data of patients with DM from the Korean National Health Insurance Service DM cohort (2002-2017), we investigated the association of pioglitazone use with incident dementia in patients with new-onset type 2 DM. The heterogeneity of the treatment effect was examined using exploratory analyses. Using a multistate model, we assessed the extent to which incident stroke affects the association between pioglitazone use and dementia. RESULTS Pioglitazone use was associated with a reduced risk of dementia, compared with nonuse (adjusted hazard ratio [aHR] = 0.84, 95% CI 0.75-0.95); the risk reduction in dementia was greater among patients with a history of ischemic heart disease or stroke before DM onset (aHR = 0.46, 95% CI 0.24-0.90; aHR = 0.57, 95% CI 0.38-0.86, respectively). The incidence of stroke was also reduced by pioglitazone use (aHR = 0.81, 95% CI 0.66-1.00). However, when the stroke developed during the observation period of pioglitazone use, such lowered risk of dementia was not observed (aHR = 1.27, 95% CI 0.80-2.04). DISCUSSION Pioglitazone use is associated with a lower risk of dementia in patients with DM, particularly in those with a history of stroke or ischemic heart disease, suggesting the possibility of applying a personalized approach when choosing pioglitazone to suppress dementia in patients with DM.
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Affiliation(s)
- Junghee Ha
- From the Department of Psychiatry (J.H., K.Y.K., E.K.), Institute of Behavioral Science in Medicine, and Division of Geriatrics (K.J.K.), Department of Internal Medicine, and Department of Preventive Medicine (C.M.N.), and Graduate School of Medical Science (E.K.), Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Cancer Big Data Center (D.-W.C.), National Cancer Control Institute, National Cancer Center, Gyeonggi-do, Republic of Korea; and Department of Psychiatry (K.Y.K.), Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Dong-Woo Choi
- From the Department of Psychiatry (J.H., K.Y.K., E.K.), Institute of Behavioral Science in Medicine, and Division of Geriatrics (K.J.K.), Department of Internal Medicine, and Department of Preventive Medicine (C.M.N.), and Graduate School of Medical Science (E.K.), Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Cancer Big Data Center (D.-W.C.), National Cancer Control Institute, National Cancer Center, Gyeonggi-do, Republic of Korea; and Department of Psychiatry (K.Y.K.), Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Kwang Joon Kim
- From the Department of Psychiatry (J.H., K.Y.K., E.K.), Institute of Behavioral Science in Medicine, and Division of Geriatrics (K.J.K.), Department of Internal Medicine, and Department of Preventive Medicine (C.M.N.), and Graduate School of Medical Science (E.K.), Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Cancer Big Data Center (D.-W.C.), National Cancer Control Institute, National Cancer Center, Gyeonggi-do, Republic of Korea; and Department of Psychiatry (K.Y.K.), Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
| | - Keun You Kim
- From the Department of Psychiatry (J.H., K.Y.K., E.K.), Institute of Behavioral Science in Medicine, and Division of Geriatrics (K.J.K.), Department of Internal Medicine, and Department of Preventive Medicine (C.M.N.), and Graduate School of Medical Science (E.K.), Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Cancer Big Data Center (D.-W.C.), National Cancer Control Institute, National Cancer Center, Gyeonggi-do, Republic of Korea; and Department of Psychiatry (K.Y.K.), Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
| | - Chung Mo Nam
- From the Department of Psychiatry (J.H., K.Y.K., E.K.), Institute of Behavioral Science in Medicine, and Division of Geriatrics (K.J.K.), Department of Internal Medicine, and Department of Preventive Medicine (C.M.N.), and Graduate School of Medical Science (E.K.), Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Cancer Big Data Center (D.-W.C.), National Cancer Control Institute, National Cancer Center, Gyeonggi-do, Republic of Korea; and Department of Psychiatry (K.Y.K.), Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea
| | - Eosu Kim
- From the Department of Psychiatry (J.H., K.Y.K., E.K.), Institute of Behavioral Science in Medicine, and Division of Geriatrics (K.J.K.), Department of Internal Medicine, and Department of Preventive Medicine (C.M.N.), and Graduate School of Medical Science (E.K.), Brain Korea 21 FOUR Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea; Cancer Big Data Center (D.-W.C.), National Cancer Control Institute, National Cancer Center, Gyeonggi-do, Republic of Korea; and Department of Psychiatry (K.Y.K.), Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
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20
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Xu J, Ni B, Ma C, Rong S, Gao H, Zhang L, Xiang X, Huang Q, Deng Q, Huang F. Docosahexaenoic acid enhances hippocampal insulin sensitivity to promote cognitive function of aged rats on a high-fat diet. J Adv Res 2023; 45:31-42. [PMID: 35618634 PMCID: PMC10006543 DOI: 10.1016/j.jare.2022.04.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 03/18/2022] [Accepted: 04/24/2022] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION Diminished brain insulin sensitivity is associated with reduced cognitive function. Docosahexaenoic acid (DHA) is known to maintain normal brain function. OBJECTIVES This study aimed to determine whether DHA impacts hippocampal insulin sensitivity and cognitive function in aged rats fed a high-fat diet (HFD). METHODS Eight-month-old female Sprague-Dawley rats were randomly divided into three groups (n = 50 each). Rats in the aged group, HFD group, and DHA treatment group received standard diet (10 kcal% fat), HFD (45 kcal% fat), and DHA-enriched HFD (45 kcal% fat, 1% DHA, W/W) for 10 months, respectively. Four-month-old female rats (n = 40) that received a standard diet served as young controls. Neuroinflammation, oxidative stress, amyloid formation, and tau phosphorylation in the hippocampus, as well as systemic glucose homeostasis and cognitive function, were tested. RESULTS DHA treatment relieved a block in the insulin signaling pathway and consequently protected aged rats against HFD-induced hippocampal insulin resistance. The beneficial effects were explained by a DHA-induced decrease in systemic glucose homeostasis dysregulation, hippocampal neuroinflammation and oxidative stress. In addition, DHA treatment broke the reciprocal cycle of hippocampal insulin resistance, Aβ burden, and tau hyperphosphorylation. Importantly, treatment of model rats with DHA significantly increased their cognitive capacity, as evidenced by their increased hippocampal-dependent learning and memory, restored neuron morphology, enhanced cholinergic activity, and activated cyclic AMP-response element-binding protein. CONCLUSION DHA improves cognitive function by enhancing hippocampal insulin sensitivity.
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Affiliation(s)
- Jiqu Xu
- Department of Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China
| | - Ben Ni
- Department of Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China
| | - Congcong Ma
- Department of Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China
| | - Shuang Rong
- Department of Nutrition and Food Hygiene, School of Public Health, Wuhan University of Science and Technology, Wuhan 430065, P.R. China
| | - Hui Gao
- Department of Clinical Nutrition, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, P.R. China
| | - Li Zhang
- Department of Neurology, Hubei Provincial Hospital of Integrated Chinese & Western Medicine, No. 11, Lingjiaohu Road, Wuhan 430015, P.R. China
| | - Xia Xiang
- Department of Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China
| | - Qingde Huang
- Department of Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China
| | - Qianchun Deng
- Department of Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China
| | - Fenghong Huang
- Department of Nutriology, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China; Hubei Key Laboratory of Lipid Chemistry and Nutrition, Oil Crops Research Institute, Chinese Academy of Agricultural Sciences, 2 Xudong Second Road, Wuhan 430062, P.R. China.
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Patel RS, Lui A, Hudson C, Moss L, Sparks RP, Hill SE, Shi Y, Cai J, Blair LJ, Bickford PC, Patel NA. Small molecule targeting long noncoding RNA GAS5 administered intranasally improves neuronal insulin signaling and decreases neuroinflammation in an aged mouse model. Sci Rep 2023; 13:317. [PMID: 36609440 PMCID: PMC9822944 DOI: 10.1038/s41598-022-27126-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 12/26/2022] [Indexed: 01/09/2023] Open
Abstract
Shifts in normal aging set stage for neurodegeneration and dementia affecting 1 in 10 adults. The study demonstrates that lncRNA GAS5 is decreased in aged and Alzheimer's disease brain. The role and targets of lncRNA GAS5 in the aging brain were elucidated using a GAS5-targeting small molecule NPC86, a frontier in lncRNA-targeting therapeutic. Robust techniques such as molecular dynamics simulation of NPC86 binding to GAS5, in vitro functional assays demonstrating that GAS5 regulates insulin signaling, neuronal survival, phosphorylation of tau, and neuroinflammation via toll-like receptors support the role of GAS5 in maintaining healthy neurons. The study demonstrates the safety and efficacy of intranasal NPC86 treatment in aged mice to improve cellular functions with transcriptomic analysis in response to NPC86. In summary, the study demonstrates that GAS5 contributes to pathways associated with neurodegeneration and NPC86 has tremendous therapeutic potential to prevent the advent of neurodegenerative diseases and dementias.
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Affiliation(s)
- Rekha S. Patel
- grid.281075.90000 0001 0624 9286James A. Haley Veterans Hospital, Research Service, 13000 Bruce B. Downs Blvd., Tampa, FL 33612 USA
| | - Ashley Lui
- grid.170693.a0000 0001 2353 285XDepartment of Molecular Medicine, University of South Florida, Tampa, FL 33612 USA
| | - Charles Hudson
- grid.281075.90000 0001 0624 9286James A. Haley Veterans Hospital, Research Service, 13000 Bruce B. Downs Blvd., Tampa, FL 33612 USA
| | - Lauren Moss
- grid.170693.a0000 0001 2353 285XDepartment of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33612 USA
| | - Robert P. Sparks
- Present Address: UMass Chan Medical School, Worcester, MA 01655 USA
| | - Shannon E. Hill
- grid.170693.a0000 0001 2353 285XDepartment of Molecular Medicine, University of South Florida, Tampa, FL 33612 USA ,grid.170693.a0000 0001 2353 285XUSF Health Byrd Institute, University of South Florida, Tampa, FL 33612 USA
| | - Yan Shi
- grid.170693.a0000 0001 2353 285XDepartment of Chemistry, University of South Florida, Tampa, FL 33612 USA
| | - Jianfeng Cai
- grid.170693.a0000 0001 2353 285XDepartment of Chemistry, University of South Florida, Tampa, FL 33612 USA
| | - Laura J. Blair
- grid.281075.90000 0001 0624 9286James A. Haley Veterans Hospital, Research Service, 13000 Bruce B. Downs Blvd., Tampa, FL 33612 USA ,grid.170693.a0000 0001 2353 285XDepartment of Molecular Medicine, University of South Florida, Tampa, FL 33612 USA ,grid.170693.a0000 0001 2353 285XUSF Health Byrd Institute, University of South Florida, Tampa, FL 33612 USA
| | - Paula C. Bickford
- grid.281075.90000 0001 0624 9286James A. Haley Veterans Hospital, Research Service, 13000 Bruce B. Downs Blvd., Tampa, FL 33612 USA ,grid.170693.a0000 0001 2353 285XDepartment of Neurosurgery and Brain Repair, University of South Florida, Tampa, FL 33612 USA
| | - Niketa A. Patel
- grid.281075.90000 0001 0624 9286James A. Haley Veterans Hospital, Research Service, 13000 Bruce B. Downs Blvd., Tampa, FL 33612 USA ,grid.170693.a0000 0001 2353 285XDepartment of Molecular Medicine, University of South Florida, Tampa, FL 33612 USA
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22
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Agarwal K, Katare DP, Jakhmola-Mani R. Foresee Novel Targets for Alzheimer's Disease by Investigating Repurposed Drugs. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2023; 22:1209-1231. [PMID: 35733313 DOI: 10.2174/1871527321666220622162622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/22/2022] [Accepted: 04/12/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Alzheimer's Disease (AD) is the most rampant neurodegenerative disorder which has caused havoc worldwide. More than a century has passed since the first case of AD was reported, but still, no stable treatment is known to humanity. The available medications only provide temporary relief and are not a cure for the disease. The hunt for advanced techniques in drug development has paved the way for drug repurposing, i.e., repositioning or reutilizing drugs as an innovative approach. METHODOLOGY Several drugs which were repurposed for AD were collected by following PRISMA 2020 systemic review. Databases like PubMed, ScienceDirect, JSTOR, and SciELO were used for data extraction. Further, the Drugbank database was used to download all the identified drugs. Later, the Swiss Target Prediction tool was used to identify protein receptors for these drugs and the biological pathway followed by them. RESULTS Drugs like Zileuton, Salbutamol, Baricitinib, Carmustine, Paclitaxel, and Nilotinib were observed to be involved in regulation of neurotransmitters. Similarly, Metformin, Liraglutide, UDCA, and Bexarotene are involved in protein kinase cascades which also is one of the prime processes in metabolic disorders like AD. Furthermore, drugs like Rosiglitazone, Pioglitazone, and Lonafarnib are involved in interleukin-3 biosynthetic processes, which is again one of the most important processes studied in AD treatment. CONCLUSION The study concluded that the reviewed drugs that follow similar biological and molecular processes could be repurposed for AD if chosen judiciously with current medications and thus, drug repurposing is a promising approach that can be utilized to find a cure for AD within a brief time and fewer resources compared to de novo drug synthesis. Although certain loopholes still need to be worked upon, the technique has great prospects. Furthermore, in silico methods can be utilized to justify the findings and identify the best drug candidate.
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Affiliation(s)
- Kritie Agarwal
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, India
| | - Deepshikha Pande Katare
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, India
| | - Ruchi Jakhmola-Mani
- Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, India
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23
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Gupta MK, Gouda G, Sultana S, Punekar SM, Vadde R, Ravikiran T. Structure-related relationship: Plant-derived antidiabetic compounds. STUDIES IN NATURAL PRODUCTS CHEMISTRY 2023:241-295. [DOI: 10.1016/b978-0-323-91294-5.00008-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/06/2023]
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24
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Zhou C, Jung CG, Kim MJ, Watanabe A, Abdelhamid M, Taslima F, Michikawa M. Insulin Deficiency Increases Sirt2 Level in Streptozotocin-Treated Alzheimer's Disease-Like Mouse Model: Increased Sirt2 Induces Tau Phosphorylation Through ERK Activation. Mol Neurobiol 2022; 59:5408-5425. [PMID: 35701718 PMCID: PMC9395464 DOI: 10.1007/s12035-022-02918-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/07/2022] [Indexed: 11/11/2022]
Abstract
Accumulating evidence suggests that insulin deficiency is a risk factor for Alzheimer's disease (AD); however, the underlying molecular mechanisms are not completely understood. Here, we investigated the effects of insulin deficiency on AD-like pathologies using an insulin-deficient amyloid-β (Aβ) precursor protein (APP) transgenic mouse model (Tg2576 mice). Female Tg2576 mice were injected intraperitoneally with streptozotocin (STZ) to induce insulin deficiency, and their body weights, serum glucose levels, and serum insulin levels were evaluated. STZ-treated mice showed exacerbated Aβ accumulation, tau hyperphosphorylation, glial activation, neuroinflammation, and increased Sirt2 protein levels in the brain, as determined by two-dimensional gel electrophoresis (2-DE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and Western blotting. Furthermore, our in vitro experiments revealed that insulin depletion or interleukin-6 treatment increased Sirt2 protein levels in both Neuro2a and Neuro2a-P301L cells. The overexpression of Sirt2 in these cells induced tau hyperphosphorylation through extracellular signal-regulated kinase (ERK) activation. Conversely, Sirt2 knockdown reversed tau hyperphosphorylation in these cells. We showed for the first time that Sirt2 is upregulated in the brains of STZ-treated Tg2576 mice and is involved in tau phosphorylation through ERK activation. Our findings suggest that Sirt2 is a promising therapeutic target for the treatment of AD.
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Affiliation(s)
- Chunyu Zhou
- Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601 Japan
| | - Cha-Gyun Jung
- Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601 Japan
| | - Mi-Jeong Kim
- Department of Food & Biotechnology, Korea University, Sejong, 30019 South Korea
| | - Atsushi Watanabe
- Laboratory of Research Advancement, Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511 Japan
| | - Mona Abdelhamid
- Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601 Japan
| | - Ferdous Taslima
- Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601 Japan
| | - Makoto Michikawa
- Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi 467-8601 Japan
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Guzmán-Ruiz MA, Jiménez A, Cárdenas-Rivera A, Guerrero-Vargas NN, Organista-Juárez D, Guevara-Guzmán R. Regulation of Metabolic Health by an "Olfactory-Hypothalamic Axis" and Its Possible Implications for the Development of Therapeutic Approaches for Obesity and T2D. Cell Mol Neurobiol 2022; 42:1727-1743. [PMID: 33813677 PMCID: PMC11421737 DOI: 10.1007/s10571-021-01080-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 03/12/2021] [Indexed: 12/12/2022]
Abstract
The olfactory system is responsible for the reception, integration and interpretation of odors. However, in the last years, it has been discovered that the olfactory perception of food can rapidly modulate the activity of hypothalamic neurons involved in the regulation of energy balance. Conversely, the hormonal signals derived from changes in the metabolic status of the body can also change the sensitivity of the olfactory system, suggesting that the bidirectional relationship established between the olfactory and the hypothalamic systems is key for the maintenance of metabolic homeostasis. In the first part of this review, we describe the possible mechanisms and anatomical pathways involved in the modulation of energy balance regulated by the olfactory system. Hence, we propose a model to explain its implication in the maintenance of the metabolic homeostasis of the organism. In the second part, we discuss how the olfactory system could be involved in the development of metabolic diseases such as obesity and type two diabetes and, finally, we propose the use of intranasal therapies aimed to regulate and improve the activity of the olfactory system that in turn will be able to control the neuronal activity of hypothalamic centers to prevent or ameliorate metabolic diseases.
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Affiliation(s)
- Mara Alaide Guzmán-Ruiz
- Laboratorio Sensorial, Departamento de Fisiología, Facultad de Medicina, Edificio A, 4º piso, Universidad Nacional Autónoma de México (UNAM), 04510, Ciudad de México, México.
| | - Adriana Jiménez
- Laboratorio Sensorial, Departamento de Fisiología, Facultad de Medicina, Edificio A, 4º piso, Universidad Nacional Autónoma de México (UNAM), 04510, Ciudad de México, México
| | - Alfredo Cárdenas-Rivera
- Centro de Investigación en Bioingeniería, Universidad de Ingeniería y Tecnología, Lima, Perú
| | - Natalí N Guerrero-Vargas
- Departamento de Anatomía, Facultad de Medicina, Universidad Nacional Autónoma de México, México City, México
| | - Diana Organista-Juárez
- Laboratorio Sensorial, Departamento de Fisiología, Facultad de Medicina, Edificio A, 4º piso, Universidad Nacional Autónoma de México (UNAM), 04510, Ciudad de México, México
| | - Rosalinda Guevara-Guzmán
- Laboratorio Sensorial, Departamento de Fisiología, Facultad de Medicina, Edificio A, 4º piso, Universidad Nacional Autónoma de México (UNAM), 04510, Ciudad de México, México.
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26
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Kazkayasi I, Telli G, Nemutlu E, Uma S. Intranasal metformin treatment ameliorates cognitive functions via insulin signaling pathway in ICV-STZ-induced mice model of Alzheimer's disease. Life Sci 2022; 299:120538. [PMID: 35395244 DOI: 10.1016/j.lfs.2022.120538] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 03/17/2022] [Accepted: 04/03/2022] [Indexed: 02/01/2023]
Abstract
AIMS The relationship between type 2 diabetes and Alzheimer's disease (AD) provides evidence that insulin and insulin sensitizers may be beneficial for the treatment of AD. The present study investigated the effect and mechanism of action of intranasal metformin treatment on impaired cognitive functions in an experimental mice model of AD. MAIN METHODS Intracerebroventricularly (ICV) streptozotocin (STZ)-injected mice were treated with intranasal or oral metformin for 4 weeks. Learning and memory functions were evaluated using Morris water maze. Metformin and Aβ42 concentrations were determined by liquid chromatography tandem mass spectrometry and ELISA respectively. The expressions of insulin receptor, Akt and their phosphorylated forms were determined in the hippocampi and cerebral cortices of mice. KEY FINDINGS ICV-STZ-induced AD mice displayed impaired learning and memory functions which were improved by metformin treatment. ICV-STZ injection or intranasal/oral metformin treatments had no effect on blood glucose concentrations. Intranasal treatment yielded higher concentration of metformin in the hippocampus and lower in the plasma compared to oral treatment. ICV-STZ injection and metformin treatments did not change amyloid β-42 concentration in the hippocampus of mice. In hippocampal and cortical tissues of ICV-STZ-induced AD mice, insulin receptor (IR) and Akt expressions were unchanged, while phosphorylated insulin receptor (pIR) and pAkt expressions decreased compared to control. Metformin treatments did not change IR and Akt expressions but increased pIR and pAkt expressions. SIGNIFICANCE The present study showed for the first time that intranasal metformin treatment improved the impaired cognitive functions through increasing insulin sensitivity in ICV-STZ-induced mice model of AD.
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Affiliation(s)
- Inci Kazkayasi
- Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey.
| | - Gokcen Telli
- Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey
| | - Emirhan Nemutlu
- Hacettepe University, Faculty of Pharmacy, Department of Analytical Chemistry, Ankara, Turkey
| | - Serdar Uma
- Hacettepe University, Faculty of Pharmacy, Department of Pharmacology, Ankara, Turkey
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Zhu S, Bai Q, Li L, Xu T. Drug repositioning in drug discovery of T2DM and repositioning potential of antidiabetic agents. Comput Struct Biotechnol J 2022; 20:2839-2847. [PMID: 35765655 PMCID: PMC9189996 DOI: 10.1016/j.csbj.2022.05.057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 05/30/2022] [Accepted: 05/30/2022] [Indexed: 12/19/2022] Open
Abstract
Repositioning or repurposing drugs account for a substantial part of entering approval pipeline drugs, which indicates that drug repositioning has huge market potential and value. Computational technologies such as machine learning methods have accelerated the process of drug repositioning in the last few decades years. The repositioning potential of type 2 diabetes mellitus (T2DM) drugs for various diseases such as cancer, neurodegenerative diseases, and cardiovascular diseases have been widely studied. Hence, the related summary about repurposing antidiabetic drugs is of great significance. In this review, we focus on the machine learning methods for the development of new T2DM drugs and give an overview of the repurposing potential of the existing antidiabetic agents.
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Affiliation(s)
- Sha Zhu
- Key Lab of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Qifeng Bai
- Key Lab of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu 730000, PR China
- Corresponding author.
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28
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Erichsen JM, Fadel JR, Reagan LP. Peripheral versus central insulin and leptin resistance: Role in metabolic disorders, cognition, and neuropsychiatric diseases. Neuropharmacology 2022; 203:108877. [PMID: 34762922 PMCID: PMC8642294 DOI: 10.1016/j.neuropharm.2021.108877] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 10/14/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023]
Abstract
Insulin and leptin are classically regarded as peptide hormones that play key roles in metabolism. In actuality, they serve several functions in both the periphery and central nervous system (CNS). Likewise, insulin and leptin resistance can occur both peripherally and centrally. Metabolic disorders such as diabetes and obesity share several key features including insulin and leptin resistance. While the peripheral effects of these disorders are well-known (i.e. cardiovascular disease, hypertension, stroke, dyslipidemia, etc.), the CNS complications of leptin and insulin resistance have come into sharper focus. Both preclinical and clinical findings have indicated that insulin and leptin resistance are associated with cognitive deficits and neuropsychiatric diseases such as depression. Importantly, these studies also suggest that these deficits in neuroplasticity can be reversed by restoration of insulin and leptin sensitivity. In view of these observations, this review will describe, in detail, the peripheral and central functions of insulin and leptin and explain the role of insulin and leptin resistance in various metabolic disorders, cognition, and neuropsychiatric diseases.
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Affiliation(s)
- Jennifer M Erichsen
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA.
| | - Jim R Fadel
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA
| | - Lawrence P Reagan
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC, 29208, USA; Columbia VA Health Care System, Columbia, SC, 29208, USA
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29
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Dwivedi V, Gupta RK, Gupta A, Chaudhary VK, Gupta S, Gupta V. Repurposing Novel Antagonists to p7 Viroporin of HCV Using in silico Approach. LETT DRUG DES DISCOV 2022. [DOI: 10.2174/1570180819666220124112150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Abstract:
Background: P7 viroporin in HCV is a cation-selective ion channel-forming protein, functional in the oligomeric form. It is considered to be a potential target for anti-HCV compounds due to its crucial role in viral entry, assembly and release.
Method:
Conserved crucial residues present in HCV p7 protein were delineated with a specific focus on the genotypes 3a &1b prevalent in India from the available literature. Using the Flex-X docking tool, a library of FDA-approved drugs was docked on the receptor sites prepared around crucial residues. In the present study, we propose drug repurposing to target viroporin p7, which may help in the rapid development of effective anti-HCV therapies.
Results:
With our approach of poly-pharmacology, a variety of drugs currently identified classified as antibiotics, anti-parasitic, antiemetic, anti-retroviral, and anti-neoplastic were found to dock successfully with the p7 viroporin. Noteworthy among these are general-purpose cephalosporin antibiotics, leucal, phthalylsulfathiazole, and granisetron, which may be useful in acute HCV infection and anti-neoplastic sorafenib and nilotinib, which may be valuable in advanced HCV-HCC cases.
Conclusion:
This study could pave the way for quick repurposing of these compounds as anti-HCV therapeutics.
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Affiliation(s)
- Varsha Dwivedi
- Department of Microbiology, Ram Lal Anand College, Delhi University, Benito Juarez Road, New Delhi, India
| | - Rakesh Kumar Gupta
- Department of Microbiology, Ram Lal Anand College, Delhi University, Benito Juarez Road, New Delhi, India
| | - Amita Gupta
- Department of Biochemistry and Centre for Innovation in Infectious Disease Research, Education and Training, University of Delhi South Campus, Benito Juarez Marg, New Delhi, India
| | - Vijay K Chaudhary
- Department of Biochemistry and Centre for Innovation in Infectious Disease Research, Education and Training, University of Delhi South Campus, Benito Juarez Marg, New Delhi, India
| | - Sanjay Gupta
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Vandana Gupta
- Department of Microbiology, Ram Lal Anand College, Delhi University, Benito Juarez Road, New Delhi, India
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30
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Lei H, Hu R, Luo G, Yang T, Shen H, Deng H, Chen C, Zhao H, Liu J. Altered Structural and Functional MRI Connectivity in Type 2 Diabetes Mellitus Related Cognitive Impairment: A Review. Front Hum Neurosci 2022; 15:755017. [PMID: 35069149 PMCID: PMC8770326 DOI: 10.3389/fnhum.2021.755017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 12/13/2021] [Indexed: 12/16/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is associated with cognitive impairment in many domains. There are several pieces of evidence that changes in neuronal neuropathies and metabolism have been observed in T2DM. Structural and functional MRI shows that abnormal connections and synchronization occur in T2DM brain circuits and related networks. Neuroplasticity and energy metabolism appear to be principal effector systems, which may be related to amyloid beta (Aβ) deposition, although there is no unified explanation that includes the complex etiology of T2DM with cognitive impairment. Herein, we assume that cognitive impairment in diabetes may lead to abnormalities in neuroplasticity and energy metabolism in the brain, and those reflected to MRI structural connectivity and functional connectivity, respectively.
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Mandwie M, Karunia J, Niaz A, Keay KA, Musumeci G, Rennie C, McGrath K, Al-Badri G, Castorina A. Metformin Treatment Attenuates Brain Inflammation and Rescues PACAP/VIP Neuropeptide Alterations in Mice Fed a High-Fat Diet. Int J Mol Sci 2021; 22:ijms222413660. [PMID: 34948457 PMCID: PMC8706124 DOI: 10.3390/ijms222413660] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 12/28/2022] Open
Abstract
High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective peptides endowed with anti-inflammatory properties. Alterations to the PACAP/VIP system could be pivotal during the development of HFD-induced neuroinflammation. To unveil the pathogenic mechanisms underlying HFD-induced neuroinflammation and assess metformin’s therapeutic activities, (1) we determined if HFD-induced proinflammatory activity was present in vulnerable brain regions associated with the development of comorbid behaviors, (2) investigated if the PACAP/VIP system is altered by HFD, and (3) assessed if metformin rescues such diet-induced neurochemical alterations. C57BL/6J male mice were divided into two groups to receive either standard chow (SC) or HFD for 16 weeks. A further HFD group received metformin (HFD + M) (300 mg/kg BW daily for 5 weeks) via oral gavage. Body weight, fasting glucose, and insulin levels were measured. After 16 weeks, the proinflammatory profile, glial activation markers, and changes within the PI3K/AKT intracellular pathway and the PACAP/VIP system were evaluated by real-time qPCR and/or Western blot in the hypothalamus, hippocampus, prefrontal cortex, and amygdala. Our data showed that HFD causes widespread low-grade neuroinflammation and gliosis, with regional-specific differences across brain regions. HFD also diminished phospho-AKT(Ser473) expression and caused significant disruptions to the PACAP/VIP system. Treatment with metformin attenuated these neuroinflammatory signatures and reversed PI3K/AKT and PACAP/VIP alterations caused by HFD. Altogether, our findings demonstrate that metformin treatment rescues HFD-induced neuroinflammation in vulnerable brain regions, most likely by a mechanism involving the reinstatement of PACAP/VIP system homeostasis. Data also suggests that the PI3K/AKT pathway, at least in part, mediates some of metformin’s beneficial effects.
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Affiliation(s)
- Mawj Mandwie
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (M.M.); (J.K.); (A.N.); (G.A.-B.)
| | - Jocelyn Karunia
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (M.M.); (J.K.); (A.N.); (G.A.-B.)
| | - Aram Niaz
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (M.M.); (J.K.); (A.N.); (G.A.-B.)
| | - Kevin A. Keay
- Laboratory of Neural Structure and Function, School of Medical Science (Neuroscience), University of Sydney, Sydney, NSW 2006, Australia;
| | - Giuseppe Musumeci
- Department of Biomedical and Biotechnological Sciences, Anatomy, Histology and Movement Sciences Section, School of Medicine, University of Catania, 95125 Catania, Italy;
| | - Claire Rennie
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (C.R.); (K.M.)
| | - Kristine McGrath
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (C.R.); (K.M.)
| | - Ghaith Al-Badri
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (M.M.); (J.K.); (A.N.); (G.A.-B.)
| | - Alessandro Castorina
- Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia; (M.M.); (J.K.); (A.N.); (G.A.-B.)
- Laboratory of Neural Structure and Function, School of Medical Science (Neuroscience), University of Sydney, Sydney, NSW 2006, Australia;
- Correspondence:
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Arendt Nielsen T, Sega R, Uggerhøj Andersen C, Vorum H, Mohr Drewes A, Jakobsen PE, Brock B, Brock C. Liraglutide Treatment Does Not Induce Changes in the Peripapillary Retinal Nerve Fiber Layer Thickness in Patients with Diabetic Retinopathy. J Ocul Pharmacol Ther 2021; 38:114-121. [PMID: 34918951 DOI: 10.1089/jop.2021.0055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Purpose: Liraglutide treatment has shown promising anti-inflammatory and nerve regenerative results in preclinical and clinical trials. We sought to assess if liraglutide treatment would induce nerve regeneration through its anti-inflammatory and neurotrophic mechanisms by increasing peripapillary retinal nerve fiber layer (RNFL) thickness in individuals with long-term type 1 diabetes. Methods: Secondary analyses were performed on a prospective, double-blinded, randomized, placebo-controlled trial on adults with type 1 diabetes, distal symmetric polyneuropathy (DSPN), and confirmed diabetic retinopathy, who were randomized 1:1 to either 26 weeks placebo or liraglutide treatment. The primary endpoint was a change in peripapillary RNFL thickness between treatments, assessed by optical coherence tomography. Results: Thirty-seven participants were included in the secondary analysis. No differences in mean peripapillary RNFL thickness (overall ΔMean RNFL thickness; liraglutide -1 (±8) μm (-1%) vs. placebo -1 (±5) μm (-1%), P = 0.78, n = 37) or any of the quadrants. Peripapillary RNFL thicknesses were shown between treatments in either nonproliferative (ΔMean RNFL thickness; liraglutide -1 (±5) μm (-1%) vs. placebo 0 (±4) μm (0%), P = 0.80, N = 26) or proliferative diabetic retinopathy subgroup (ΔMean RNFL thickness; liraglutide -2 (±14) μm (-3%) vs. placebo -1 (±6) μm (-2%), P = 0.88, N = 11). Conclusions: In this study, 26 weeks of liraglutide treatment did not induce measurable changes in the assessed optic nerve thickness. Thus, this methodology does not support the induction of substantial nerve regeneration in this cohort with established retinopathy and DSPN. The trial was approved by the Danish Health and Medicines Authority. Informed consent was obtained from all participants. TODINELI study: EUDRA CT: 2013-004375-12, Ethics Ref: N-20130077 Clinical trial registration number: clinicaltrials.gov NCT02138045.
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Affiliation(s)
- Thomas Arendt Nielsen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Ophthalmology, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
| | - Rok Sega
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital & Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Carl Uggerhøj Andersen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Ophthalmology, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
| | - Henrik Vorum
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Department of Ophthalmology, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital & Clinical Institute, Aalborg University, Aalborg, Denmark.,Steno Diabetes Center North, Aalborg, Denmark
| | - Poul Erik Jakobsen
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Steno Diabetes Center North, Aalborg, Denmark.,Department of Endocrinology, Aalborg University Hospital, Aalborg, Denmark
| | - Birgitte Brock
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.,Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Christina Brock
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital & Clinical Institute, Aalborg University, Aalborg, Denmark.,Steno Diabetes Center North, Aalborg, Denmark
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33
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Network medicine for disease module identification and drug repurposing with the NeDRex platform. Nat Commun 2021; 12:6848. [PMID: 34824199 PMCID: PMC8617287 DOI: 10.1038/s41467-021-27138-2] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/04/2021] [Indexed: 12/17/2022] Open
Abstract
Traditional drug discovery faces a severe efficacy crisis. Repurposing of registered drugs provides an alternative with lower costs and faster drug development timelines. However, the data necessary for the identification of disease modules, i.e. pathways and sub-networks describing the mechanisms of complex diseases which contain potential drug targets, are scattered across independent databases. Moreover, existing studies are limited to predictions for specific diseases or non-translational algorithmic approaches. There is an unmet need for adaptable tools allowing biomedical researchers to employ network-based drug repurposing approaches for their individual use cases. We close this gap with NeDRex, an integrative and interactive platform for network-based drug repurposing and disease module discovery. NeDRex integrates ten different data sources covering genes, drugs, drug targets, disease annotations, and their relationships. NeDRex allows for constructing heterogeneous biological networks, mining them for disease modules, prioritizing drugs targeting disease mechanisms, and statistical validation. We demonstrate the utility of NeDRex in five specific use-cases.
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34
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Soldevila-Domenech N, Cuenca-Royo A, Babio N, Forcano L, Nishi S, Vintró-Alcaraz C, Gómez-Martínez C, Jiménez-Murcia S, Fernández-Carrión R, Gomis-González M, Alvarez-Sala A, Carlos S, Pintó X, Corella D, Díez-Espino J, Castañer O, Fernández-Aranda F, Salas-Salvadó J, de la Torre R. Metformin Use and Cognitive Function in Older Adults With Type 2 Diabetes Following a Mediterranean Diet Intervention. Front Nutr 2021; 8:742586. [PMID: 34676236 PMCID: PMC8523839 DOI: 10.3389/fnut.2021.742586] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 09/07/2021] [Indexed: 12/28/2022] Open
Abstract
Background and Purpose: Both adherence to the Mediterranean diet (MedDiet) and the use of metformin could benefit the cognitive performance of individuals with type 2 diabetes, but evidence is still controversial. We examined the association between metformin use and cognition in older adults with type 2 diabetes following a MedDiet intervention. Methods: Prospective cohort study framed in the PREDIMED-Plus-Cognition sub-study. The PREDIMED-Plus clinical trial aims to compare the cardiovascular effect of two MedDiet interventions, with and without energy restriction, in individuals with overweight/obesity and metabolic syndrome. The present sub-study included 487 cognitively normal subjects (50.5% women, mean ± SD age of 65.2 ± 4.7 years), 30.4% of them (N = 148) with type 2 diabetes. A comprehensive battery of neurocognitive tests was administered at baseline and after 1 and 3 years. Individuals with type 2 diabetes that exhibited a good glycemic control trajectory, either using or not using metformin, were compared to one another and to individuals without diabetes using mixed-effects models with inverse probability of treatment weights. Results: Most subjects with type 2 diabetes (83.1%) presented a good and stable glycemic control trajectory. Before engaging in the MedDiet intervention, subjects using metformin scored higher in executive functions (Cohen's d = 0.51), memory (Cohen's d = 0.38) and global cognition (Cohen's d = 0.48) than those not using metformin. However, these differences were not sustained during the 3 years of follow-up, as individuals not using metformin experienced greater improvements in memory (β = 0.38 vs. β = 0.10, P = 0.036), executive functions (β = 0.36 vs. β = 0.02, P = 0.005) and global cognition (β = 0.29 vs. β = -0.02, P = 0.001) that combined with a higher MedDiet adherence (12.6 vs. 11.5 points, P = 0.031). Finally, subjects without diabetes presented greater improvements in memory than subjects with diabetes irrespective of their exposure to metformin (β = 0.55 vs. β = 0.10, P < 0.001). However, subjects with diabetes not using metformin, compared to subjects without diabetes, presented greater improvements in executive functions (β = 0.33 vs. β = 0.08, P = 0.032) and displayed a higher MedDiet adherence (12.6 points vs. 11.6 points, P = 0.046). Conclusions: Although both metformin and MedDiet interventions are good candidates for future cognitive decline preventive studies, a higher adherence to the MedDiet could even outweigh the potential neuroprotective effects of metformin in subjects with diabetes.
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Affiliation(s)
- Natalia Soldevila-Domenech
- Integrative Pharmacology and Systems Neurosciences Research Group, Neurosciences Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Aida Cuenca-Royo
- Integrative Pharmacology and Systems Neurosciences Research Group, Neurosciences Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Nancy Babio
- Department of Biochemistry and Biotechnology, Hospital Universitari de Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere i Virgili, Human Nutrition Unit, Universitat Rovira i Virgili, Reus, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Laura Forcano
- Integrative Pharmacology and Systems Neurosciences Research Group, Neurosciences Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Stephanie Nishi
- Department of Biochemistry and Biotechnology, Hospital Universitari de Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere i Virgili, Human Nutrition Unit, Universitat Rovira i Virgili, Reus, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Cristina Vintró-Alcaraz
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain
- Psychiatry and Mental Health Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Carlos Gómez-Martínez
- Department of Biochemistry and Biotechnology, Hospital Universitari de Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere i Virgili, Human Nutrition Unit, Universitat Rovira i Virgili, Reus, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Susana Jiménez-Murcia
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain
- Psychiatry and Mental Health Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Rebeca Fernández-Carrión
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Preventive Medicine, School of Medicine, University of Valencia, Valencia, Spain
| | - Maria Gomis-González
- Integrative Pharmacology and Systems Neurosciences Research Group, Neurosciences Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Andrea Alvarez-Sala
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Preventive Medicine, School of Medicine, University of Valencia, Valencia, Spain
| | - Silvia Carlos
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Navarra Health Research Institute (IDISNA), Pamplona, Spain
| | - Xavier Pintó
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Lipid Unit, Department of Internal Medicine, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain
- Faculty of Medicine, Universitat de Barcelona, Barcelona, Spain
| | - Dolores Corella
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Preventive Medicine, School of Medicine, University of Valencia, Valencia, Spain
| | - Javier Díez-Espino
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain
- Navarra Health Research Institute (IDISNA), Pamplona, Spain
| | - Olga Castañer
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Cardiovascular Risk and Nutrition Research Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
- Endocrinology Service, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
| | - Fernando Fernández-Aranda
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
- Department of Psychiatry, University Hospital of Bellvitge, Barcelona, Spain
- Psychiatry and Mental Health Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, School of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
| | - Jordi Salas-Salvadó
- Department of Biochemistry and Biotechnology, Hospital Universitari de Sant Joan de Reus, Institut d'Investigacions Sanitàries Pere i Virgili, Human Nutrition Unit, Universitat Rovira i Virgili, Reus, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
| | - Rafael de la Torre
- Integrative Pharmacology and Systems Neurosciences Research Group, Neurosciences Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain
- Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain
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Simó R, Simó-Servat O, Bogdanov P, Hernández C. Neurovascular Unit: A New Target for Treating Early Stages of Diabetic Retinopathy. Pharmaceutics 2021; 13:pharmaceutics13081320. [PMID: 34452281 PMCID: PMC8399715 DOI: 10.3390/pharmaceutics13081320] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 01/02/2023] Open
Abstract
The concept of diabetic retinopathy as a microvascular disease has evolved and is now considered a more complex diabetic complication in which neurovascular unit impairment plays an essential role and, therefore, can be considered as a main therapeutic target in the early stages of the disease. However, neurodegeneration is not always the apparent primary event in the natural story of diabetic retinopathy, and a phenotyping characterization is recommendable to identify those patients in whom neuroprotective treatment might be of benefit. In recent years, a myriad of treatments based on neuroprotection have been tested in experimental models, but more interestingly, there are drugs with a dual activity (neuroprotective and vasculotropic). In this review, the recent evidence concerning the therapeutic approaches targeting neurovascular unit impairment will be presented, along with a critical review of the scientific gaps and problems which remain to be overcome before our knowledge can be transferred to clinical practice.
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Affiliation(s)
- Rafael Simó
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (O.S.-S.); (P.B.); (C.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
- Correspondence:
| | - Olga Simó-Servat
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (O.S.-S.); (P.B.); (C.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Patricia Bogdanov
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (O.S.-S.); (P.B.); (C.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
| | - Cristina Hernández
- Diabetes and Metabolism Research Unit, Vall d’Hebron Research Institute (VHIR), 08035 Barcelona, Spain; (O.S.-S.); (P.B.); (C.H.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ICSIII), 28029 Madrid, Spain
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36
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Mone P, Gambardella J, Pansini A, de Donato A, Martinelli G, Boccalone E, Matarese A, Frullone S, Santulli G. Cognitive Impairment in Frail Hypertensive Elderly Patients: Role of Hyperglycemia. Cells 2021; 10:2115. [PMID: 34440883 PMCID: PMC8391431 DOI: 10.3390/cells10082115] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 12/11/2022] Open
Abstract
Endothelial dysfunction is a key hallmark of hypertension, which is a leading risk factor for cognitive decline in older adults with or without frailty. Similarly, hyperglycemia is known to impair endothelial function and is a predictor of severe cardiovascular outcomes, independent of the presence of diabetes. On these grounds, we designed a study to assess the effects of high-glucose and metformin on brain microvascular endothelial cells (ECs) and on cognitive impairment in frail hypertensive patients. We tested the effects of metformin on high-glucose-induced cell death, cell permeability, and generation of reactive oxygen species in vitro, in human brain microvascular ECs. To investigate the consequences of hyperglycemia and metformin in the clinical scenario, we recruited frail hypertensive patients and we evaluated their Montreal Cognitive Assessment (MoCA) scores, comparing them according to the glycemic status (normoglycemic vs. hyperglycemic) and the use of metformin. We enrolled 376 patients, of which 209 successfully completed the study. We observed a significant correlation between MoCA score and glycemia. We found that hyperglycemic patients treated with metformin had a significantly better MoCA score than hyperglycemic patients treated with insulin (18.32 ± 3.9 vs. 14.94 ± 3.8; p < 0.001). Our in vitro assays confirmed the beneficial effects of metformin on human brain microvascular ECs. To our knowledge, this is the first study correlating MoCA score and glycemia in frail and hypertensive older adults, showing that hyperglycemia aggravates cognitive impairment.
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Affiliation(s)
- Pasquale Mone
- ASL Avellino, 83100 Avellino, Italy; (A.P.); (S.F.)
- Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80121 Naples, Italy;
- Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA;
| | - Jessica Gambardella
- Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA;
- International Translational Research and Medical Education Consortium (ITME), University “Federico II” of Naples, 80131 Naples, Italy
| | | | - Antonio de Donato
- Department of Mental and Physical Health and Preventive Medicine, University of Campania “Luigi Vanvitelli”, 80121 Naples, Italy;
| | | | | | | | | | - Gaetano Santulli
- Department of Medicine (Cardiology), Wilf Family Cardiovascular Research Institute, Fleischer Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine, New York, NY 10461, USA;
- International Translational Research and Medical Education Consortium (ITME), University “Federico II” of Naples, 80131 Naples, Italy
- Department of Molecular Pharmacology, Einstein Institute for Aging Research, Einstein-Sinai Diabetes Research Center (ES-DRC), Albert Einstein College of Medicine, New York, NY 10461, USA
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Li Y, Wang R, Li Q, Wang YJ, Guo J. Gut Microbiota and Alzheimer's Disease: Pathophysiology and Therapeutic Perspectives. J Alzheimers Dis 2021; 83:963-976. [PMID: 34366348 DOI: 10.3233/jad-210381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive decline in cognitive function. Amyloid-β protein accumulation is believed to be the key pathological hallmark of AD. Increasing evidence has shown that the gut microbiota has a role in brain function and host behaviors. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine, and immune pathways. With increasing age, the gut microbiota diversity decreases, and the dominant bacteria change, which is closely related to systemic inflammation and health status. Dysbiosis of the gut microbiota is related to cognitive impairment and neurodegenerative diseases. The purpose of this review is to discuss the impacts of the gut microbiota on brain function and the development of AD. It is a feasible target for therapeutic invention. Modulating the composition of the gut microbiota through diet, physical activity or probiotic/prebiotic supplements can provide new prevention and treatment options for AD.
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Affiliation(s)
- Yanli Li
- Department of Neurology, First Hospital, Shanxi Medical University, Shanxi, China
| | - Rui Wang
- Department of Neurology, First Hospital, Shanxi Medical University, Shanxi, China
| | - Qian Li
- Department of Neurology, First Hospital, Shanxi Medical University, Shanxi, China
| | - Yan-Jiang Wang
- Department of Neurology and Center for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Junhong Guo
- Department of Neurology, First Hospital, Shanxi Medical University, Shanxi, China
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Al Sabaani N. Exendin-4 inhibits high glucose-induced oxidative stress in retinal pigment epithelial cells by modulating the expression and activation of p 66Shc. Cutan Ocul Toxicol 2021; 40:175-186. [PMID: 34275397 DOI: 10.1080/15569527.2020.1844727] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE Activation of p66Sch, an adaptor protein, is associated with oxidative stress and apoptosis and has been implicated in the pathogenesis of diabetes-induced retinal pigment epithelial cell damage and diabetic retinopathy. Exendin-4 is a glucagon-like protein that protects against diabetic retinopathy, but the mechanism of action is not well understood. This study aimed to investigate whether Exendin-4 could protect against high glucose-induced oxidative stress and apoptosis in the adult human retinal pigment epithelial-19 cell line by modulating levels and activation of p66Shc and to study the underlying mechanisms. MATERIALS AND METHODS Adult human retinal pigment epithelial-19 cells were cultured under low (5 µM) or high glucose (100 µM) conditions in the presence or absence of Exendin-4 and with or without pre-incubation with Exendin-9-39, a glucagon-like peptide-1 receptor antagonist. RESULTS In a dose-dependent manner, Exendin-4 inhibited high glucose-induced cell death and decreased levels of reactive oxygen species, lactate dehydrogenase release, and single single-stranded DNA. At the most effective concentration (100 µM), Exendin-4 reduced mitochondrial levels of phospho-p66Shc (Ser36), cytoplasmic levels of cleaved caspase-3 and cytochrome-c, and NADPH oxidase levels in high glucose-treated cells. It also increased levels of glutathione and magnesium superoxide dismutase and protein levels of magnesium superoxide dismutase but downregulated total protein levels of protein kinase-β and p66Shc and inhibited c-Jun N-terminal kinase phosphorylation in both low- and high glucose-treated cells. All these Exendin-4 effects, however, were inhibited by Exendin-9-39. CONCLUSIONS Exendin-4 protects against high glucose-induced adult human retinal pigment epithelial-19 cell damage by increasing antioxidants, downregulating NADPH, and inhibiting mitochondria-mediated apoptosis, effects that are associated with the inhibition of c-Jun N-terminal kinase and downregulation of protein kinase-β and p66Shc.
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Affiliation(s)
- Nasser Al Sabaani
- Ophthalmology Department, College of Medicine, King Khalid University, Abha, Saudi Arabia
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Bini J, Bhatt S, Hillmer AT, Gallezot JD, Nabulsi N, Pracitto R, Labaree D, Kapinos M, Ropchan J, Matuskey D, Sherwin RS, Jastreboff AM, Carson RE, Cosgrove K, Huang Y. Body Mass Index and Age Effects on Brain 11β-Hydroxysteroid Dehydrogenase Type 1: a Positron Emission Tomography Study. Mol Imaging Biol 2021; 22:1124-1131. [PMID: 32133575 DOI: 10.1007/s11307-020-01490-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
CONTEXT Cortisol, a glucocorticoid steroid stress hormone, is primarily responsible for stimulating gluconeogenesis in the liver and promoting adipocyte differentiation and maturation. Prolonged excess cortisol leads to visceral adiposity, insulin resistance, hyperglycemia, memory dysfunction, cognitive impairment, and more severe Alzheimer's disease phenotypes. The intracellular enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol; yet the amount of 11β-HSD1 in the brain has not been quantified directly in vivo. OBJECTIVE We analyzed positron emission tomography (PET) scans with an 11β-HSD1 inhibitor radioligand in twenty-eight individuals (23 M/5F): 10 lean, 13 overweight, and 5 obese individuals. Each individual underwent PET imaging on the high-resolution research tomograph PET scanner after injection of 11C-AS2471907 (n = 17) or 18F-AS2471907 (n = 11). Injected activity and mass doses were 246 ± 130 MBq and 0.036 ± 0.039 μg, respectively, for 11C-AS2471907, and 92 ± 15 MBq and 0.001 ± 0.001 μg for 18F-AS2471907. Correlations of mean whole brain and regional distribution volume (VT) with body mass index (BMI) and age were performed with a linear regression model. RESULTS Significant correlations of whole brain mean VT with BMI and age (VT = 15.23-0.63 × BMI + 0.27 × Age, p = 0.001) were revealed. Age-adjusted mean whole brain VT values were significantly lower in obese individuals. Post hoc region specific analyses revealed significantly reduced mean VT values in the thalamus (lean vs. overweight and lean vs. obese individuals). Caudate, hypothalamus, parietal lobe, and putamen also showed lower VT value in obese vs. lean individuals. A significant age-associated increase of 2.7 mL/cm3 per decade was seen in BMI-corrected mean whole brain VT values. CONCLUSIONS In vivo PET imaging demonstrated, for the first time, correlation of higher BMI (obesity) with lower levels of the enzyme 11β-HSD1 in the brain and correlation of increased 11β-HSD1 levels in the brain with advancing age.
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Affiliation(s)
- Jason Bini
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA. .,Yale University PET Center, 801 Howard Ave, PO Box 208048, New Haven, CT, 06520-8048, USA.
| | - Shivani Bhatt
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Ansel T Hillmer
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.,Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Jean-Dominique Gallezot
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Nabeel Nabulsi
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Richard Pracitto
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - David Labaree
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Michael Kapinos
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Jim Ropchan
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - David Matuskey
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.,Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.,Department of Neurology, Yale University School of Medicine, New Haven, CT, USA
| | - Robert S Sherwin
- Department of Internal Medicine, Endocrinology, Yale University School of Medicine, New Haven, CT, USA
| | - Ania M Jastreboff
- Department of Internal Medicine, Endocrinology, Yale University School of Medicine, New Haven, CT, USA.,Department of Pediatrics, Pediatric Endocrinology, Yale University School of Medicine, New Haven, CT, USA
| | - Richard E Carson
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
| | - Kelly Cosgrove
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA.,Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
| | - Yiyun Huang
- Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA
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Muñoz-Jiménez M, Zaarkti A, García-Arnés JA, García-Casares N. Antidiabetic Drugs in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review. Dement Geriatr Cogn Disord 2021; 49:423-434. [PMID: 33080602 DOI: 10.1159/000510677] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 07/30/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Considering that Alzheimer's disease (AD) and diabetes mellitus share pathophysiological features and AD remains with no cure, antidiabetic drugs like intranasal insulin, glitazones, metformin, and liraglutide are being tested as a potential treatment. OBJECTIVE The aim of this systematic review was to assess the efficacy of antidiabetic drugs in patients with AD, mild cognitive impairment (MCI), or subjective cognitive complaints (SCCs). Cognition was studied as the primary outcome and modulation of AD biomarkers, and imaging was also assessed as a secondary outcome. METHODS We conducted a search in the electronic databases PubMed/MEDLINE, EMBASE, and Scopus seeking clinical trials evaluating the effect on cognition of antidiabetic drugs in patients with AD, MCI, or SCCs. RESULTS A total of 23 articles were found eligible. Intranasal regular insulin improved verbal memory in most studies, especially in apoE4- patients, but results in other cognitive domains were unclear. Detemir improved cognition after 2 months of treatment, but it did not after 4 months. Pioglitazone improved cognition in diabetic patients with AD or MCI in 3 clinical trials, but it is controversial as 2 other studies did not show effect. Metformin and liraglutide showed promising results, but further research is needed as just 2 clinical trials involved each of these drugs. Almost all drugs tested were shown to modulate AD biomarkers and imaging. CONCLUSIONS Intranasal insulin, pioglitazone, metformin, and liraglutide are promising drugs that could be useful in the treatment of AD. However, many questions remain to be answered in future studies, so no particular antidiabetic drug can currently be recommended to treat AD.
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Affiliation(s)
- Mario Muñoz-Jiménez
- Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain
| | - Alí Zaarkti
- Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain
| | - Juan Antonio García-Arnés
- Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain.,Department of Pharmacology, Faculty of Medicine, University of Málaga, Málaga, Spain
| | - Natalia García-Casares
- Department of Medicine, Faculty of Medicine, University of Málaga, Málaga, Spain, .,Centro de Investigaciones, Médico-Sanitarias (C.I.M.ES), University of Málaga, Málaga, Spain, .,Instituto de Investigación, Biomédica de Málaga (I.B.I.M.A.), Málaga, Spain,
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Saleh RA, Eissa TF, Abdallah DM, Saad MA, El-Abhar HS. Peganum harmala enhanced GLP-1 and restored insulin signaling to alleviate AlCl 3-induced Alzheimer-like pathology model. Sci Rep 2021; 11:12040. [PMID: 34103557 PMCID: PMC8187628 DOI: 10.1038/s41598-021-90545-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 04/22/2021] [Indexed: 02/05/2023] Open
Abstract
Peganum harmala (P. harmala) is a folk medicinal herb used in the Sinai Peninsula (Egypt) as a remedy for central disorders. The main constituents, harmine and harmaline, have displayed therapeutic efficacy against Alzheimer's disease (AD); however, the P. harmala potential on sensitizing central insulin to combat AD remains to be clarified. An AD-like rat model was induced by aluminum chloride (AlCl3; 50 mg/kg/day for six consecutive weeks; i.p), whereas a methanolic standardized P. harmala seed extract (187.5 mg/kg; p.o) was given to AD rats starting 2 weeks post AlCl3 exposure. Two additional groups of rats were administered either the vehicle to serve as the normal control or the vehicle + P. harmala seed extract to serve as the P. harmala control group. P. harmala enhanced cognition appraised by Y-maze and Morris water maze tests and improved histopathological structures altered by AlCl3. Additionally, it heightened the hippocampal contents of glucagon-like peptide (GLP)-1 and insulin, but abated insulin receptor substrate-1 phosphorylation at serine 307 (pS307-IRS-1). Besides, P. harmala increased phosphorylated Akt at serine 473 (pS473-Akt) and glucose transporter type (GLUT)4. The extract also curtailed the hippocampal content of beta amyloid (Aβ)42, glycogen synthase (GSK)-3β and phosphorylated tau. It also enhanced Nrf2, while reduced lipid peroxides and replenished glutathione. In conclusion, combating insulin resistance by P. harmala is a novel machinery in attenuating the insidious progression of AD by enhancing both insulin and GLP-1 trajectories in the hippocampus favoring GLUT4 production.
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Affiliation(s)
- Rofida A Saleh
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Tarek F Eissa
- Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), Giza, Egypt
| | - Dalaal M Abdallah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Muhammed A Saad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- Department of Pharmacology and Toxicology, School of Pharmacy, Newgiza University, Cairo, Egypt
| | - Hanan S El-Abhar
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
- Department of Pharmacology, Toxicology & Biochemistry, Faculty of Pharmaceutical Sciences and Pharmaceutical Industries, Future University in Egypt, Cairo, Egypt
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El Massry M, Alaeddine LM, Ali L, Saad C, Eid AA. Metformin: A Growing Journey from Glycemic Control to the Treatment of Alzheimer's Disease and Depression. Curr Med Chem 2021; 28:2328-2345. [PMID: 32900343 DOI: 10.2174/0929867327666200908114902] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/30/2020] [Accepted: 07/07/2020] [Indexed: 11/22/2022]
Abstract
Metabolic stress, transduced as an altered cellular redox and energy status, presents as the main culprit in many diseases, including diabetes. However, its role in the pathology of neurological disorders is still not fully elucidated. Metformin, a biguanide compound, is an FDA approved antidiabetic drug generally used for the treatment of type 2 diabetes. The recently described wide spectrum of action executed by this drug suggests a potential therapeutic benefit in a panoply of disorders. Current studies imply that metformin could play a neuroprotective role by reversing hallmarks of brain injury (metabolic dysfunction, neuronal dystrophy and cellular loss), in addition to cognitive and behavioral alterations that accompany the onset of certain brain diseases such as Alzheimer's disease (AD) and depression. However, the mechanisms by which metformin exerts its protective effect in neurodegenerative disorders are not yet fully elucidated. The aim of this review is to reexamine the mechanisms through which metformin performs its function while concentrating on its effect on reestablishing homeostasis in a metabolically disturbed milieu. We will also highlight the importance of metabolic stress, not only as a component of many neurological disorders, but also as a primary driving force for neural insult. Of interest, we will explore the involvement of metabolic stress in the pathobiology of AD and depression. The derangement in major metabolic pathways, including AMPK, insulin and glucose transporters, will be explored and the potential therapeutic effects of metformin administration on the reversal of brain injury in such metabolism dependent diseases will be exposed.
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Affiliation(s)
- Mohamed El Massry
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Lynn M Alaeddine
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Leen Ali
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Celine Saad
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
| | - Assaad A Eid
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Bliss Street, 11-0236, Riad El-Solh 1107-2020, Beirut, Lebanon
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Tournissac M, Vu TM, Vrabic N, Hozer C, Tremblay C, Mélançon K, Planel E, Pifferi F, Calon F. Repurposing beta-3 adrenergic receptor agonists for Alzheimer's disease: beneficial effects in a mouse model. ALZHEIMERS RESEARCH & THERAPY 2021; 13:103. [PMID: 34020681 PMCID: PMC8140479 DOI: 10.1186/s13195-021-00842-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/04/2021] [Indexed: 12/14/2022]
Abstract
Background Old age, the most important risk factor for Alzheimer’s disease (AD), is associated with thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals and its stimulation, through β3 adrenergic receptor (β3AR) agonists or cold acclimation, counteracts metabolic deficits in rodents and humans. Studies in animal models show that AD neuropathology leads to thermoregulatory deficits, and cold-induced tau hyperphosphorylation is prevented by BAT stimulation through cold acclimation. Since metabolic disorders and AD share strong pathogenic links, we hypothesized that BAT stimulation through a β3AR agonist could exert benefits in AD as well. Methods CL-316,243, a specific β3AR agonist, was administered to the triple transgenic mouse model of AD (3xTg-AD) and non-transgenic controls from 15 to 16 months of age at a dose of 1 mg/kg/day i.p. Results Here, we show that β3AR agonist administration decreased body weight and improved peripheral glucose metabolism and BAT thermogenesis in both non-transgenic and 3xTg-AD mice. One-month treatment with a β3AR agonist increased recognition index by 19% in 16-month-old 3xTg-AD mice compared to pre-treatment (14-month-old). Locomotion, anxiety, and tau pathology were not modified. Finally, insoluble Aβ42/Aβ40 ratio was decreased by 27% in the hippocampus of CL-316,243-injected 3xTg-AD mice. Conclusions Overall, our results indicate that β3AR stimulation reverses memory deficits and shifts downward the insoluble Aβ42/Aβ40 ratio in 16-month-old 3xTg-AD mice. As β3AR agonists are being clinically developed for metabolic disorders, repurposing them in AD could be a valuable therapeutic strategy. Supplementary Information The online version contains supplementary material available at 10.1186/s13195-021-00842-3.
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Affiliation(s)
- Marine Tournissac
- Faculté de pharmacie, Université Laval, 1050 Avenue de la Médecine, Quebec, QC, G1V 0A6, Canada.,Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval (Pavillon CHUL), 2705 Boulevard Laurier, Quebec, QC, G1V 4G2, Canada
| | - Tra-My Vu
- Faculté de pharmacie, Université Laval, 1050 Avenue de la Médecine, Quebec, QC, G1V 0A6, Canada.,Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval (Pavillon CHUL), 2705 Boulevard Laurier, Quebec, QC, G1V 4G2, Canada
| | - Nika Vrabic
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval (Pavillon CHUL), 2705 Boulevard Laurier, Quebec, QC, G1V 4G2, Canada
| | - Clara Hozer
- UMR CNRS/MNHN 7179, Mécanismes Adaptatifs et Évolution, 1 Avenue du Petit Château, 91800, Brunoy, France
| | - Cyntia Tremblay
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval (Pavillon CHUL), 2705 Boulevard Laurier, Quebec, QC, G1V 4G2, Canada
| | - Koralie Mélançon
- Faculté de pharmacie, Université Laval, 1050 Avenue de la Médecine, Quebec, QC, G1V 0A6, Canada.,Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval (Pavillon CHUL), 2705 Boulevard Laurier, Quebec, QC, G1V 4G2, Canada
| | - Emmanuel Planel
- Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval (Pavillon CHUL), 2705 Boulevard Laurier, Quebec, QC, G1V 4G2, Canada.,Département de psychiatrie et neurosciences, Faculté de médecine, Université Laval, 1050 Avenue de la Médecine, Quebec, QC, G1V 0A6, Canada
| | - Fabien Pifferi
- UMR CNRS/MNHN 7179, Mécanismes Adaptatifs et Évolution, 1 Avenue du Petit Château, 91800, Brunoy, France
| | - Frédéric Calon
- Faculté de pharmacie, Université Laval, 1050 Avenue de la Médecine, Quebec, QC, G1V 0A6, Canada. .,Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval (Pavillon CHUL), 2705 Boulevard Laurier, Quebec, QC, G1V 4G2, Canada.
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44
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Erichsen JM, Calva CB, Reagan LP, Fadel JR. Intranasal insulin and orexins to treat age-related cognitive decline. Physiol Behav 2021; 234:113370. [PMID: 33621561 PMCID: PMC8053680 DOI: 10.1016/j.physbeh.2021.113370] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 02/19/2021] [Indexed: 02/06/2023]
Abstract
The intranasal (IN) administration of neuropeptides, such as insulin and orexins, has been suggested as a treatment strategy for age-related cognitive decline (ARCD). Because dysfunctional neuropeptide signaling is an observed characteristic of ARCD, it has been suggested that IN delivery of insulin and/or orexins may restore endogenous peptide signaling and thereby preserve cognition. IN administration is particularly alluring as it is a relatively non-invasive method that directly targets peptides to the brain. Several laboratories have examined the behavioral effects of IN insulin in young, aged, and cognitively impaired rodents and humans. These studies demonstrated improved performance on various cognitive tasks following IN insulin administration. Fewer laboratories have assessed the effects of IN orexins; however, this peptide also holds promise as an effective treatment for ARCD through the activation of the cholinergic system and/or the reduction of neuroinflammation. Here, we provide a brief overview of the advantages of IN administration and the delivery pathway, then summarize the current literature on IN insulin and orexins. Additional preclinical studies will be useful to ultimately uncover the mechanisms underlying the pro-cognitive effects of IN insulin and orexins, whereas future clinical studies will aid in the determination of the most efficacious dose and dosing paradigm. Eventually, IN insulin and/or orexin administration may be a widely used treatment strategy in the clinic for ARCD.
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Affiliation(s)
- Jennifer M Erichsen
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC 29208, United States.
| | - Coleman B Calva
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC 29208, United States
| | - Lawrence P Reagan
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC 29208, United States; Columbia VA Health Care System, Columbia, SC, 29208, United States
| | - Jim R Fadel
- University of South Carolina School of Medicine, Department of Pharmacology, Physiology, and Neuroscience, Columbia, SC 29208, United States
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Wang M, Chen W, Chen J, Yuan S, Hu J, Han B, Huang Y, Zhou W. Abnormal saccharides affecting cancer multi-drug resistance (MDR) and the reversal strategies. Eur J Med Chem 2021; 220:113487. [PMID: 33933752 DOI: 10.1016/j.ejmech.2021.113487] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/24/2021] [Accepted: 04/15/2021] [Indexed: 02/07/2023]
Abstract
Clinically, chemotherapy is the mainstay in the treatment of multiple cancers. However, highly adaptable and activated survival signaling pathways of cancer cells readily emerge after long exposure to chemotherapeutics drugs, resulting in multi-drug resistance (MDR) and treatment failure. Recently, growing evidences indicate that the molecular action mechanisms of cancer MDR are closely associated with abnormalities in saccharides. In this review, saccharides affecting cancer MDR development are elaborated and analyzed in terms of aberrant aerobic glycolysis and its related enzymes, abnormal glycan structures and their associated enzymes, and glycoproteins. The reversal strategies including depletion of ATP, circumventing the original MDR pathway, activation by or inhibition of sugar-related enzymes, combination therapy with traditional cytotoxic agents, and direct modification on the sugar moiety, are ultimately proposed. It follows that abnormal saccharides have a significant effect on cancer MDR development, providing a new perspective for overcoming MDR and improving the outcome of chemotherapy.
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Affiliation(s)
- Meizhu Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China; Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China
| | - Wenming Chen
- Department of Pharmaceutical Production Center, The First Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China
| | - Jiansheng Chen
- College of Horticulture, South China Agricultural University, 483, Wushan Rd, Guangzhou, Guangdong province, 510642, China
| | - Sisi Yuan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China
| | - Jiliang Hu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China
| | - Bangxing Han
- Department of Biological and Pharmaceutical Engineering, West Anhui University, Lu'an, Anhui, China; Anhui Engineering Laboratory for Conservation and Sustainable Utilization of Traditional Chinese Medicine Resources, West Anhui University, Lu'an, Anhui, China
| | - Yahui Huang
- College of Horticulture, South China Agricultural University, 483, Wushan Rd, Guangzhou, Guangdong province, 510642, China.
| | - Wen Zhou
- Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
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46
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Role of insulin receptor substance-1 modulating PI3K/Akt insulin signaling pathway in Alzheimer's disease. 3 Biotech 2021; 11:179. [PMID: 33927970 DOI: 10.1007/s13205-021-02738-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease, also regarded as "type 3 diabetes" for the last few years because of the brain insulin resistance (IR) and dysregulation of insulin signaling in the brain, which can further promote pathological progression of AD. IRS-1/PI3K/Akt insulin signaling pathway disorder and its downstream cascade reaction are responsible for cognitive decline in the brain. In recent years, a growing number of studies has documented that dysregulation of insulin signaling is a key feature of AD and has crucial correlations with serine/tyrosine (Ser/Tyr) phosphorylation of insulin receptor substance-1(IRS-1). Phosphorylation of this protein has been identified as an important molecule involved in the process of amyloid-β (Aβ) deposition into senile plaques (SPs) and tau hyperphosphorylation into neurofibrillary tangles (NFTs). In this paper, we review the links between IRS-1 and the PI3K/Akt insulin signaling pathway, and highlight phosphorylated IRS-1 which negatively regulated by downstream effector of Akt such as mTOR, S6K, and JNK, among others in AD. Furthermore, anti-diabetic drugs including metformin, thiazolidinediones, and glucagon-like peptide-1 (GLP-1) analogue could modulate IRS-1 phosphorylation, brain IR, PI3K/Akt insulin signaling pathway, and other pathologic processes of AD. The above suggest that anti-diabetic drugs may be promising strategies for AD disease-modifying treatments.
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47
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Vanhaelen Q. Web-based Tools for Drug Repurposing: Successful Examples of Collaborative Research. Curr Med Chem 2021; 28:181-195. [PMID: 32003659 DOI: 10.2174/0929867327666200128111925] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/23/2019] [Accepted: 11/30/2019] [Indexed: 11/22/2022]
Abstract
Computational approaches have been proven to be complementary tools of interest in identifying potential candidates for drug repurposing. However, although the methods developed so far offer interesting opportunities and could contribute to solving issues faced by the pharmaceutical sector, they also come with their constraints. Indeed, specific challenges ranging from data access, standardization and integration to the implementation of reliable and coherent validation methods must be addressed to allow systematic use at a larger scale. In this mini-review, we cover computational tools recently developed for addressing some of these challenges. This includes specific databases providing accessibility to a large set of curated data with standardized annotations, web-based tools integrating flexible user interfaces to perform fast computational repurposing experiments and standardized datasets specifically annotated and balanced for validating new computational drug repurposing methods. Interestingly, these new databases combined with the increasing number of information about the outcomes of drug repurposing studies can be used to perform a meta-analysis to identify key properties associated with successful drug repurposing cases. This information could further be used to design estimation methods to compute a priori assessment of the repurposing possibilities.
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Affiliation(s)
- Quentin Vanhaelen
- Insilico Medicine, 307A, Core Building 1, 1 Science Park East Avenue, Hong Kong Science Park, Pak Shek Kok, Hong Kong
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48
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Degree Adjusted Large-Scale Network Analysis Reveals Novel Putative Metabolic Disease Genes. BIOLOGY 2021; 10:biology10020107. [PMID: 33546175 PMCID: PMC7913176 DOI: 10.3390/biology10020107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/24/2021] [Accepted: 01/30/2021] [Indexed: 11/16/2022]
Abstract
Simple Summary To explore some of the low-degree but topologically important nodes in the Metabolic disease (MD) network, we propose a background-corrected betweenness centrality (BC) and identify 16 novel candidates likely to play a role in MD. MD specific protein–protein interaction networks (PPINs) were constructed using two known databasesHuman Protein Reference Database (HPRD) and BioGRID. The identified candidates have been found to play a role in diverse conditions including co-morbidities of MD, neurological and immune system-related conditions. Abstract A large percentage of the global population is currently afflicted by metabolic diseases (MD), and the incidence is likely to double in the next decades. MD associated co-morbidities such as non-alcoholic fatty liver disease (NAFLD) and cardiomyopathy contribute significantly to impaired health. MD are complex, polygenic, with many genes involved in its aetiology. A popular approach to investigate genetic contributions to disease aetiology is biological network analysis. However, data dependence introduces a bias (noise, false positives, over-publication) in the outcome. While several approaches have been proposed to overcome these biases, many of them have constraints, including data integration issues, dependence on arbitrary parameters, database dependent outcomes, and computational complexity. Network topology is also a critical factor affecting the outcomes. Here, we propose a simple, parameter-free method, that takes into account database dependence and network topology, to identify central genes in the MD network. Among them, we infer novel candidates that have not yet been annotated as MD genes and show their relevance by highlighting their differential expression in public datasets and carefully examining the literature. The method contributes to uncovering connections in the MD mechanisms and highlights several candidates for in-depth study of their contribution to MD and its co-morbidities.
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Chen H, Wang B, Li G, Steele JR, Stayte S, Vissel B, Chan YL, Yi C, Saad S, Machaalani R, Oliver BG. Brain health is independently impaired by E-vaping and high-fat diet. Brain Behav Immun 2021; 92:57-66. [PMID: 33221488 DOI: 10.1016/j.bbi.2020.11.028] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/02/2020] [Accepted: 11/18/2020] [Indexed: 12/30/2022] Open
Abstract
Tobacco smoking and high-fat diet (HFD) independently impair short-term memory. E-cigarettes produce e-vapour containing flavourings and nicotine. Here, we investigated whether e-vapour inhalation interacts with HFD to affect short-term memory and neural integrity. Balb/c mice (7 weeks, male) were fed a HFD (43% fat, 20 kJ/g) for 16 weeks. In the last 6 weeks, half of the mice were exposed to tobacco-flavoured e-vapour from nicotine-containing (18 mg/L) or nicotine-free (0 mg/L) e-fluids twice daily. Short-term memory function was measured in week 15. HFD alone did not impair memory function, but increased brain phosphorylated (p)-Tau and astrogliosis marker, while neuron and microglia levels were decreased. E-vapour exposure significantly impaired short-term memory function independent of diet and nicotine. Nicotine free e-vapour induced greater changes compared to the nicotine e-vapour and included, increased systemic cytokines, increased brain p-Tau and decreased postsynaptic density protein (PSD)-95 levels in chow-fed mice, and decreased astrogliosis marker, increased microglia and increased glycogen synthase kinase levels in HFD-fed mice. Increased hippocampal apoptosis was also differentially observed in chow and HFD mice. In conclusion, E-vapour exposure impaired short-term memory independent of diet and nicotine, and was correlated to increased systemic inflammation, reduced PSD-95 level and increased astrogliosis in chow-fed mice, but decreased gliosis and increased microglia in HFD-fed mice, indicating the inflammatory nature of e-vapour leading to short term memory impairment.
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Affiliation(s)
- Hui Chen
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia
| | - Baoming Wang
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia; Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, NSW 2037, Australia
| | - Gerard Li
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia
| | - Joel R Steele
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia
| | - Sandy Stayte
- Centre for Neuroscience and Regenerative Medicine, Faculty of Science, University of Technology Sydney, NSW, Australia; St Vincent's Centre for Applied Medical Research, St Vincent's Health Network Sydney, NSW 2010, Australia
| | - Bryce Vissel
- Centre for Neuroscience and Regenerative Medicine, Faculty of Science, University of Technology Sydney, NSW, Australia; St Vincent's Centre for Applied Medical Research, St Vincent's Health Network Sydney, NSW 2010, Australia
| | - Yik Lung Chan
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia; Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, NSW 2037, Australia
| | - Chenju Yi
- Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China.
| | - Sonia Saad
- Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, NSW 2065, Australia
| | - Rita Machaalani
- SIDS and Sleep Apnea Laboratory, Sydney Medical School (Central), University of Sydney, NSW 2006, Australia
| | - Brian G Oliver
- School of Life Sciences, Faculty of Science, University of Technology Sydney, NSW 2007, Australia; Respiratory Cellular and Molecular Biology, Woolcock Institute of Medical Research, NSW 2037, Australia.
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50
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Uddin MS, Rahman MM, Sufian MA, Jeandet P, Ashraf GM, Bin-Jumah MN, Mousa SA, Abdel-Daim MM, Akhtar MF, Saleem A, Amran MS. Exploring the New Horizon of AdipoQ in Obesity-Related Alzheimer's Dementia. Front Physiol 2021; 11:567678. [PMID: 33584324 PMCID: PMC7873563 DOI: 10.3389/fphys.2020.567678] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Accepted: 12/21/2020] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia, which causes abnormalities in learning, thinking, memory, as well as behavior. Generally, symptoms of AD develop gradually and aggravate over time, and consequently severely interfere with daily activities. Furthermore, obesity is one of the common risk factors for dementia. Dysregulation of adipokine and adipocyte dysfunction are assumed to be accountable for the high risk of obesity in people that develop many related disorders such as AD. Moreover, it has been observed that the dysfunction of adipose is connected with changes in brain metabolism, brain atrophy, cognitive decline, impaired mood, neuroinflammation, impaired insulin signaling, and neuronal dysfunction in people with obesity. Conversely, the pathological mechanisms, as well as the molecular players which are involved in this association, have been unclear until now. In this article, we discuss the impact of adiponectin (AdipoQ) on obesity-related Alzheimer's dementia.
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Affiliation(s)
- Md. Sahab Uddin
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Md. Motiar Rahman
- Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Mohammad Abu Sufian
- Department of Pharmacy, Southeast University, Dhaka, Bangladesh
- Pharmakon Neuroscience Research Network, Dhaka, Bangladesh
| | - Philippe Jeandet
- Research Unit, Induced Resistance and Plant Bioprotection, EA 4707, SFR Condorcet FR CNRS 3417, Faculty of Sciences, University of Reims Champagne-Ardenne, Reims Cedex, France
| | - Ghulam Md. Ashraf
- Pre-clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - May N. Bin-Jumah
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Shaker A. Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, New York, NY, United States
| | - Mohamed M. Abdel-Daim
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
- Pharmacology Department, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
| | - Muhammad Furqan Akhtar
- Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore, Pakistan
| | - Ammara Saleem
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, Pakistan
| | - Md. Shah Amran
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka, Bangladesh
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